Wednesday, February 28, 2007

Arthur Schlesinger dies at 89   posted by Razib @ 2/28/2007 09:24:00 PM

Arthur Schlesinger dies at 89.


Tuesday, February 27, 2007

A note on the Common Disease-Common Variant debate   posted by p-ter @ 2/27/2007 05:19:00 PM

One of the more heated debates in human medical genetics in the last decade or so has been centered around the Common Disease-Common Variant (CDCV) hypothesis. As the name implies, the hypothesis posits that genetic susceptibility to common diseases like hypertension and diabetes is largely due to alleles which have moderate frequency in the population. The competing hypothesis, also cleverly named, is the Common Disease-Rare Variant (CDRV) hypothesis, which suggests that multiple rare variants underlie susceptibility to such diseases. As different techniques must be used to find common versus rare alleles, this debate would seem to have major implications for the field. Indeed, the major proponents of the CDCV hypothesis were the movers and shakers beind the HapMap, a resource for the design of large-scale association studies (which are effective at finding common variants, much less so for rare variants).

However, CDCV versus CDRV is an utterly false dichotomy, as I'll explain below. This point has slipped past many of the human geneticists who actually do the work of mapping disease genes, and I feel the problem is this: essentially, geneticists are looking for a gene or the gene, so they naturally want to know whether to take an approach that will be the best for finding common variants or one for finding rare variants. However, common diseases do not follow simple Mendelian patterns-- there are multiple genes that influence these traits, and the frequencies of these alleles has a distribution. A decent null hypothesis, then, is to assume that the the frequencies of alleles underlying a complex phenotype is essentially the same as the overall distribution of allele frequencies in the population-- that is, many rare variants and some common variants.

This argument would seem to favor the CDRV hypothesis. Not so. The key concept for explaining why is one borrowed from epidemiology called the population attributable risk--essentially, the number of cases in a population that can be attributed to a given risk factor. An example: imgaine smoking cigarettes gives you a 5% chance of developing lung cancer, while working in an asbestos factory gives you a 70% chance. You might argue that working in an asbestos factory is a more important risk factor than cigarette smoking, and you would be correct--on an individual level. On a population level, though, you have to take into account the fact that millions more people smoke than work in asbestos factories. If everyone stopped smoking tomorrow, the number of lung cancer cases would drop precipitously. But if all asbestos factory workers quit tomorrow, the effect on the population level of lung cancer would be minimal. So you can see where I'm going with this: common susceptibility alleles contribute disproportinately to the population attributable risk for a disease. In type II diabetes, for example, a single variant with a rather small effect but a moderate frequency accounts for 21% of all cases[cite].

So am I then arguing in favor of the CDCV hypotheis? Of course not-- rare variants, aside from being predictive for disease in some individuals, also give important insight into the biology of the disease. But it is possible right now, using genome-wide SNP arrays and databases like the HapMap, to search the entire genome for common variants that contribute to disease. This is an essential step--finding the alleles that contribute disproportionately to the population-level risk for a disease. Eventually, the cost of sequencing will drop to a point where rare variants can also be assayed on a genome-wide, high-throughput scale, but that's not the case yet. Once it is, expect the CDRV hypothesis to be trumpted as right all along.

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CHRM2 and Intelligence   posted by Fly @ 2/27/2007 09:35:00 AM

CHRM2 Gene Variants Associated with Intelligence

"Some of the participants in the study also took the Wechsler Adult
Intelligence Scale-Revised, a traditional IQ test. In all, members of 200
families, including more than 2,150 individuals, took the Wechsler test, and those results were matched to differences in individuals' DNA.

By comparing individual differences embedded in DNA, the team zeroed in on CHRM2, the neuronal receptor gene on chromosome 7. The CHRM2 gene activates multitude of signaling pathways in the brain involved in learning, memory and other higher brain functions. The research team doesn't yet understand how the gene exerts its effects on intelligence."
Dick's team is not the first to notice a link between intelligence and the CHRM2 gene. In 2003, a group in Minnesota looked at a single marker in the gene and noted that the variation was related to an increase in IQ. A more recent Dutch study looked at three regions of DNA along the gene and also noticed influences on intelligence. In this new study, however, researchers tested multiple genetic markers throughout the gene.

"If we look at a single marker, a DNA variation might influence IQ scores between two and four points, depending on which variant a person carries," Dick explains. "We did that all up and down the gene and found that the variations had cumulative effects, so that if one person had all of the 'good' variations and another all of the 'bad' variations, the difference in IQ might be 15 to 20 points. Unfortunately, the numbers of people at those extremes were so small that the finding isn't statistically significant, but the point is we saw fairly substantial differences in our sample when we combined information across multiple regions of the gene."

Dick says the next step is to look at the gene and its numerous variants to learn what is going on biologically that might affect cognitive performance. Presently, she says it's too early to predict how small changes in the gene might be influencing communication in the brain to affect intelligence, and she says it's nearly certain CHRM2 is not the only gene involved.

Prior GNXP references to CHRM2:

Thompson and Gray: Neuroscience, genes, and IQ

More red meat

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New blog posts   posted by rosko @ 2/27/2007 01:52:00 AM

As a make-up for having hardly any time to post during the Week of Science, I have just added a set of four posts of pure science to my blog in rapid succession. On is on something that was already mentioned here, but the others are unrelated to anything on GNXP, so if you want to check them out, you can read them.

Monday, February 26, 2007

Recent Human Evolution in the house   posted by Razib @ 2/26/2007 10:17:00 PM

Early man 'couldn't stomach milk'
Working with scientists from Mainz University in Germany, the UCL team looked for the gene that produces the lactase enzyme in Neolithic skeletons dating between 5480BC and 5000BC.

These are believed to be from some of the earliest farming communities in Europe.

The lactase gene was absent from the DNA extracted from these skeletons, suggesting that these early Europeans would not be tolerant to milk.

The paper will be Absence of the Lactase-Persistence associated allele in early Neolithic Europeans in PNAS. First LCT, then OCA2, and god knows what else? There is a limit in terms of what you can do with archeoDNA, but if the action went down in the last 10,000 years then it isn't such a sweat.

One thing, the summary in Science is weird. Check it:
The culture-historical hypothesis is that, shortly after the domestication of livestock, a few lucky farmers with a genetic anomaly hit white gold: nourishment via milk. Then, according to this theory, natural selection took over and these lactase-persistent folks proceeded to populate much of Europe with their milk-guzzling offspring. A competing hypothesis argues that ancient Europeans domesticated milk-bearing livestock because lactase persistence was already quite common in certain populations.

Quite common? The area of the genome around LCT was hit by a hammer blow of selection less than 10,000 years ago, that's why researchers use it to check if their methods for detecting selection are working. The fact that independent events of lactase persistence exist among other populations via alternative genetic architectures seems to indicate clearly the power of gene-culture coevolution. What's up with Science doing a "look at both sides" framework when the evidence is so lopsided? I suppose selection could have been induced by a causative factor aside from milk, but I think we're verging into Humean skepticism at this point, denying the ability to discern causality at all....

Carl Zimmer has much more....

Related: Lactose tolerance by a different stroke. Lactose tolerance/intolerance. Are multiple lactose tolerance mutations surprising? Genes & culture & milk. Lactose tolerance, is it "dominant"? Milk digestion, it does a body good.

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Sunday, February 25, 2007

Academic Blogs directory   posted by Razib @ 2/25/2007 09:28:00 PM

I noticed a post at Crooked Timber about something called The Academic Blog Portal. It's a wiki. Both Gene Expressions are listed in the biology section. It is interesting to compare the representation of different disciplines, there are, for example, more linguistics and philosophy blogs than biology blogs, but also, more history blogs. Not all fields are represented to their proportion in academia, for example, only 4 engineering blogs.


Typical GNXP reader?   posted by Razib @ 2/25/2007 07:28:00 PM

Ultrabrown points me to an interesting site which profiles the demographics of a blog. Check out gnxp...there are obviously some issues, but good for a laugh.

Related: Previous polls of readers.


The tactics of deceit   posted by Razib @ 2/25/2007 04:56:00 PM

Over at The Edge the philosopher Daniel Dennett and evolutionary geneticist H. Allen Orr just had an exchange over Richard Dawkins' The God Delusion. I am not particularly interested in the details of this debate, rather, on the front page this selection from Dennett's letter caught my attention:
When I explained then in a private letter to you what I had meant, you conceded to me in your private response that you had not seen my point in the light I intended, and that my claim was not in fact the blunder you had said it was....

What could Dennett mean? I immediately thought back to this:

I did indeed misspeak (p. 126), but the result was ambiguity, not error. The issue is complicated: it depends on whether you're measuring the (average) speed of departure from a starting point in genetic space, or the speed of attainment of some particular evolutionary product. I meant the former. [Dennett]

Now I've been in the population genetics business for some time and, frankly, I have no idea what Dennett is talking about. And-I can find no polite way of putting this-it's hard to escape the conclusion that Dennett has no idea what he's talking about, either. Even the most charitable interpretation I can come up with is just plain wrong. [Orr's response]

Dennett's phrasing was awkward and peculiar to say the least. Orr is an evolutionary geneticist who "was awarded the Dobzhansky Prize by the Society for the Study of Evolution and the Young Investigator Prize by the American Society of Naturalists." In regards to a technical understanding of evolution Dennett was way out of his league. And only an analytic philosopher could confuse population genetic theory with such lexical opacity. That being said, I did not believe that Orr did not understand what Dennett was trying to say, unpolished though he was. This is how I unpacked it:

1) Because most mutations are deleterious, selection is generally a force for constraint, maintaining the ancestral state.

2) In contrast, random genetic drift operates upon evolutionarily neutral variation, so it exhibits (approximately) equal effect on mutants and ancestral alleles over the long term.

3) These insights lead to the contention of Kimura et. al. that most evolutionary change is driven by the substitution of neutral mutations, with random genetic drift a major engine. Even though the vast majority of neutral mutations go extinct, a small number perpetually substitute themselves over ancestral variants at a constant rate (i.e., the rate of substitution is proportional to the rate of mutation).

4) But, when there is a positively selected mutant, natural selection operates far faster in regards to fixing the variant than random genetic drift and stochastic processes might in the typical population size.

It is more complicated than that...but my point is that though Dennett wasn't exactly clear, I think a reasonable observer could understand what he was getting at, or at least the somewhat confusing waters into which he had ventured. Orr did not acknowledge this. As I said, Orr is a world renowned evolutionary geneticist (as he implies in his response), so I was skeptical that he was as clueless as he'd let on.

So, when I read Dennett's full letter, I was not surprised. Here is what he says:
You leveled very serious charges of error and incomprehension in that review, and when I challenged them, you responded with a haughty dismissal of my objections (in an exchange in the Boston Review). Quoting an example, dealing with the speed of evolution: "Now I've been in the population genetics business for some time and, frankly, I have no idea what Dennett is talking about. And-I can find no polite way of putting this-it's hard to escape the conclusion that Dennett has no idea what he's talking about either."

Dennett is bringing up exactly what I remembered in The Boston Review! This was 10 years ago, but Dennett obviously still resents Orr mocking him. In private correspondence Dennett states that Orr admitted that he wasn't really wrong, and Orr's response to this new salvo from Dennett does not contradict that characterization.

I writing about this for one primary reason: I thought, at the time, that H. Allen Orr was striking a low blow dishonestly when he could have stood on firm ground, though with a weaker impact. I've thought about this exchange on & off for several years now, and have considered blogging it, because I think it is perhaps a reflection of H. Allen Orr's character. Most of the readers of The Boston Review don't spend their free time reading The Genetical Theory of Natural Selection or Motoo Kimura's papers, they wouldn't be able to parse from Dennett's somewhat confused phrasing what he was trying to get at. In other words, assuming that Dennett wasn't a moron they couldn't really map his verbal exposition onto a range of evolutionary models, because it isn't exactly as if a broadly educated person is familiar with the great Neutralist vs. Selectionist debate of the 1970s. They were relying on H. Allen Orr's expertise. I just can't believe that H. Allen Orr didn't understand what Dennett was trying to say, or, that he couldn't have seen what he was getting at if he hadn't prejudged Dennett and his ideas as a whole. If I had been him I would have pointed out that Dennett's graceless exposition of the relationship between neutral and selective forces in evolution should be a clue that the man doesn't have the technical competency to engage in such an ambitious meta-project as the one he laid out in Darwin's Dangerous Idea. Instead, Orr is implying that Dennett simply doesn't know what he's talking about, and making him out to be the fool. This is rhetorically far more powerful, and I am sure it persuaded most readers of The Boston Review, who are not going to be conversant in the details of evolutionary genetics and trust H. Allen Orr. After all, who are you going to listen to on this topic? A philosopher or an evolutionary geneticist?

To my mind Orr did a disservice to science and intellectual discourse. He went for the knockout, calling an intellectual ignorant is basically undermining their worth. Saying that they are a bit confused lacks a similar punch. But the readers of The Boston Review, or the lay audience in general, is not looking for a legal case where you are an advocate for your position at all costs, because science and intellectual discourse is more than one battle, it is a long war against our moral and personal failings, against pride, against ego, against self-interest and self-aggrandizement. Most of the battles are lost, but slowly the war grinds on and the trenches keep moving inch by inch. Ph.D. scientists make considerably less in income than their intellectual inferiors in law or medicine. But the field in which they operate is one of great prestige, of civilizational significance. Presumably they wish to engage in the adventure of the ages, at the cost of financial status. Scientists are human, as the politics which suffuses any university department would confirm, but, like monks meditating upon the nature of God, abjuring themselves of worldly pleasures and satisfactions, scientists have to err on the side of truth as they see it, and not a short term rhetorical victory. For what shall it profit a man, if he shall gain the whole world, and lose his own soul?

Addendum: Readers can follow the links and judge for themselves if Dennett wasn't clear in his intent, even if he was being muddled about it. Perhaps Orr didn't understand what Dennett was trying to say. But if Orr could comprehend the opaque prose in The Genetical Theory, I can't see why he couldn't parse what Dennett was trying to get at. And just to be clear, though I point a finger at Orr on this occasion, rest assured that I understand that we are all guilty of this particular sin, and that includes myself. I simply want to emphasize Orr's transgression here because I think it is important for us to remember that no matter the satisfaction that victory in one battle gives us, we are not fighting without a long term purpose, and dishonorable victories are fundamentally Pyrrhic.

Addendum II: Also, I understand that in practice science between the bounds of accepted & rejected consensus is quite the bloodsport, and an adversarial & amoral dynamic is common. Though this injects quite a bit of "noise" into the system, I trust over the long haul that the scientific culture will beat expectation in modeling reality. That being said, the issue I am pointing to here is slight of hand by gatekeepers. Orr writes reviews books as an evolutionary geneticist, with all the expertise that that entails. His behavior in this case was repulsive to me because he sacrificed the chance to elucidate the nature of evolutionary change to a broad audience so that he could mock (in, I suspect, a dishonest manner) someone and so win a point in an exchange of letters. I will refrain from an evolutionary psychological analysis of how this was truly "rational" from Orr's individual perspective....


Origami   posted by p-ter @ 2/25/2007 07:56:00 AM

ALDaily points to this excellent article on the world's top origami artists. This guy has a hell of a bio:
Lang kept folding while earning a master's in electrical engineering at Stanford and a Ph.D. in applied physics at Caltech. As he worked on his dissertation-"Semiconductor Lasers: New Geometries and Spectral Properties"-he designed an origami hermit crab, a mouse in a mousetrap, an ant, a skunk, and more than fifty other pieces. They were dense and crisp and precise but also full of character: his mouse conveys something fundamentally mouse-ish, his ant has an essential ant-ness. His insects were especially beautiful. While in Germany for postdoctoral work, he and Diane were taken with Black Forest cuckoo clocks; the carved casings, pinecone-shaped weights, pendulums, and pop-out birds wouldn't seem to be a natural for origami, but Lang thought otherwise. He started a job at NASA's Jet Propulsion Laboratory, in Pasadena, in 1988, shortly after he had finished folding a life-sized cuckoo clock. It had taken him three months to design, and six hours to fold, and it made Lang a sensation in the origami world.

ADDENDUM: Andrew Gelman posts a picture of an origami tarantula, along with the corresponding fold pattern required to make it.


Saturday, February 24, 2007

A very recent speciation time of human-chimp   posted by the @ 2/24/2007 03:32:00 PM

Hobolth A, Christensen OF, Mailund T, Schierup MH (2007) Genomic Relationships and Speciation Times of Human, Chimpanzee, and Gorilla Inferred from a Coalescent Hidden Markov Model. PLoS Genet 3(2): e7

They estimate 4.1 million years ago. It's open access so no excerpts needed.

Human cloning "inevitable"   posted by p-ter @ 2/24/2007 12:26:00 PM

According to the editors of Nature.
[W]hat has been universally deemed as unacceptable is the pursuit of human reproductive cloning - or the production of what some have called a delayed identical twin. Here, the two issues that have dominated the discussion have been dignity and safety. There is a consensus that dignity is not undermined if a human offspring is valued in its own right and not merely as a means to an end. But there is no consensus that we will eventually know enough about cloning for the risks of creating human clones to be so small as to be ethically acceptable.

The debate may seem to have been pre-empted by prompt prohibition. But as the science of epigenetics and of development inevitably progresses, those for whom cloning is the only means to bypass sterility or genetic disease, say, will increasingly demand its use. Unless there is some unknown fundamental biological obstacle, and given wholly positive ethical motivations, human reproductive cloning is an eventual certainty.

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Friday, February 23, 2007

Epigenetics: the hippest field on the block   posted by p-ter @ 2/23/2007 07:15:00 PM

The current issue of Cell is dedicated to the rapidly changing field of epigenetics, loosely defined at the ensemble of chromatin and DNA modifications that structure the genome and control gene expression. The only review I've worked my way through yet is this one: Timescales of Genetic and Epigenetic Inheritance.
According to classical evolutionary theory, phenotypic variation originates from random mutations that are independent of selective pressure. However, recent findings suggest that organisms have evolved mechanisms to influence the timing or genomic location of heritable variability. Hypervariable contingency loci and epigenetic switches increase the variability of specific phenotypes; error-prone DNA replicases produce bursts of variability in times of stress. Interestingly, these mechanisms seem to tune the variability of a given phenotype to match the variability of the acting selective pressure. Although these observations do not undermine Darwin's theory, they suggest that selection and variability are less independent than once thought.
The authors limit themselves largely to bacteria and yeast, but they document a great deal of evidence that parameters like the mutation rate change in response to external stimuli, perhaps in almost a "directed" fashion. Some work in primates has shown a correlation between the amount of mutation raining down on a population and the amount of beneficial mutations that arise. Could "directed" mutagenesis be an explanation for this?

The main points from the paper are summarized in the figure below; essentially, epigenetic inheritance is a way for a population to respond to environmental changes that occur on time scales shorter than those needed for genetic evolution.

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Explaining (some) Global Inequality: Genes, Culture, or Luck?   posted by Herrick @ 2/23/2007 11:48:00 AM

Economists Wacziarg (Stanford) and Spolaore (Tufts) are using Cavalli-Sforza's genetic distance data. They find that countries that are genetically different from the rest of humanity tend to be poorer, even after controlling for lots of popular variables (like geography and colonial experience, two recent favorites). Their explanation: It's easier to get ideas from people who are similar--a contrast with much of the trade literature, where it's easier to get gains from trade from people who are dissimilar.

As Google Scholar shows, W&S have drawn some attention. Along related lines, Bill Easterly and his coauthors remind us that the countries that were more innovative in 1000 BC tend to be richer today--so not much is new under the sun.

Of course, W&S remind us that it's essentially impossible to disentangle genetic versus cultural stories when looking at nation-level data--and they note that their genetic measures are based on neutral markers, so it's "different," not "worse."

By contrast, one way to interpret Easterly's result is mere path persistence: A multiple-equilibrium story where you get it right once through sheer luck, and afterwards you're likely to stay lucky forever. Difficult to disprove--maybe it's a fair coin, and the West and East Asia just flipped Heads...

Genes, culture, luck: All three stories deserve some attention over the next few years. Two big problems: Measuring culture and luck. Genetic differences, those we'll be able to measure, with greater precision every year. But that's almost as much a curse as a blessing, since it'd be extremely valuable to be able to disentangle these hypotheses.

Thursday, February 22, 2007

William Wilberforce   posted by Razib @ 2/22/2007 10:26:00 PM

This week's In Our Time is about William Wilberforce. Unfortunately, many on this side of the pond don't recognize the name. They should.

MicroRNA editing   posted by Fly @ 2/22/2007 01:45:00 PM


"What we found was that, in certain cases, edited versions of these microRNAs are being produced that differ from the unedited versions by only a single nucleotide change," says Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and senior author on the study.

"These edited microRNAs are not encoded in the DNA, which means that at least two versions can being produced by one gene. This was not anticipated - it was something really new.

Looking more closely, we realized that the substitution we'd identified occurred in a particularly critical region of the molecule, the first 7 or 8 nucleotides - out of a total of only 19 or 21 - that define the molecule's target specificity. This suggested that the change might well redirect these edited microRNAs to silence entirely different sets of genes from the unedited versions."


Social Irrationality?   posted by John Emerson @ 2/22/2007 09:44:00 AM

Race IQ and SES   posted by the @ 2/22/2007 12:31:00 AM

Jensen (1998) makes a point that is worth repeating:
The pernicious notion that IQ discriminates mainly along racial lines, however, is utterly false.

Jensen presents what should be a predictable pattern for a highly heritable trait:
Source % of Variance Average IQ Difference
Between races (within social classes)
14 30 12
Between social classes (within races)
8 6
Interaction of race and social class
Between families (within race and social class)
26 65 9
Within families (siblings)
39 11
Measurement error
5 4
100 17

This can be demonstrated most clearly in terms of a statistical method known as the analysis of variance. Table 11.1 shows this kind of analysis for IQ data obtained from equal-sized random samples of black and white children in California schools. Their parents' social class (based on education and occupation) was rated on a ten-point scale. In the first column in Table 11.1 the total variance of the entire data set is of course 100 percent and the percentage of total variance attributable to each of the sources6 is then listed in the first column. We see that only 30 percent of the total variance is associated with differences between race and social class, whereas 65 percent of the true-score variance is completely unrelated to IQ differences between the races and social classes, and exists entirely within each racial and social class group. The single largest source of IQ variance in the whole population exists within families, that is, between full siblings reared together in the same family. The second largest source of variance exists between families of the same race and the same social class. The last column of Table 11.1 shows what happens when each of the variances in the first column is transformed into the average IQ difference among members of the given classification. For example, the average difference between blacks and whites of the same social class is 12 IQ points. The average difference between full siblings (reared together) is 11 IQ points. Measurement error (i.e., the average difference between the same person tested on two occasions) is 4 IQ points. (By comparison, the average difference between persons picked at random from the total population is 17 IQ points.) Persons of different social class but of the same race differ, on average, only 6 points, more or less, depending on how far apart they are on the scale of socioeconomic status (SES). What is termed the interaction of race and social class (8 percent of the variance) results from the unequal IQ differences between blacks and whites across the Spectrum of SES, as shown in Figure 11.2. This interaction is a general finding in other studies as well. Typically, IQ in the black population is not as differentiated by SES as in the white population, and the size of the mean W-B difference increases with the level of SES.

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Wednesday, February 21, 2007

The Economist   posted by Razib @ 2/21/2007 11:20:00 PM

Just a you think it is worth $100 a year to subscribe to The Economist? I was a subscriber several years back and let it lapse mostly because I found that I wasn't checking in every week.


Eric Alterman, a nationalist socialist   posted by Razib @ 2/21/2007 09:18:00 PM

A few weeks ago I watched Bloggingheads.TV which I found really amusing. Eric Alterman was in a discussion with someone named Bill Scher. I don't know anything about Scher aside from the fact that he makes Jonah Goldberg seem really intellectual and a deep thinker (see their diavlog). But I was struck by the following exchange over foreign policy:
Alterman: "People in these countries don't want us, they hate us, they hate everything about us, they hate the idea of democracy, it's inconsistent with their vision of Islamic republics, which is what they clearly want. So you just like glossing over that, but I think that's fundamental. I think the promotion of democracy in the Arab world creates anti-American terrorists."

Scher: "Well, I mean, democracy in the broader sense, what kind of government do those people want. It doesn't have to be Jeffersonian-"

Alterman: "I don't want them to have the kind of government that they want. OK. I don't want Jordan and Pakistan and Saudi Arabia to have the kind of government that they want, because they will want to kill me with it!

I generally cheered for Alterman here. Whether you are an interventionist or not, the whole rhetoric about democracy and its universal appeal on both the Left and Right has gotten out of control. Whether there is a universal yearning for democratic freedom or not, its acceptance as a background assumption in the public discourse has become nearly religious. When someone like Alterman challenges it, you see a "deer in headlights" tendency. There are few counter arguments because people assume any contrary position is either absurd or immoral. These sort of dreamy tendencies are fine when you aren't an imperial power that has to make real-politik decisions (e.g., Iceland?), but at this point bad decisions informed by fallacious assumptions can cost a lot, at home and abroad.

To make the world as you wish it to be, you must first comprehend how it truly is.

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Tuesday, February 20, 2007

Religion & Politics & Derb   posted by Razib @ 2/20/2007 11:35:00 PM

Check out Derb's latest column for NRO.

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Admin, etc.   posted by Razib @ 2/20/2007 10:29:00 PM

I've received a half dozen complaints about the slowness of the site due to the technorati widget, so I've removed it for now. I see an improvement in load time. Yay or nay?

Also, to the right you should see an RSS feed logo from feedburner. I've always had a feed, with a small link provided, but I figured that regular readers should really be encouraged to use this. Of course, the RSS won't tell you which comment threads are hopping, but in terms of maximizing time utilization I think it's a good move. You can always bookmark the Haloscan thread of interest (speaking of which, anyone know a better offsite comment service? I don't like onsite comments because they are liable to take a site down because of repeated hits).

Finally, for those of you down with RSS, I highly recommend adding a few Google News queries to your feeds. For instance, I have genetics & evolution always updating in Google Reader (which has some downsides, but I like the total integration with my google home page). You can see the RSS links to the bottom left. The PLOS network also has an excellent set of feeds (page down) so you don't need to keep checking on their site for new articles (other journals have them too, but I don't find them as user friendly or value added).

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Left-handedness and pedophilia: Brain damage   posted by agnostic @ 2/20/2007 05:58:00 PM

It seems that "pathological" left-handedness and pedophilia might share a common origin in some early developmental disturbance(s), possibly a brain infection (or group of infections). I first read about the potential fitness costs that left-handers suffer in a passing remark of Harpending & Cochran (2006), although when I searched PubMed for "left-handed" and "longevity," I found that the results have been somewhat inconsistent. However, a new study in Epidemiology on longevity and handedness in a large, representative sample of Dutch women (Ramadhani et al. 2007) confirms the earlier reports of decreased longevity among left-handers. The Hazard Ratios for left-handers vs. right-handers showed that lefties were more likely to die of all causes, and even more so for specific causes such as colorectal cancer and cerebrovascular diseases (PDF pp. 2-3):

Table 2 shows that, after adjustment for age, SES, BMI, and cigarette smoking status, left-handed women had a 1.36 times higher risk of dying from all causes than non-left-handed women. The adjusted HR for total mortality, after excluding the first 5 years of follow-up time, was 1.58 (95% CI = 1.03--2.42). With regard to cancer mortality, left-handed women had a 1.7 times greater risk of dying from any type of cancer (CI = 1.0--2.7), a 4.6 times higher risk of dying from colorectal cancer (1.5--14), and a 2.0-fold higher risk of dying from breast cancer (0.83--4.6). Handedness was weakly associated with overall mortality from diseases of the circulatory system (1.3, 0.54--3.3), although left-handed women had a 3.7 times greater risk of dying from cerebrovascular diseases than non-left-handed women. Left-handedness was not associated with mortality attributable to causes other than the above-mentioned.

A separate study from the same group of researchers (Ramadhani et al. 2006) also found that the severity of a bacterial meningitis infection correlated with handedness, such that those with stronger infections were more likely to become left-handed and lower in IQ. They note that since the infection happens before the other events, the former likely contributes to causing the latter (pp. 2528-9):

Fig. 1 shows that children with a meningitis severity score above the median had a 6.2 times higher risk of becoming lefthanded at school age compared to those below the median (95% CI 2.0--18.6). Furthermore, those who contracted meningitis below the median age of 1.8 years had a 12.3 times higher risk (95% CI 2.6--58.0) compared to a 5.9 times higher risk (95% CI 1.6--21.7) among children who contracted meningitis at older age.
. . .
More specific analyses on cognitive function are shown in Table 3, with left-handed children generally performing worse on the cognitive tests. Left-handed children had an almost seven points lower IQ (p = 0.018), a one point lower vocabulary score of WISC-r (p = 0.061), and an almost five points lower Beery score (p = 0.069) than their non-left-handed counterparts.

Turning next to handedness among pedophiles, Bogaert (2001) examined a Kinsey Institute dataset for the handedness data of 286 criminal pedophiles (those who had a victim of either sex under age 12). His findings, where NRH means Non-Right-Handedness (pp. 467-8):

Although the effects were small, it should be noted that a 5% difference means about a 30% change in NRH (e.g. 15.7% in pedophiles vs. 11.5% in controls).
. . .
In contrast, education is not related to the handedness/pedophilia relationship. Pedophiles had elevated NRH relative to controls with or without controlling for education. This result suggests that, even though pedophiles have a rate of NRH comparable to other offenders (or perhaps slightly higher), there may be a different mechanism underlying the handedness/pedophile relationship than the handedness/(general) criminality relationship. Thus, elevated NRH in pedophiles probably does not merely represent a 'criminal/antisocial behavior' tendency, because of, for example, general cognitive and/or educational difficulties. Instead, these data may indicate that elevated NRH in pedophiles reflects [Central Nervous System] abnormalities that, in part, directly affects their sexual preference systems (see [24] for a review of CNS abnormalities in pedophiles).

Next are two studies done by Cantor and colleagues. In the first, Cantor et al. (2004) examined men who were referred to a clinic for inappropriate sexual behavior, using phallometric responses (which measure penile arousal) to various erotic stimuli in order to divide the men categorically into pedophiles (those attracted to children under 12), hebephiles (those attracted to 12-16 year-olds), and teleiophiles (those attracted to adults). They found (p. 8):

The group differences did not change appreciably after the addition of the covariates [i.e., Age and Wechsler Full Scale IQ; agnostic], F(2, 294) = 6.31, eta^2 = .041, p = .002, and simple effects contrasts showed that both the pedophilia group and the hebephilia group reported significantly less right-handedness than did the teleiophilia group, t(294) = -3.51, eta^2 = .040, p = .001 (twotailed), and t(294) = -2.14, eta^2 = .015, p = .033 (two-tailed), respectively.

The researchers then used a continuous measure of sexual interest, namely the degree to which they become aroused when viewing different stimuli (p. 8-9):

The results indicated that, in general, measures of cognitive ability correlated negatively with sexual response to children and positively with sexual response to adults. Handedness, however, was significantly related to phallometric response to children, only. [From Table 4, partial correlation of arousal by prepubescent stimuli and handedness = -.13, p less than .05, where negative handedness indicates left-handedness; agnostic.] There was little evidence of association between the neuropsychological variables and sexual response to stimuli depicting pubescents in the laboratory.

They conclude that the relationship between handedness, cognitive ability, and pedophilia is that they are all caused by an early collection of brain perturbations, not that poor cognitive ability leads one (probabilistically) to develop pedophilic interests, since IQ was controlled for. Their follow-up article (Cantor et al. 2005) has two studies, the first of which was a successful replication of their previous findings. The second study classified patients categorically as right-handed or non-right-handed, in contrast to their continuous measure in the 2004 study, so that they could report Odds Ratios, making their results more comparable to those of other studies. By measuring penile arousal to stimuli involving adults, pubescents, and prepubescents, as before, the authors slotted the patients into those primarily attracted to one of the three age groups, as well as which sex they were most attracted to.

The relationship between sexual preferences and handedness was only significant for those attracted to prepubescents (although there was a trend toward lower right-handedness among those attracted most to pubescents), with or without controlling for IQ. Their Table II shows that after controlling for IQ in their logistic regression, the B-coefficient for age preference in predicting handedness was 1.26 (SE = .34), and the Odds Ratio was 3.54 (95% CI = 1.84--6.81), p = 0.0002. Next the researchers categorized the patients based not on their penile response to stimuli, but on their actual sexual offenses against others, again sorting by age and sex of the victim. At first, there was a trend in the same direction as the results obtained from measuring genital response, but the trends were not significant.

They thought that incest cases might be confounding the results -- for example, men who commit crimes against intrafamilial individuals might be engaging in a facultative behavior similar to men who have sex with men in prison, rather than have obligate pedophilic preferences. After removing patients who had intrafamilial victims, the results became significant. In particular, their Table V shows that in a similar regression analysis as before, the best predictor of handedness was a preference for prebubescents, even controlling for IQ: B = 1.06 (SE = .47), OR = 2.9 (95% CI = 1.15--7.28), p = 0.02. Admittedly the results are less striking when measuring sexual preferences according to their actual sexual offenses than when measuring it by their arousal to erotic stimuli, but this may well be because the latter is a purer measure of preferences, since it doesn't involve the vagaries of choosing and offending against a real person.

In sum, there is a significant relationship between non-right-handedness and pedophilic preferences, and this is likely the result of an early developmental disturbance to the brain. Since these studies were conducted in modern Western countries, things like lack of proper nutrition in the mother are probably not what's going on. As hinted at in the study of meningitis and handedness, it is more likely that an infection causes the damage -- these are one of the sources of environmental insults whose effects we still have yet to curtail, beyond ameliorating some of the more horrendous cases like smallpox. Of course, the pathogen responsible for non-right-handedness doesn't have to be the same as that which causes pedophilia; the affected individual might have been born in an unusually high pathogen-load area, or have a weakened immune system in general, and so on.

One thing seems pretty clear, though: common cases of deviance from Darwinian fitness are most likely caused by environmental insults, with pathogens being the most obvious culprit (see Cochran, Ewald, & Cochran 2000 for the rationale). That result isn't guaranteed a priori, but it is a far more reasonable "working hypothesis" for a particular case than imagining how, for example, pedophilia might have been adaptive in the past, or how it represents the tail of a distribution for "caring for children," or how pedophilia-normal heterozygotes might enjoy a fitness advantage, and so on. Mental, financial, and time resources are all limited, so we should follow the course that all good detectives do: first look at the person you most suspect, based on the accumulated knowledge of similar past cases. Real life is not a Law & Order episode where the least likely culprit routinely turns out to be the one who dunnit. If they're cleared, then move on to the exotic suspects.

Related: Left-handedness post from the archives.


Bogaert, AF (2001). Handedness, criminality, and sexual offending. Neuropsychologia, 39, 465-9.

Cantor, JM, R Blanchard, BK Christensen, R Dickey, PE Klassen, AL Beckstead, T Blak, & ME Kuban (2004). Intelligence, memory, and handedness in pedophilia. Neuropsychology, 18, 3-14.

Cantor, JM, PE Klassen, R Dickey, BK Christensen, ME Kuban, T Blak, NS Williams, & R Blanchard (2005). Handedness in pedophilia and hebephilia. Archives of Sexual Behavior, 34, 447-59.

Cochran, GM, PW Ewald, & KD Cochran (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine, 43, 406-48.

Harpending, H & G Cochran (2006). Genetic diversity and genetic burden in humans. Infection, Genetics, and Evolution, 6, 154-62.

Ramadhani, MK, SG Elias, PA van Noord,DE Grobbee, PH Peeters, & CS Uiterwaal (2007). Innate handedness and disease-specific mortality in women. Epidemiology, 18, 208-12.

Ramadhani, MK, I Koomen, DE Grobbee, CA van Donselaar, A Marceline van Furth, CS Uiterwaal (2006). Increased occurrence of left-handedness after severe childhood bacterial meningitis: support for the pathological left-handedness hypothesis. Neuropsychologia, 44, 2526-32.

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Monday, February 19, 2007

Why Sam Harris & co. matter   posted by Razib @ 2/19/2007 10:25:00 PM

Recently Ayaan Hirsi Ali has been making the rounds on the talk shows because of a new book. A few weeks ago she was on a Boston radio show, and you can listen to the whole interview, but, I suggest you fast forward to 24:30 and listen to the female Muslim caller. Listen to her voice, the outrage and shock, the tremor because she can't abide what she hears. I generally listen to a radio feed while I'm at work and Ali has been on a few shows, and this is a common response. Whatever reasoned critiques this variety of caller has of Ali's assertions (I am, for example, not positively inclined toward Ayaan's recent tack of repackaging herself as a Muslim by culture), the emotional impact of seeing their religion criticized and verbally raped makes them nearly unhinged. This is not an abnormal reaction, people attach great value to their religious identity, and when it is assaulted, even rhetorically, they take it quite personally. Remember that the persecution of Christians in the Roman Empire was in large part justified by their 'atheism,' their public disrespect of the traditional gods not their own. The concept of blasphemy, violation of taboo, is pretty universal. That being said, after the 18th century Christendom, and what became post-Christian Western civilization, shed the taboo against criticizing religion. It is simply part of the freedoms we take for granted. Most of the callers who have reacted with outrage against Ayaan Hirsi Ali are immigrants, and to me it seems quite clear that their outlook has been shaped by the inviolable nature of Islam and Islamic ideals in their societies of origin. When people talk of a "Western Islam," I think one of the things one must look to as a metric or indicator is acceptance of violation and blasphemy, a disrespect that Christianity has become accustomed to over the past few centuries.

One may contend that provocateurs such as Ayaan and Sam Harris go too far in violating the public pieties, but if you listen closely to what the caller asserts you can see why such a violation is necessary. Her reiteration of the "true Islam" in direct contradiction to the general way Islam is practiced does nothing to establish a common ground, it reflects the dreamland of her own imaginings. Fundamentally, those like myself who are secular but generally disinclined toward engaging in an anti-religious jihad because we see neither the point or the possibility of a final victory are skeptical of the hope of a modus vivendi when the delusion extends from down on high toward the mundane world of facts on the ground. Believe what you will of the divine, but accept the reality of the profane and do not fib like a child because you wish it to be so. Your parents may tell you that you are the most beautiful and smartest child of them all, but once you enter preschool you start seeing that there is more to the world than you could ever have imagined. So let's hope that preschool is in session, inshallah.

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Seen on the streets of San Francisco   posted by Matt @ 2/19/2007 02:59:00 PM

See another sign here, and consider making your own here

Sunday, February 18, 2007

Next-generation sequencing   posted by p-ter @ 2/18/2007 07:46:00 PM

Nature Biotechnology has a little news article profiling some of the companies driving the cost of sequencing down. There's ambition in spades:
Companies have also started to win bids under the NHGRI $1,000 genome program. Unlike the $100,000 technologies, which focus on refining and improving existing methods, the conception of a $1,000 genome requires an entirely different paradigm-a discontinuous innovation. Helicos' technology, unlike the cluster-based approaches of 454, Agencourt and Solexa, could provide such a leap: in the first commercial award under the $1,000 program, it received, in October 2006, a $2 million grant to further develop its single-molecule approach.

According to Steve Lombardi, senior vice president of Marketing at Helicos, "If you had perfect chemistry, and each step was 99.99%, the instrument would generate 100 billion bases a day. The instrument is being designed for that throughput, but the first-generation chemistry will have a smaller yield-around 600 megabases per day." Improvements in chemistry could move Helicos to the $1,000 genome "in the first few years," he claims-well ahead of the NHGRI goal of 2014.
Everyone talks about personalized medicine and whatnot, but my first reaction is: wow, are microarrays already almost obsolete? With 600 megabases per day (the human genome is 3300 megabases), SAGE on a huge scale is possible...

Prenatal DNA testing: as simple as drawing blood?   posted by p-ter @ 2/18/2007 01:52:00 PM

Ever since the presence of fetal DNA in maternal plasma was demonstrated a decade ago, a number of teams have been searching for the best way to put this information into practice, so far with fairly disappointing results. The problem, of course, is that maternal DNA is also present in maternal plasma, and given that half a child's DNA comes from the mother, it's rather difficult to distinguish the two. The easiest applications, then, are when there is some DNA in the fetus that simply cannot be maternal--a Y chromosome, for example. Sex testing via this method should be rather trivial, though perhaps not that useful (the classic "look at the ultrasound and see if there's a penis" method also proves rather reliable).

After sex determination, testing for aneuploidies like Down's syndrome should be next lowest hanging fruit. Currently, the levels of a number of proteins are tested in expecting mothers, and those who have levels at the extremes of the distributions are advised to undergo amniocentesis to confirm or negate the results (the best tests now have a detection rate of about 80% and a 7% false positive rate, which, while not awful, certainly isn't diagnostic). As amniocentesis carries a non-negligible risk of causing a miscarriage, it would be desirable to get better results non-invasively.

Two new papers attack this problem from different angles--one uses paternal information to find SNPs that distingush maternal from fetal DNA, and the other cleverly uses levels of RNA from a gene expressed only in the placenta. Neither is going to replace amniocentesis just yet, but technology marches on...

Eventually, will it be possible to get an entire fetal genotype non-invasively? It's certainly possible, and this could have major implications for "neo-eugenic" practices. Currently, if a couple concieves a child naturally (no IVF), there are only a limited number of genetic tests it's worthwhile to do, as methods for obtaining the fetus's genetic information carry the potential cost of killing it. Once that cost is gone and our knowledge of genetics progresses a bit, parents could theoretically "screen" their children for whatever trait they desire without passing through the rather unromantic (and expensive) IVF step. Will many parents abort a child because they don't like its eye color? Doubtful, but some small percentage will choose to terminate pregnancies for reasons that seem rather cold-hearted.

Legend & history   posted by Razib @ 2/18/2007 08:55:00 AM

A few months ago a friend made an offhand comment about how they were on the side of the "Andalusian model." His assumption was that Al-Andalus, Muslim Spain, was far superior in its method of dealing with religious pluralism than Christian Spain. I've read a fair amount of popular & scholarly work on this period and region, and the reality is more complex than the hype. The friend holds a Ph.D. in a social science from Harvard and has a position as an assistant professor at a moderately elite university. He isn't an uintelligent individual. I tried to communicate to him a few general points:

1) Religious pluralism was a reality in both Christian and Muslim Spain

2) Subordination at the expense of the religion promoted by the the elite was the norm throughout this period

3) Persecution of Jews occurred both in Muslim & Christian Spain

4) One can see a general trend where the dominant religion, whether it be Christianity or Islam, tends to become less tolerant when its numbers are great enough to dispense with accommodation with the majority (or what has become a minority)

The issue that I had was that my friend was making an identity between Muslim Spain and the post-Enlightenment West in regards to freedom of religion when that freedom did not exist in the former. Al-Andalus' tolerance only exists on a relative scale in comparison to the later Spanish expulsion of Jews, Morsicos (crypto-Muslims) and persecution of religious nonconformists (Protestants). The expulsion of Jews from Spain looms large in our minds because of its recency (and its memory in the Sephardic Diaspora), but the pogroms in Muslim Spain during the 10th or 12th centuries were nothing to sneeze at. Similarly, Jews and Muslims played roles in the life of Christian states throughout the transitionary period from 1000 to 1500 (e.g., Muslim soldiers were employed by Christian kings). It would not be factually incorrect to romanticize some of the medieval Spanish kindgoms set against the oppressive nature of the Spanish monarchy after 1492.

There are two major issues that loom in the background for me. First, was Al-Andalus more tolerant than Christian Spain? Let's say we evaluate the period between 700 and 1800. If you construct a "persecution" index with a host of parameters (e.g., expectation someone is subject to a pogrom in any give year, etc.) I would probably bet on Al-Andalus. That is, integrating over the time from conquest to reconquest religious minorities might have had a better time of it in Muslim Spain than Christian Spain from 700 to 1800. That being said, the difference is quantitative, not qualitative. Second, one needs to put the contextual issues on the table. Muslims were a small minority in their domains for the first few centuries of Al-Andalus, so it was simply not practically feasible to engage in excessive religious persecution. Similarly, afer the Visigothic monarchy converted to Catholic Christianity from the Arian sect in the 6th century there seems to have been more persecution of Jews. Why? Was Catholicism fundamentally more anti-Semitic than Arianism? I suspect not, rather, the Visigothic elite before their conversion were a religious minority, and as such they were in no position to use the ideology of religious conformity to support their rule since they themselves were at variance with the majority confession. After their conversion to Catholicism they had nothing to lose, and everything to gain, by engaging in religious intolerance as it solidified their rule and identification with the religious majority whom they had so recently joined. Similarly, the Catholic rulers of the Iberian peninsula did not become any less tolerant over the five centuries of the reconquest, the demographic balance of power shifted from Muslims to Christians (just as Christians had once converted to Islam, so Muslims who lived under Christian rule slowly converted over time to Christianity).1 What people tend to do with cultures in a historical context is similar to what they do with individuals in regards to the Fundamental Attribution Error. Instead of Muslim or Christian tolerance & intolerance emerging out of the situation, they become reduced to cultural essences. My friend had internalized and essence of Muslim Spanish culture that it was "tolerant" as a matter of principle when in reality it seems more a matter of pragmatism. The reconquista states also engaged in this pragmatism for centuries before the expulsions and forced conversions began. Conversely, during times of chaos and stress, and when Muslims had attained numerical dominance, Jews and Christians also were on the receiving end of Islamic persecution.

Which brings me to my final point: attitudes and sentiments about Muslim Spain are not about history or an analysis of the data, they are about the beliefs we hold about the modern world in regards to the values we deem to be precious. That is, my friend, scholar though he is, was not really interested in the nature of life in medieval Spain, he was making a comment about his adherence to the principle of religious toleration and the separation of church & state. Muslim Spain is simply a notional marker, a signal, the historical details are pretty much irrelevant, it is the legend that matters. I bring my friend's educational qualifications up because this is a person who is intellectual in orientation, but in hindsight I realize that bringing up the minutiae of historical detail is pointless, and fundamentally a distraction for him. The history is grist for the mill of ideology, not a thing in and of itself. An analogy might be the Bible, no matter the reality of the scholarship Christians will extract from the text and historical details points of relevance to them and their daily lives. Similarly, conservatives and liberals will take from the life of Thomas Jefferson the slices which are relevant to them, no matter the reality of the sum total of his beliefs and sentiments.

This does not mean we can not glean reality from the past, and understand how it was. Rather, I am implying that for most humans such scholarly points of detail are not important, the past is a fiction which simply allows them to justify their own ideals with a more ancient patina. Of course, on this blog I do insist upon fidelity to reality as we understand it. It is simply an acknowledgement of reality and its power than I concede that historical accuracy is of little concern to most, and so it shall ever be.

1 - The Moriscos expelled in 1600 were crypto-Muslims who could not be assimilated into the Spanish state because of the nominal nature of their Catholicism. But, that does not mean that all Muslims living under Spanish rule were destined to become Moriscos, rather, it seems likely that the great majority converted, just as many Jews became Catholics.

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Etruscans   posted by Razib @ 2/18/2007 12:30:00 AM

Over at my other blog I have three posts on Etruscans. Dienekes has been covering the topic closely as expected. The key here is that genetics seems to have answered the age old question of where the Etruscan people, one of the most important influences upon ancient Rome, came from. The Etruscans seem to have spoken a non-Indo-European language and emerged rather mysteriously during the early first millenium BCE to dominate the northwest coast of Italy (roughly, modern day Tuscany). Herodotus transmitted the legend that the Etruscans were originally from Lydia (roughly, western Anatolia), but the "Father of Lies" lacks a certain rock hard credibility. Understandably, contemporary scholars were skeptical of this exogenous origin, and the dominant tradition during the late 20th century among archeologists and historians was that folk movements were of minimal demographic impact. A less exciting, but more plausible, explanation seemed to be that the Etruscans were an indigenous cultural tradition influenced by the spread of Greek and Phoenician civilization to the western Mediterranean. But in this case, the sexy answer was the right one. I'm generally persuaded by Henry Harpending's contention that reading "neutral" markers has an aspect of tea leaf interpretation, but this is far more applicable to grand narratives which are global in scope. Genetics does not lend itself to answering all questions, in particular due to the genetic exchange between neighboring populations equilibrating allele frequencies over the generations, but in this case the long distance migration of a whole people in an alien genetic landscape left a discernable impact down to the modern day.

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Saturday, February 17, 2007

New Leutgeb/Moser - place cell paper   posted by amnestic @ 2/17/2007 07:11:00 AM

The Leutgebs and the Mosers have brought us another interesting datapoint regarding how the hippocampus segregates or lumps the representation of spatial environmens. They recorded from the CA3 and dentate gyrus subregions of the hippocampus while they moved rats between a series of 'morphed' environments, moving gradually from a circular to a square arena. The idea is that CA3 tends to lump representations while DG tends to split them apart. No time to chat right now, but here's an excerpt from the commentary by Andre Fenton:
The authors confirm that CA3 place cells respond to small deviations in the spatial environment by lumping. In other words, the same neuronal discharge patterns were observed in CA3 regardless of whether the rat was in a morphed or unmorphed circular or square box. Larger deviations from either environment caused rate remapping in CA3. The dentate gyrus was quite different. Single dentate granule cells had more firing fields than did individual CA3 cells. Granule cells responded to small morph deviations in the rat's environment by changing both firing rates and firing fields unpredictably. Thus, the dentate gyrus proves a consummate information splitter and the CA3 more of a lumper (see the figure). Small changes in spatial input information caused large changes in dentate gyrus output to CA3 but virtually no changes in CA3 output to CA1.

I had a dream last night that I was at a seminar where Stefan Leutgeb was explaining these findings and Edvard Moser was in the audience and began correcting Leutgeb and they got into an argument but started speaking in French. Miraculously in my dream I could understand French and was able to impress the student next to me by explaining the argument. I don't remember what they were arguing about though. Too-da-loo.

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Friday, February 16, 2007

Poll the experts!   posted by Razib @ 2/16/2007 07:54:00 PM

Do you remember the age before polling in politics? I don't. Today we bemoan the emphasis on polls and idealize the past, before candidates knew in scientific and statistically significant detail the temperature of the democratic water. But no one is going to ban polls in the near future, for every person who complains about survey data there are hundreds who are clicking refresh over & over to find the most recent tracking results on their website of choice.

I think something similar is necessary for the sciences (or scholarship in general). Is George Lakoff a laughing stock (as Chris would have us believe), or a thinker of gigantic Aristotelian proportions? I suppose if you were a cognitive scientist you'd know, your sample of individuals in the field with whom you'd engaged in personal communication would be vast and you could get a sense of the direction that the wind was blowing. But for someone outside the field you basically have to trust someone on the inside and hope they aren't misleading you (or, themselves). Is multi-level selection the next big thing in evolutionary biology, as Bora claims, or is it a relatively marginal and muddled field, my own general perception? Bora has made the Kuhnian claim that multi-level selection's day will come when the older scientists die off, but how do we know that his perception is correct? One's own sample is obviously going to be biased toward those with whom one is on common ground with, perhaps there are enormous social science departments steeped in conceptual metaphor theory that Chris has no knowledge of because he is boxed in within his old fashioned world of symbolicists?

I think my point is pretty clear here: in the sciences quite often laypeople are in the position where they know with great confidence that a theory is absolutely accepted at its level of precision (e.g., Newtonian Mechanics) or totally rejected (e.g., the Aether theories). It is as if our knowledge of allele frequencies was certain with any degree of confidence only if they were operationally fixed (i.e., greater than 99%) or very rare or non-existent (i.e., less than 1%). Not only would my proposal help the public, I think it could give scientists some perspective about their position within their discipline.

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Thursday, February 15, 2007

Interesting twist in the Sullivan-Harris debate   posted by the @ 2/15/2007 07:48:00 PM

Sam Harris and Andrew Sullivan have been debating religion. Here's an interesting excerpt from Sullivan's Feb 14 entry:

...That is because I have never met a human being or a human mind that is "contingency-free", and never will. No child grows up without the contingent facts of their family, place, genes, and any number of details that make us who we are. You and I would be very different people if we had different contingent genetics and different contingent histories. This is the experience of being human, an experience eternally different from the dream of your new, unfettered, purely rational "education," where the young are severed from the toxins of contingent culture and faith and family....

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All diabetes, all the time   posted by p-ter @ 2/15/2007 06:01:00 PM

Keeping with the diabetes theme, the first genome-wide association study of Type II diabetes has been published, and it's extraordinarily promising. Besides picking up the oft-replicated TCF7L2 gene mentioned before, they pick up three other loci, including finding a non-synonymous mutations in a zinc transporter. That's notable because 1. non-synonymous mutations clearly can have phenotypic effects (there's no wondering, could this really do something?), and 2. drug targeting of zinc transport is feasible (TCF7L2 is a transcription factor, and when you start playing with transcription factors you risk messing with a lot of pathways). The news article accompanying this study has some good perspective:
In 1918, Ronald Aylmer Fisher, an evolutionary biologist and pioneer of modern statistics, published a paper on the genetic causes of disease that brought together two rival factions. Geneticists promoted a paradigm in which diseases worked a lot like Mendel's pea plants, with just one or two genes responsible for each condition. Biometricians, however, advocated a continuous distribution of phenotypes. Fisher suggested that many mendelian traits could result in the continuous distribution of a disease. In doing so, he established the conceptual basis for the search for complex disease genes that continues today.

But Fisher's theories had a more immediate impact on animals and agriculture than on medicine — in people, it's much easier to study and measure mendelian diseases and traits. Even the much-heralded Human Genome Project in the 1990s didn't help as much as expected.
It has taken time for big GWA studies to be completed. "Many people didn't know how much association studies would deliver," says Peter Donnelly, a lead investigator of the Wellcome Trust Case Control Consortium, which began collecting samples for GWA studies in 2005.

Yet new results, including a study on type 2 diabetes published this week, suggest that the GWA approach will bear fruit, and lots of it....Modern biology may finally have begun to bring technological and scientific rigour to Fisher's decades-old insights.

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Thrifty genotype, again and again   posted by p-ter @ 2/15/2007 05:17:00 PM

Speaking of the thrifty genotype hypothesis, a new paper from the cats at deCODE Genetics takes an in depth look at one of the loci consistently implicated in Type II diabetes. According to the authors, the succeptibility allele is ancestral, and the other, non-ancestral allele shows signs of being under recent positive selection in all the populations studied. Even more interestingly, the protective allele is associated with decreases in levels of circulating ghrelin (a hormone that increases appetite) and increases in levels of circulating leptin (a hormone that decreases appetite). This would seem, by my reckoning, to be consistent with the thrifty genotype hypothesis. In addition,
We obtained rough age estimates for HapA [the protective allele] based on its recombination history: 11,933, 8,401 and 4,051 years for the CEU, East Asian and YRI HapMap groups, respectively. Although tentative, these ages coincide broadly with the onset of agriculture in the three geographic regions represented by the HapMap groups.

On the other hand, the succeptibility allele is associated with decreased BMI after controlling for diabetic status, though I'm not sure that has any bearing on the hypothesis.

The authors conclude, bizarrely, "we note our findings contradict a key prediction of the thrifty-genotype hypothesis, insofar as HapBT2D, a major risk factor for type 2 diabetes, is negatively associated with BMI and is not the variant that contributed to adaptive evolution in the recent past."


I can only conclude, based on that statement, that the authors aren't really clear on what the thrifty genotype hypothesis is. The original Neel paper (which is cited in this paper, so the authors have hopefully read it) makes a few simple claims, the most important of which is that the "diabetic genotype" was favorable up until the transition from the hunter-gatherer lifestyle to agriculture. It certainly does not claim that a diabetes-causing allele should be under recent positive selection, nor am I sure how anyone could get that impression. I'm inclined to take the exact opposite conclusion from this paper than the authors--that is, this data seems to support, rather than contradict, a key prediction of the thrifty genotype hypothesis, insofar as the ancestral allele leads to succeptibility, and the derived allele, which arose at about the time of agriculture, mat be associated with reduced appetite.

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Wednesday, February 14, 2007

Human biodiversity @ SI   posted by Razib @ 2/14/2007 09:23:00 PM

Readers interested in the range of human phenotypic variation will be interested in inspecting the new SI model index. In particular, some readers might find the Brazil models gallery of particular interest. A certain GNXP contributor will appreciate this photo.

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Incest Avoidance 101   posted by p-ter @ 2/14/2007 06:41:00 PM

A key part of the kin selection theory of altruism is, well, that people can differentiate between "kin" and "not kin". A new paper gives a model for how kinship is calculated:
As predicted, the kin detection system uses two distinct, ancestrally valid cues to compute relatedness: the familiar other's perinatal association with the individual's biological mother, and duration of sibling coresidence.
That is, the kinship detector goes off if someone spends a lot of time with your mom, or if you've lived together for a while. The methods used to determine the level of "kinship" you feel for your sibling are the perfect Valentine's day reading material:
Instrument 3: disgust imagining sexual acts with a sibling (Likert)

Subjects were asked how disgusting they would find engaging in various sexual and nonsexual behaviours on a 7-point Likert-like scale (0, not disgusting at all; 6, extremely disgusting). Among these were sexual acts with particular opposite sex siblings. For each opposite sex sibling, independent ratings for passionately kissing, and having sex with 'your sibling' were summed to produce a dependent variable, sexual disgust (Likert).
Instrument 4: disgust imagining sexual acts with a sibling (rank)

A subset of participants who completed Instrument 3 also completed Instrument 4 (N = 375), which asked participants to assign a unique rank of disgust from 1 (not disgusting at all) to 50 (extremely disgusting) to eight acts, some of which involved sexual contact with a family member, short of intercourse. Using the rank of the sexual act involving a sibling, a variable, sexual disgust (rank), was constructed (women, mean = 47.36, s.d. = 3.99; men, mean = 45.51, s.d. = 9.91).

Petitions   posted by Matt McIntosh @ 2/14/2007 11:26:00 AM

Dear Henry Farrell,

Like many others of your ideological inclinations, you make much of the recent petition in favor of raising the minimum wage which was signed by over 650 economists. I will see you and raise you.

Careful where you point that thing, it's loaded.



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Tuesday, February 13, 2007

It's good to be black...and white   posted by Razib @ 2/13/2007 06:34:00 PM

This story, China's changing skin colour caught my attention. The relevant points:
"Traditionally, the first objective of a woman is to have pale white skin because whitening can cover many flaws. Many Chinese women will put on sun protection just to go next door because they're so afraid of getting any kind of sun rays," he added.
Dark skin in Imperial times was associated with labouring in the fields.
But for a growing number of young Chinese people, dark skin now means having the money to afford foreign holidays or Western-style glamour.
And a deep dark tan would appear to be one of the easiest ways to show that you are basking in China's new-found wealth.

Of course, "dark" is relative, just as "light" is relative. The article is a bit impressionistic for my taste, but, let's assume that it is suggestive of a counter-trend to the historical norm (I know there is a hip-hop counterculture among Japanese youth where tanning is fashionable). There are two issues:

1) International models, or at least non-local models, have influence. Before the rise of European hegemony in places like Japan black hair and epicanthic eye folds were considered beautiful. Today hair lightening and eye surgery are common in the Far East.

2) Within society mores (partly driven by emulation of global standards) where the transition to factory work has resulted in an urban proletariat that is indoors most of the time and a professional class which has time for "sun and fun" trips abroad.

Obviously this is more complicated than "darker = affluent," as a dark skinned South Asian or Africans are obviously not dark because of their trips abroad, so I doubt they would be the objects of any assumptions about their disposable income or usage of leisure. Nevertheless, I do think that it is interesting that the same cultural shift affected much of the Western world in the early 20th century, as the association of white skin with aristocratic shielding from outdoor labor became confounded by the fact much of labor now occurred indoors and so resulted in light skin. One can see similar shifts in other areas, in the United States obesity has a low SES implication, while a fit and trim look suggests someone who can afford high quality but low fat food and possible items such as a gym membership. This is obviously a shift from the previous norm, still found in many cultures where the median caloric intake is far lower (the rise in obesity in India and China is a phenomenon of the upper classes from what I know).

But now I want to focus on the past, and the emergence of light skin. I've talked about the genetics of skin color a fair amount, but an interesting point is that some loci, such as MC1R in East Asians and OCA2 Europeans (OCA2 is the major loci which controls blue eyes vs. non in Europeans, but it has some affect on skin color as well) have been under recent positive selection, within in the last 10,000 years. What's going on here?

I'll offer a tentative hypothesis, though I don't assume this is a sufficient condition: agriculture resulted in far greater social stratification was possible before as small hyper-fertile elites emerged. These elites did not engage in farming as a day to day activity (they might have been males warriors and their households), and so were environmentally lighter skinned. Additionally, hypergamy existed in these communities whereby high status males would engage in polygyny and selected the "fairest" females from the population. The elites were self-conscious about their light skins, and so the beauty norms shifted toward this model. Within the general populations there was some heritable variation in skin color, and those women who were genetically lighter skinned were socially promoted far more often than those who were not into the harems of elite men. These men had offspring who tended to become genetically lighter skinned. This process would repeat every generation, and as the elite always repopulated lower classes (perhaps the elite had secure grain stores that they monopolized that allowed them to survive famines) the light skin kept percolating down from on high. So the parameters I am suggesting are:

1) Greatly increased male reproductive skew, with a strong correlation between fitness and high status, caused by the onset of agriculture.

2) Hypergamy of genetically light skinned females into the elite, resulting in a correlation between light skin and high status which had genetic, as well as environmental, roots. Of course, lighter skinned women would also be fitter than darker skinned women simply because presumably their mates would be better providers.

Of course, I suspect there was some tendency to prefer lighter skinned females naturally because of its correlation within a population with youth and fertility (women get darker with successive pregnancies and after puberty). And, I think there might be other selective factors at work. But this is a start.

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The British: More patient than the Greeks?   posted by Herrick @ 2/13/2007 04:17:00 PM

Economic historian Greg Clark is arguing that the British may be "Genetically Capitalist." Tyler Cowen has his doubts. One of piece of evidence that should grab the attention of economists: The long term decline in inflation-adjusted interest rates over the past few centuries:
All societies before 1400 for which we have sufficient evidence to calculate interest rates show high rates by modern standards. In ancient Greece loans secured by real estate generated returns of close to 10 percent on average all the way from the fifth century BC to the second century BC. The temple of Delos, which received a steady inflow of funds in offerings, invested them at a standard 10 percent mortgage rate throughout this period.
He also looks at Roman Egypt, Sumeria, India, and the Ottoman Empire, and always finds the same story: A high cost of borrowing. But then around 1100, something changed: the cost of borrowing started falling fairly steadily in England, dropping down to the 2 or 3% inflation-adjusted rates we see today.

Why? Clark argues it's because in England the patient were more fertile than the impatient--and that the patient passed on their traits either culturally or genetically. Clark checks out the usual suspects--risk in particular--and finds that it's tough to explain away the big story: It looks like borrowers and lenders are a lot more patient than they used to be.

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SNPs, copy numbers & gene expression   posted by Razib @ 2/13/2007 01:54:00 AM

Had to link to a paper with such a title. Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes:
...SNPs and CNVs captured 83.6% and 17.7% of the total detected genetic variation in gene expression, respectively, but the signals from the two types of variation had little overlap....

Here's a quote from a popular press article:
"We've been able to look back into our history and find changes that are older and likely to be shared among populations," explained Dr Manolis Dermitzakis, senior author and Project Leader at the Wellcome Trust Sanger Institute. "But we also find many that are newer and less widespread."

"These are part of our recent evolution and a step along the way to understanding the origin and personal consequences of genetic change, not least for our wellbeing. This is a first generation map of biologically important DNA sequence variation"

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Monday, February 12, 2007

Ledoux and Lomborg   posted by amnestic @ 2/12/2007 08:18:00 PM

As long as we're posting videos, you can catch Joseph Ledoux discussing the latest projects in his lab in the NIH neuroscience seminar series (video and audio available here). Also, all-around controversial dude, Bjorn Lomborg, does a TED talk about world problems and says AIDS prevention is high priority.

The Mooney-Sokal op-ed   posted by the @ 2/12/2007 07:40:00 PM

I already miss Just Science week...

Chris Mooney and Alan Sokal wrote an op-ed in the LA Times titled "Can Washington get smart about science?" This post is a response of sorts, mostly an appeal to recognize that the "war on science" goes beyond the participants identified by Mooney and Sokal. For the most part, I am operating under the assumption that the problems identified by Mooney and Sokal are real and important, but I will argue that the problem they identify extends into academia.

I'll briefly summarize my main argument, and then try to respond to specific anticipated issues.

Main argument:

Per the Mooney-Sokal op-ed, when political figures obscure science for political ends, it distorts the ability of science to inform policy. Likewise, when academic scientists and scholars seek to obscure science (e.g., cognitive science, neuroscience, behavioral genetics and evolutionary psychology) for political ends, they are contributing to the same problem.

Ostensibly, politicians attack science where they fear that the results will be damaging to their policy preferences. We can imagine that they might have yet been able to defend their policy preferences while accepting the empirical findings of scientists, but that they found it easier or more effective to sow doubt about the science itself (see this post). For discussion, let's stipulate that this is a generally bad practice for a variety of reasons. In another form, religious individuals and organizations fear the corrosive effect of Darwinism on religious belief, moral values, etc. In response, they attack the empirical findings of Darwinism rather than confronting the issue at the intersection between facts and values.

A highly analogous situation has existed and continues to exist with respect to various areas of science in which the opposition to science comes from with academia, but the motivations for the opposition are primarily political, particularly the fear of that the results will have corrosive effects on the preferred moral and political positions. The most vivid case was the controversy over sociobiology, where Gould, Lewontin and others attacked sociobiology for predominantly political reasons (including their commitment to Marxism). The phenomena is seen in the resistance to new results from "the sciences of mind, brain, genes, and evolution" documented by Pinker in The Blank Slate. And it is seen in social prohibitions against research or discourse on certain "dangerous" topics in the human sciences (and others) as taboo subjects, exemplified in the response to Larry Summers' speech.

To approximately the extent that it's appropriate to identify the problem in Washington as a "Republican" war on science, it is appropriate to identify the problem in academia as a "Leftist" war on science. Each is damaging to the proper application of science to public policy. Each can be confronted at the same time without having to split resources between the two fights. And to confront one without confronting the other only opens one to accusations of unequal or biased treatment of the subject.


What is the problem in academia?

The political interference with science in academia is a different phenomenon than the 1990s "science wars" over postmodern criticisms of science. It is better identified as left-political objection to certain results, predominantly from the human science, and especially as they relate to human evolution, human behavior and society. This interference occurs in sciences at many levels of progress or scholarly acceptance. It includes the differential scientific treatment of hypotheses based on inferences about their political and moral consequences, rather than on their scientific merits. It includes the differential acclaim and reward given in the media and by scientific publishers to scientific hypotheses based on inferences about their political and moral consequences. And for the most taboo topics, it includes public disapprobation of scientists on the basis of inferences about the political and moral implications of hypotheses they advance, interference with their ability to publish, interference with their ability to secure funding, threats to their job security, and legal threats.

Perhaps the best studied example is the sociobiology debate, one of the most extreme and publicly visible episodes. The debate has been summarized in various books (e.g., Defenders of the Truth), and a suitable summary of the political motivations behind the strongest positions against sociobiology can be read at GNXP here. Pinker (2002) has explored many facets of the issue in detail, expanding beyond the scope of the sociobiology debate. It may help to quote Pinker's (2006) summary of The Blank Slate to give a sense of the situation:
I've suggested that the dominant theory of human nature in modern intellectual life is based on the Blank Slate, the Noble Savage, and the Ghost in the Machine, and that these doctrines have been challenged by the sciences of mind, brain, genes, and evolution. The challenges have also been seen to threaten sacred moral values. But, in fact, that doesn'’t follow. On the contrary, I think a better understanding of what makes us tick, and of our place in nature, can clarify those values. This understanding shows that political equality does not require sameness, but rather policies that treat people as individuals with rights; that moral progress does not require that the mind is free of selfish motives, only that it has other motives to counteract them; that responsibility does not require that behavior is uncaused, only that it responds to contingencies of credit and blame; and that meaning in life does not require that the process that shaped the brain have a purpose, only that the brain itself have a purpose.

Finally, I've argued that grounding values in a blank slate is a mistake. It's a mistake because it makes our values hostages to fortune, implying that some day, discoveries from the field or lab could make them obsolete. And it's a mistake because it conceals the downsides of denying human nature, including persecution of the successful, totalitarian social engineering, an exaggeration of the effects of the environment (such as in parenting and the criminal justice system), a mystification of the rationale behind responsibility, democracy, and morality, and the devaluating of human life on Earth. [source]
All of these topics share in common the accusation that they are dangerous. We can get a sense of this concept from the 2006 question:
The history of science is replete with discoveries that were considered socially, morally, or emotionally dangerous in their time; the Copernican and Darwinian revolutions are the most obvious. What is your dangerous idea? An idea you think about (not necessarily one you originated) that is dangerous not because it is assumed to be false, but because it might be true?[source]
The lengthy discussion at is worth exploring.

Though a sociological process that is beyond me to detail, the most dangerous topics become taboo as the inferred political implications of research findings move from merely unpleasant to unthinkable. Thankfully we live in a time where intellectual heresies are not punished with death (or house arrest), but there are still social and professional impediments to the investigation of taboo topics, mostly from the left within academia, but also from the right. I will return to taboo topics later.

Even granting the existence of a "Left's war on science", isn't the "Republican war on science" much worse?

I don't know, and I'm not sure how one would measure this. No mere compilation of anecdotes would be sufficient to decide that issue and so I will not build one here. As Razib has pointed out, the sample space is so large that all but the most thoughtful and careful answers to that question is bound to be marred by sample biasing. Similarly, Will Wilkinson has pointed out in a similar context that confirmation bias is a problem in attempting to answer this kind of question.

Instead, I argue that there is a strong analogy between the motivations and end results of each party's war on science, with results of a similar kind if not magnitude. The analogy is most obvious in the two-front attacks on Darwininism (from left and right). A lengthy quote from Pinker captures the problem:
Many people are sorry to "lose God" when they hear of these findings, or at least sorry to lose the values that have traditionally been associated with God. There has been a widespread fear and loathing of human nature, both from the left and from the right, for some reasons that are distinct and some that are overlapping.

From the academic left, there was a vehement, and sometimes violent, reaction to the people who first publicized these ideas in the 1970s, such as E. O. Wilson. An example is the manifesto called Against Sociobiology, written by Stephen Jay Gould and Richard Lewontin and published in the New York Review of Books, which said:

The reason for the survival of these recurrent determinist theories is that they consistently tend to provide a genetic justification of the status quo, and of existing privileges for certain groups according to class, race, or sex. These theories provided an important basis for the enactment of sterilization laws, and also for the eugenics policies which led to the establishment of gas chambers in Nazi Germany.

Because of such accusations, Wilson, was often picketed and assaulted when he spoke about these ideas in the 1970s and 1980s. One campus poster read, "Come and hear Edward O. Wilson, sociobiologist and the prophet of right-wing patriarchy. Bring noisemakers."

For all this, the right-wing patriarchy wasn’t so thrilled with these ideas either. There were also denunciations from the religious and cultural right, such as an essay by Andrew Ferguson in the Weekly Standard which said that "biological theories of the mind are sure to give you the creeps, because whether a behavior is moral, whether it signifies virtue, is a judgment that the new science, and materialism in general, cannot make." He contrasted it with the Judeo-Christian view, according to which "human beings are persons from the start, endowed with a soul, created by God, and infinitely precious. And this is the common understanding the new science means to undo." (This, I think, is the real motivation behind the movement to discredit Darwinism in the schools by teaching "Intelligent Design" as an alternative, rather than a concern to provide students with the best theory of where earthworms and mushrooms and oak trees came from.) Another example is Tom DeLay's theory of the cause of the Columbine High School shootings, who said that such outbursts are inevitable "because our school systems teach children that they are nothing but glorified apes, evolutionized out of some primordial soup of mud." And the US House Judiciary Committee heard the following testimony about the dangers of Darwinism from a representative of the Discovery Institute (the main force behind the revival of creationism). They were told about the pernicious effects of biological thinking in popular culture such as the lyrics to a rock song:

You and me, baby
Ain't nothing but mammals,
So let's do it like they do it
On The Discovery Channel.

Though these reactions seem extreme, they raise serious moral and political issues. Indeed, the brouhaha at my own institution (Harvard) last January shows that they are by no means a thing of the past. I think it's essential to look at the connection between the politics and the science with some care, and to ask why are there such emotional reactions, and how are they best addressed. [source]

What's the point of bringing this up? How does this relate to the Mooney-Sokal op-ed?

First, note that Mooney and Sokal call for a response from the community:
TO ADDRESS this new crisis over the relationship between science and politics, we propose a combination of political activism and institutional reform.
I would argue that anyone heeding this call is obliged to consider the issue of the academic left's treatment of science if for no other reason than intellectual honesty and openness. They should take the time to familiarize themselves with the controversy and should attempt to make a determination for themselves about the issues. This is the "consciousness raising" motivation for my post.

To further this appeal to reason, I'll quote from review of The Blank Slate in the journal Social Anarchism, which is a admirable display of intellectual openness (along the lines of Peter Singer's A Darwinian Left; credit):
In these first years of the new century anarchism, as a philosophy and as an ongoing praxis, is faced with a number of disconcerting adjustments. Chief among these is the growing evidence that we, along with most other ideologies on the Left, have based our theory on a mistaken concept of human nature. We have learned over the years to distrust words like sociobiology, evolutionary psychology, cognitive science, and above all that dreaded buzzword, "hard-wired" -- yet we can no longer ignore the fact that these sciences are probably right about human nature. It does exist; it has biological roots; and while it does enjoy a large measure of free will, its most basic drives and emotions are indeed hard-wired. The Left has long resisted and denied these facts, on the grounds that they might justify discrimination based on heredity, or that they militate against the possibility of radical social reform, or both. I hope to demonstrate that these fears are groundless.
If there's one good thing we have learned from modern science, going all the way back to Bacon and Galileo, it's this: you can't pick and choose your evidence to fit your preconceived opinion." [source]
Second, if those who heed the Mooney-Sokal call ignore these issues (e.g., remain ignorant of them), they will open themselves to counter-arguments that they are simply ideologically motivated themselves, and thus their specific arguments can be dismissed. I know of two relevant instances where similar arguments have been made; one is a response to The Republican War on Science. I quote them here to offer evidence that this kind of response is fresh on the mind of potential critics, not to suggest that the responses are themselves correct in their original context.

John Holbo:
Being pro-science is, on average, part of your self-conception if you are an 'enterpriser'. You are an optimistic believer in the power of technology and science to generate wealth and improve human life. This lot will look at Mooney's cover and feel personally slandered. 'How can I be part of a war on science? I think the X-Prize is great! I want science to make me live forever! I love my new digital camera! Liberals are the ones who are always refusing to look at the facts. Look what they did to poor Larry Summers because he tried to speak truth to power! They buried their heads in the sand when The Bell Curve came out! Whimpering about 'frankenfood'. Postmodern nonsense! [source]
Jonah Goldberg:
And that gets us to the heart of why this study is more bogus than a $6 dollar Rolex. Virtually all of the characteristics the authors attribute to the right can be equally laid at the feet of the left. If you think left-wingers have a high tolerance for ambiguity, tell one it's not clear that Head Start does any good at all. Talk to them about racial differences. Say: "Even if gay marriage were worth doing, there would be many devastating negative consequences." Mention that a factory closing can be a good thing. Tell them it's okay for economists to put a specific monetary value on a human life. Tell them intelligence tests measure intelligence. Tell them something can be simultaneously bad and constitutional. Indeed, don't get me started on the myopia of the left on constitutional questions; tell a campus liberal that Brown v. Board of Education had a good effect but was a terribly reasoned decision and they will look at you as if you'd said grobn gleebin grobbin grobin while standing on one foot. I've just watched my wife spend a year debating Title IX please don't tell me that feminists have a rich love of exchange and a gift for understanding nuance.[source]

I argue that it won't be sufficient to merely deny that there are problems on the left. This argument is too easily defeated, and it opens one's other arguments to suspicion. I suggest that the only way to address the issue of the "left's war" is to tackle it head on.

Taboo topics

Although it is a sad admission, I recognize that many academics are not prepared to separate their moral feelings about many taboo topics from their treatment of scientific research which addresses them. However, I argue it is essential to recognize that this is a failing, not a virtue; just as it is a failing, not a virtue, for politicians to ignore and misrepresent scientific findings for political ends regardless of their justification. Some may be tempted to argue that some "dangerous ideas" are legitimately dangerous and research on them should be proscribed. If these same people want to address the issues of Republican political interference with science, they will have explain why this is not a case of special pleading.

For example, I don't think it's obvious that fundamentalist Christian fears that Darwinism will lead to the death of morality and the collapse of civil society are less reasonable or strongly-believed than the fear that the discovery of a genetic or biological contribution to social inequalities will lead to death of empathy for the disadvantaged and the collapse of all progressive values. Parenthetically, I don't think either inference is warranted as I actually believe both antecedents to be true without finding myself compelled to endorse either consequent.

To make these issues concrete, I'll offer a partial listing of taboo research topics:
* sex differences in intelligence, personality, aptitudes, emotions, and interests (remember Larry Summers)
* homosexuality, especially its causes and consequences
* human reproductive cloning and human genetic enhancement
* racial and ethnic group differences in socially-valued traits like intelligence and social-disvalued traits like propensity to criminal behavior, especially their causes (e.g. the CHC hypothesis of Ashkenazi intelligence, Arthur Jensen's 1969 HER paper)
* the social value and impact, current and historical of religions
* native/tribal peoples, especially the nastiness of their societies, their impacts on their environment, and the causes of their conquest by Europeans (think Jared Diamond -- GGS and Collapse)
* intelligence differences between individuals, their causes, their impacts on social outcomes, and dysgenic trends (e.g., the real topic of The Bell Curve)
* rape and other aspects of human sexual behavior
* markets for adoption, egg "donation", human organs, etc.
* anything else related to race that isn't emotionally uplifting (e.g., biological contributions to health outcome disparities)

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The many faces of microRNAs   posted by rosko @ 2/12/2007 07:20:00 PM

First of all I would like to invite you all to come and check out my new blog, Science, Theory, and Liberty, at Unlike here at GNXP, my week of science is just starting, since I haven't had much of a chance to post to blogs lately. Since I won't have access to a computer from Wednesday evening through Saturday night, some of the posting may actually last into early next week. If some people would actually leave some comments on some of my posts, that would be nice.

Now to the content...

As the biological community has become more appreciative of the many roles played by non-coding RNA in the cell, there have been a few key types of RNA for which new functions are being discovered at a rapid pace. One of these is the class of microRNAs, which are short pieces of RNA that fold into stem-loop structures and which are known to regulate gene expression post-transcriptionally by targeting mRNAs.

I was first introduced to this class of RNAs when I worked for a semester on a project that was trying to characterize their mechanism of action. Since then, I have witnessed many discoveries regarding their effects, and I will briefly mention some of the latest ones here:

-Marshall et. al. report on how microRNAs encoded by the Kaposi sarcoma-associated herpesvirus are highly conserved, suggesting that they contribute to the pathogenicity of the virus.
-Linsley et. al. have found that one particular family of microRNAs appears to be involved in blocking cell cycle progression out of the G0 and G1 phases.
-Flynt et. al. discovered that a particular microRNA in zebrafish regulates genes in the well-known Hedgehog developmental signaling pathway, and is involvied in the differentiation of muscle cells
-Presutti et. al. review the types of non-coding RNAs, including microRNAs, present in neurons and some findings regarding their roles in growth and synaptic plasticity.
-In probably the most directly applicable of these studies, Lee et. al. identified a microRNA signature in pancreatic cancer cells.

Meet DARPP-32   posted by Matt McIntosh @ 2/12/2007 07:14:00 PM

DARPP-32 is a regulatory protein with a lot going on that should be of interest to GNXP readers. It act as a master switch in the brain which regulates the activity of a variety of ion pumps, ion channels, neurotransmitter receptors, neuromodulators and transcription factors. (Paul Greengard won a richly deserved Nobel prize for doing the most of the heavy lifting in understanding the many important brain functions it plays a role in.)

DARPP-32 is crucial in the formation and control of the information pathways that carry signals between the striatum and prefrontal cortex. This makes it extremely interesting for several reasons, first and foremost being that it plays a central role in working memory (probably influencing g), motivation, attention, and reward-based learning. Secondly, it appears to be at the nexus of the action of pretty much all classes of psychotropic drugs.

Of course something this important is going to cause a lot of havoc when it doesn't work right, and as you'd expect it's been implicated in a variety of disorders -- most recently to schizophrenia. (That list is getting mighty long.) There's long been speculations about the similarities between schizophrenia and psychomimimetics (hence the name), and DARPP-32 mediation seems to provide a concrete link between the two.

Another interesting thing is that the common allele for DARPP-32 which has been linked to schizophrenia is neither a necessary nor sufficient condition for exhibiting schizophrenic pathology. Schizophrenia has also been linked to Borna virus, which is also neither sufficient nor necessary for schizophrenia to manifest. So what's most likely going on here is that this allele has historically had some fitness advantage, probably due to a cognitive boost of some sort, but also makes the whole system it regulates more succeptible to damage by environmental insults such as pathogens that can hop the blood-brain barrier (of which Borna virus is one, but probably not the only one). It's a good illustration of just how complex medical aetiology can get, and of course as Greg Cochran & Paul Ewald will tell you there are probably a lot of other unusual conditions that follow similar causal lines.

Is Barack black?   posted by p-ter @ 2/12/2007 04:57:00 PM

I've mentioned before that the concept of race has both a biological and social component. Now, a case study: Barack Obama. In this clip, one Debra Dickerson makes the case that Senator Obama is not "black". What to call him instead? She suggests "African African-American", while personally I prefer Mr. Colbert's suggestion: nouveau black. Trop chic !

Based on what we know about Obama's heritage--a Kenyan father and a white American mother--it's doubtful that any genotypic information would place him in a well-defined cluster (like those in this analysis). First, there's the 50-50 European/African admixture. Though estimates of the amount of European admixture in African-American populations vary by geography (in New Orleans, this estimate is about 22%, while in Charlston, SC, it's about 12% [cite]), 50% is a bit above average.

Further, there's the fact that his father is East African, while most African-Americans (as Dickerson points out) are descended from West Africans. As allele frequencies vary within Africa, this would add a further complication to any attempt at clustering. So Obama does, indeed, lie at the fuzzy intersection between African and European, at least from a genetic standpoint. From a social standpoint, I had assumed he would just be called "black", but perhaps the ultimate arbiters of "blackness" are waiting for some concessions on his part before they give him their approval.

In any case, if he's going to get his own label, "nouveau black" is as good as any; who knows, perhaps it'll catch on.

Zoobilee Zoo   posted by Razib @ 2/12/2007 06:18:00 AM

After the seriousness of A Week of Science, I thought I'd bring a little disturbing levity to the blog....

Biology a la Freakonomics: freakology?   posted by p-ter @ 2/12/2007 04:36:00 AM

A review of Survival of the Sickest, by Sharon Moalem with Jonathan Prince

I've often remarked that the field of human genetics is a veritable gold mine for dinner party anecdotes. The material is so rich--superhuman street performers, ear wax, micropenis--you just can't go wrong. Of course, these stories, while sometimes amusing, are insprired by research into serious questions; in the proper hands, genetic data give revolutionary insight into why we are the way we are, how we got here, and where we're going.

It's in this spirit of both clever storytelling and serious inquiry that Sharon Moalem writes Survival of the Sickest, a book grounded in what has come to be called "evolutionary medicine". While the focus of medicine is traditionally on proximate causes of disease (altered metabolic pathways, non-functioning receptors, and the like), Moalem, like the original populizers of the subject Robert Neese and George Williams, wants to find their ultimate causes (the evolutionary forces allowing for the existence of disease). His treatment of the subject here is clearly targeted at the layman, though there is a references section for those who care to dig into the primary literature themselves.

Most of the chapters are centered around the population genetics of a disease. This is fascinating material, and Moalem (along with his co-author) does a wonderful job presenting it. Each chapter starts with an observation--a high prevalance of Type I diabetes in Europeans, the frequency of a genetic disease called hemochromatosis, or the geographic distribution of favism, for example--which sets the stage for a series of anecdotes that eventually leads the reader to his evolutionary hypothesis (for the examples given, these hypotheses are adaptation to cold and resistance to the plague and malaria, repectively). Some of these anecdotes are worth the price of the book alone (though, it must be noted, I didn't pay for my copy, so I suppose I can't judge)--there's an investigation of the biology of a toad that allows itself to freeze solid each winter that is particularly remarkable, and the section on host manipulation by parasites would make Carl Zimmer proud. A large number of human traits are touched on from this perspective--apart from the ones mentioned above, traits like skin color, alcoholism, taste, and even skull shape get mentions[1].

While these chapters are the highlight of the book, an alert reader may notice a couple hints that perhaps the science isn't definitive on some of these stories: first, the oft-added qualifier that a given theory (for example, that the high rate of hypertension in African-Americans is due to selection for salt retention on slave boats) is "controversial", and second, that there are a number of theories for some of the observations. The prevalence of diabetes, for instance, is attributed to metabolic systems unaccustomed to carbohydrate-rich diets (pg. 26), a selective sweep for better cold response during the Younger Dryas (pg. 46), and transgenerational epigentic effects, the so-called "thrifty phenotype" hypothesis (pg. 166). These possibilities are not mutually exclusive, but a reconciliation of all of them would certainly have been desirable.

But overall, Moalem gives a striking demonstration of the power of evolutionary hypotheses to discover new apects of our biology (as long as one keeps in mind that sometimes those hypotheses turn out to be dead wrong). On straying from the basic population genetic framework, he becomes a little hyperbolic[2], but as an advertisement for the use of evolutionary information in understanding disease, Survival of the Sickest is a resounding success. Altering Theodosius Dobzhansky's famous dictum has become almost cliche, but I'll do it anyways: this book is a convincing argument that nothing in medicine makes sense except in the light of evolution.

[1] Moalem gives a cursory look at the concept of "race" with regard to these traits, but essentially chooses not to discuss it, preferring to cite a Nature Genetics editorial from 2001 as saying that "population clusters identified by genotype analysis seem to more informative than those identified by skin color or self-declaration of race". Regular readers know that much has changed since 2001; in particular, there doesn't seem to be much of a distinction between genetic clusters and clusters based on self-declaration of race [Tang et al. 2005].

[2] The chapter on "jumping genes" is particularly filled with perplexing claims about the nature of evolution. On noting that some "knockout" mice--mice in which a gene has been disabled--show no observable defect (as an aside, the mouse geneticists I know tend to be skeptical of such reports--is it really possible to rule out any effect? How many possible phenotypes were tested?), Moalem writes, "If removing whole genes often has no effect on a creature, how could such minor changes be the only chance for the evolution of a new species, or even the successful adaptation of a new one? They probably can't". After several chapters on the evolution of humans by "minor" changes (much variation in skin color is controlled by a single base pair change, lactose tolerance as well), this statement is particular puzzling. His point is that retrotransposons are perhaps mobilized by stress and can get into the germ line, which is true enough; retrotransposon insertion can serve as a source of variation. But I wouldn't stop studying "minor changes" like SNPs or copy number variants any time soon. And the suggestion that retrotransposons are responsible for observations of "puncuated equilibria" in the fossil record is perplexing as well; it seems Moalem felt he needed to mention the theory of punctuated equilibrium, and hell, the section on jumping genes was as good as any.

Dutch Height, Again   posted by DavidB @ 2/12/2007 02:18:00 AM

GNXP has carried several previous posts about the long-term increase in adult heights, for example my post here. Average height is said to have increased by several inches over the last century in most Western countries (and in post-war Japan and Korea), but the increase has been less in the USA, which started at a higher level, than in Europe. Some European countries have now overtaken the US, and the Western world's tallest people are now the Dutch.

There is apparently a new study confirming this trend, and analysing the reasons: see this report from the London Times. It may be worth mentioning a letter to the Times following this report, from one Philip Lawford, which attributed the increase in the Netherlands to the very high consumption of dairy products there, from cattle fed on growth-enhancing additives.

I doubt that this is the main reason, as the long-term trend started before the agricultural use of growth hormones, but it is worth considering as a possible marginal factor.


Sunday, February 11, 2007

Horizontal g   posted by Alex B. @ 2/11/2007 01:54:00 AM

Wherever the abilities involved are sufficiently distinct--and that is in the great majority of cases--our tetrad equation is satisfied with surprising exactitude, so that here each ability must be divisible into g and s. The letter g becomes, in this manner, a name for the factor--whatever it may be--that is common to mental tests of such a description. This is the very definition of g. (Spearman, 2005, p. 161)

General intelligence (g) has been one of the most, if not the most, aggressively studied constructs in psychology. Type the search string "general intelligence" in PsycInfo and you will return over 2000 entries, and a similar search in Pubmed pulls up over 400. If you broaden the term to just "intelligence", the respective number of entries are 65405 and 37166. While not all of the results focus on g , (e.g., AI, "social intelligence"), a large portion of them do, and the prospect of meandering your way through can be intimidating. Fortunately, the overall literature is consistent and, at least for me, highly engaging.

The study of g can be bifurcated into two distinct areas: vertical and horizontal g . Vertical g is the domain that studies g's biological relationships. It is the area that is going to eventually assimilate enough data and literature to elucidate, unquestionably, the causal mechanisms of g . From this field of study, we know that g is correlated with a variety of neural mechanisms, such at glucose metabolism (Haier, 2003), cortical development (Shaw et al., 2006), and biochemical activity (Jung et al., 2005). We know that g is highly heritable, both when measured psychometrically (Plomin & Spinath, 2002) or chronometrically (Beaujean, 2005). We know that g decreases with inbreeding (Jensen, 1983) and increases with hybrid vigor (Nagoshi & Johnson, 1986). As genome scanning becomingmore popular, we are now even beginning to see some specific genes that are implicated g.

As interesting as vertical g is, however, this entry is going to instead focus in the horizontal aspects of g . That is, how does g play out into "everyday life." Specifically, we will look three different, although related, areas: education, occupation, and general life outcomes. The reasons for doing so are twofold: (a) the more the science of horizontal g is positively promulgated, then, perhaps, the more likely people are to support the needed research into vertical g and (b) even though this area of research has been around for over a century (e.g., Galton, 1869), there are still new, important findings.

Before delving into horizontal g, however, it would behoove us to delineate a mechanism by which g could influence education, occupation, and general life outcomes.For our purposes, that mechanism is information processing. Generally defined, information processing is the pathway and mechanisms by which stimuli are perceived, attended to, retrieved, and/or used to solve problems and/or cope with exigencies in the environment (Jensen, 1998a). The cognitive psychology literature is chalked full of the nuances of the various information-processing theorists, the specifics are which cannot be delineated here (an easy-to-read intro: Ormrod, 2004). Yet, within all these theories lies the idea that people respond to stimuli in a way that involves many mechanisms (e.g., sensory register, primary memory)and a variety of neurological regions (e.g., hippocampus, amygdala, mammillary bodies). The consequence? There is ample room for individual differences in the speed and efficiency in which information is processed.

From another perspective (e.g., Kline, 1998), information is processed in irreducibly small pieces (often called bits) and the time it takes to process those bits is the BIP, the Basic period of Information Processing. Now, the time it takes Johnny to process the fact that the only integer between 2 and 4 is 3 is going to be different than the time it takes Jane. Multiply those differences by the number of people processing the fact, and voila! individual differences.

Educational Outcomes

This is probably the area most replete with data and, unsurprisingly, the g-educational achievement relationship is strong. In fact, although it differs by grade level (with it decreasing as grade level increases), most of the non-random variance in scholastic performance is accounted for by g (Thorndike, 1984). Jensen (1989, 1998b) writes that this is so due to the fact that "school learning" is, itself, quite g -loaded. Of course, there are those who write that g is just a product of education (e.g., Ceci, 1991; for a review of others, see Gottfredson, 1986), or, perhaps more egregious, that g and educational achievement are just products of the tests designed to measure them (for review and rebuttal, see Jensen, 1984). But these arguments quickly dissipate when looking at the evidence.

For example, in the latest issue of Intelligence, there were two longitudinal studies (Deary, Strand, Smith, & Fernandes, 2007; Watkins, Lei, & Canivez, 2007) that showed a strong IQ --> Educational Achievement relationship (approx. 70 from Deary), but reverse (i.e., EA --> IQ) was not there (from the Watkins study). Further evidence comes from the two major "We can improve you Education by improving your IQ" projects: Head Start and the Abecedarian Study. With regard to the former, Head Start just does not produce long-term IQ gains and, hence, does not produce long-term academic gains (Caruso, Taylor, & Detterman, 1982; Holden, 1990; Kreisman, 2003). With regard to the latter, while there has been acrimonious debate, the overall conclusion is that, like Head Start, the initial IQ gains do not last, giving even more evidence that educational achievement cannot be raised independently of g (Spitz, 1986, 1992, 1993b, 1993a).

Yet another line for arguing against the prominence of g in education is the idea that there are other traits that are just as necessary for academic success, such as motivation, personality, etc. To risk sounding like to broken record, the data shows that these traits are not nearly as potent predictors as g in predicting academic outcomes. For example, Gagne and St. Pere (2002) gives us reason to believe that motivation might just be an impotent variable in predicting academic achievement. Likewise, Laidra, Pullmann, and Allik (2007) have shown that while personality factors contribute some to the variance in educational achievement, they are dwarfed in comparison to the contribution of g.

Occupational Outcomes

There are many theories as to how g and occupational outcomes relate (see Gottfredson, 1986), but the one that is most supported by data is best explicated by Frank Schmidt and John Hunter

[g] predicts both the occupational level attained by individual and their performance within their chosen occupation. [g] correlates above .50 with later occupational level, performance in job training programs, and performance on the job. Relationships this large are rare in psychological literature and are considered "large" . . . weighted combinations of specific aptitudes (e.g., verbal, spatial, or quantitative aptitude) tailored to individual jobs do not predict job performance better than [g] measures alone, thus disconfirming the specific aptitude theory. It has been proposed that job experience is a better predictor of job performance than [g], but the research findings . . . support the opposite conclusion. . . . Nearly 100 years ago Spearman (1904) proposed that the construct of [g] is central to human affairs. The research . . . supports his proposal in the world of work, an area of life critical to individuals, organizations, and the economy as a whole.(Schmidt & Hunter, 2004, p.171; cf.Schmidt & Hunter, 1998)

One could argue that, given the high g -education relationship, that the g-occupation relationship is just a natural outgrowth.That is, once education is controlled, the g-occupation relationship significantly shrinks. But to make that argument, one would have to have a Sternberg-like approach to intelligence (Sternberg & Wagner, 1993). That is, that the cognitive skills needed for a successful education are somehow vastly different than those needed for everyday life. The data, however, indicate that the same generative process that tends to makes one successful in the educational arena is also the mechanism that tends to make one successful in the occupational arena: g (Kuncel, Hezlett, & Ones, 2004). This is not to say that other things are not important in occupational or educational outcomes; but, as with education, they are not nearly as potent predictors (Gottfredson, 2002).

Life Outcomes

Over the last decade or so, an area that has become of more interest to the intelligence community is the influence of g on general life outcomes. That is, beyond educational and occupational outcomes, does g contribute to life success? The answer here, too, seems to be a resounding yes.

IQ scores [a proxy for g] predict a wider range of important social outcomes and they correlate with more personal attributes than perhaps any other psychological trait. The ubiquity and often-considerable size of g's correlations across life's various domains suggest g truly is important in negotiating the corridors of daily life. (Gottfredson, 2003, p. 326)

But how does g relate to general life outcomes? Believe it or not, it appears that the same information-processing mechanisms that are so potent for educational and occupational outcomes also play a role in day-to-day life (Gottfredson & Deary, 2004). Gottfredson (2003, 2004b) elaborates this mechanism as follows: Life is is made up of many tasks with a wide array of complexity (Gordon, 1997). In the US and most Western nations, society is "free enough" for competence (read: g ) to make a substantial difference in who succeeds in life. As those who have "higher g" are more able to tackle the day-to-day activities of life successfully with less exerted effort, they are able to progress in life with fewer impediments (e.g., untreated illness, accidents; Gottfredson, 2004a), thus allowing them to (a) have more resources to successfully compete and (b) be able to use their resources more efficiently. This then not only allows for a higher probability of achieving satisfying life outcomes (e.g., adequate income, occupational autonomy), but also allows for a lower probability of being involved with unsatisfying life outcomes (e.g., having children without means to support them, crime/delinquency) (cf. Ellis & Walsh, 2003; Herrnstein & Murray, 1996)


Given the ubiquity of g in fostering success in many life outcomes from education achievement to occupational success, from health outcomes to criminal recidivism, social science in general and psychological science in particular would be remiss to "pretend it doesn't matter" (Gottfredson, 2000). Rather, if these fields want to strengthen their scientific integrity and acumen, they should do exact opposite. That is, bring the large, cumulative database on g and its influence on life outcomes to the forefront of a wide array of research agendas so that this corpus of data can serve as the strong underlying foundation of a generation of new investigations on g's life implications. While this line of investigation may never get to the underlying (vertical) mechanisms by which g operates, it can help foster the acceptance of doing such research and pave the way for its societal implications, whatever they may be.


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Friday, February 09, 2007

Transgenic methods in mice   posted by amnestic @ 2/09/2007 08:44:00 AM

The use of transgenic mice in all areas of mammalian biology is now routine. We have transgenic mice that get breast cancer, have no immune system, and have every possible molecular defect associated with Alzheimer's Disease. We even have Laurel and Hardy mice. Of course, my favorites are the memory mutants. There are mice that lack NMDA receptors only in the CA3 region of the hippocampus who can perform a memory task just fine as long as all the cues are there but can't figure it out if they have to fill in any of the blanks. There's the CaMKII-3'UTR mutant mouse that has an intact protein but lacks a dendritic targeting signal in the mRNA. There is the Doogie mouse which has adult expression of a subunit of the NMDA receptor (NR2B) that is predominantly found in juveniles. The adult NR2B expression was restricted to the forebrain using a now-familiar transgenic trick wherein the transgene is put under control of another gene's regulatory sequences. The Doogie mouse performs better than normal, wild-type mice on certain memory tasks. You can't always make a better mouse by turning up the proteins involved in synaptic plasticity though. For instance, overexpressing a hyperactive version of CamKII in the entorhinal cortex impairs spatial learning. Some of the first refinements of transgenic techniques were performed in the service of memory research. Memory is one of the few areas where you really need to be able to turn a gene off and then on again or vice versa. This is because memory can be divided into stages such as acquisition, consolidation, and retrieval, and if you're transgenic manipulation were permanent you couldn't distinguish an effect on one stage from another.

The tools for transgenic manipulation are slowly and steadily improving. It seems to be an incremental, heuristics-driven progress. Nudging an enhancer element over a few nucleotides ore switching out an amino acid in a fusion protein increases specificity or efficacy some X amount, so everyone starts doing it that way. Methods to target ever-more-specific cell populations in the brain and to increase temporal control over transgene expression are in constant development. Also, the list of proteins that you might want to express in a mouse brain is increasing to include fluorescent indicators of just about anything and functional proteins that can turn neural activity up and down. There are a number of good overviews with illustrations around to give you the basics. I will hit the most salient features here and discuss some recent improvements.

The most basic way of producing a transgenic mouse is to make a DNA fragment carrying the gene you want to express and inject it into a fertilized mouse egg. The endogenous DNA repair machinery detects this broken chunk and 'fixes' it by sticking it in a chromosome. This egg is then implanted in a 'pseudo-pregnant' mouse, and if it develops properly you get baby mouse whose every cell carries your inserted DNA. There are problems with this approach even though it fairly popular, and they mainly stem from the fact that the DNA inserts randomly. Your construct could, for instance, get inserted in the middle of some important gene and disrupt its function or get inserted into a 'silenced' part of the genome (think epigenetics). Luckily, there are two types of DNA repair mechanism and the second one, homologous recombination, is not so random. Homologous recombination occurs during meiosis when the 'crossing over' occurs and chromosomes from either parent trade information. It is also utilized when one double stranded chromosome breaks. The machinery uses the other chromosome as a template to write in the missing letters. The trick with homologous recombination based transgenesis is to hijack the machinery and make it use your DNA fragment as the template. Since the machinery requires some degree of homology between the sequence of the template and the broken sequence you just need to put some homologous sequences on either side of the chunk of DNA you care to stick in the middle of the gene you are targeting. You can imagine that the conditions for all of this to go down properly are fairly rare. You would have to inject like a gajillion eggs. Instead of doing that, researchers turned to selection. They sucked some embryonic stem cells out of a mouse blastocyst and cultured them. If you put a neomycin (an antibiotic kills ES cells too) resistance gene in your DNA construct along with your other transgene, you can grow the cells on plates with neomycin, and only cells that have taken up the transgenic DNA will survive. This isn't perfect though because the DNA could've been inserted randomly and we want homologous recombination (HR). So a second level of selection is necessary. One difference between HR and the random insertion is that the whole construct gets inserted in the latter, whereas in HR the 'tails' of the construct are removed. So you simply make a construct that looks like this: TK---Neomycin resistance---Gene of interest---TK. TK is an enzyme that produces deadly results in the presence of certain chemicals. So cells have to have neomycin resistance but lack TK to be selected. You can now grow up a population of very special cells enriched for just the genetic modification you wanted, inject some of those into a mouse blastocyst, and get chimeric babies that have your modification in some portion of their adult cells. You pray that one of your injected ES cells grows up to be a sperm or an egg (germline transmission) and breed your mice accordingly.

Now we can make transgenic mice, but we don't have much control over where and when the gene is expressed. The simplest way to achieve more spatial control over a transgene is to attach tissue-specific DNA control sequences before the mRNA coding part. A popular tactic among memory researchers is to use the promoter/enhancer sequences from calcium/calmodulin-dependent kinase II (CaMKII) to drive expression of whatever gene they are interested in. Expression under control of the CaMKII promoter tends toward to the forebrain, so you can manipulate a gene like a ubiquitous neurotransmitter receptor without screwing up its function in, say, the spinal cord. The more we know about the function of transcription factors and DNA enhancer elements, the greater tissue-specificity we have. It is a major advance to be able to disrupt the function of a subpopulation of inhibitory interneurons in a subregion of the neocortex rather than performing experimental lesions with an electrode or a toxin. Transgenic mouse producing companies (of which Jackson Labs is probably the best-known) offer a whole array of mice with a gene called Cre recombinase under control of different tissue-specific promoters. I don't want to go into the details of Cre recombinase. You can basically make the DNA construct carrying your favorite gene with an interrupting sequence so it is silent, and then insert it into a mouse genome. When this mouse is crossed with a tissue-specific Cre recombinase mouse, Cre will turn on the gene of interest only in the cells where it is being expressed.

Tissue-specific promoters allow some spatial and temporal control over transgene expression. For instance, if you use the promoter from a gene that is usually expressed only in adults, you can generally avoid developmental effects of your inserted gene. This degree of temporal control isn't very fine-grained though. This is where the inducible transgenic mice become important. The oldest and still the most popular systems for inducible transgene expression are the Tet-On and Tet-Off systems. The Tet Off system came first, but it is confusing and inconvenient because you use have to constantly feed the mice a drug to keep your transgene off and then release it from repression by not giving them the drug anymore. The Tet On system is much easier to talk about. You need two constructs in this system. One carries the gene for a man-made fusion protein called the reverse Tet Transactivator (rtTA); the other carries the transgene you need to express under the control of a tet operator (tetO) regulation sequence. The rtTA will be made all the time, but since the tetO is a bacterial regulatory sequence, mice shouldn't express the transgene under normal conditions. Here comes the inducible part: if you feed the mice doxycycline (a tetracycline analog that works better for some reason), it binds and activates the rtTA. Activated rtTA can bind to the tet operator sequences and turn on expression of the tetO - gene of interest. Got it? Google tet off or tet on, there are lots of biotech companies who want to sell you their system and are willing to explain it with pretty diagrams. Here's an example of two constructs you might make: 1) CaMKII Promoter - rtTA; 2) tetO - green fluorescent protein (GFP). This set would produce rtTA only in the forebrain. If you wanted to make the forebrain glow, you could feed mice doxycycline and wait a couple days. Oh, and you can quit with the doxycycline and the GFP should turn back off.

Everyone is, of course, very happy about being able to turn gene's on and off at will in mouse brains. The rtTA system isn't perfect yet though. It has problems with leakiness. That gene that is only supposed to be on when you add doxycycline is still on at some baseline level. There have been numerous attempts to tinker with the system through the years to increase the difference between baseline and induced expression. A recent paper by Shaikh and Nicholson attempted some improvements so they turn on their favorite gene, receptor for advanced glycation end products (RAGE). I love the idea of inducing RAGE (it would definitely be better than inducing Audioslave). In most cases, people use a cluster of tet operators to get good induction. One parameter that Shaikh and Nicholson tweaked was the spacing of these operator sequences. In the system they used (called TREtight), the tet operators were packed in really close to each other. They used a tissue-specific promoter to drive rtTA expression. In this case, they used the neuronal specific enolase (NSE) promoter to express rtTA in any and all neurons. They also went against a recent trend by inserting the rtTA gene and the RAGE gene in two separate constructs instead of placing the two genes in one big chunk of DNA and injecting the whole thing. I should mention that all this refinement work is happening in cell culture, not in trangenic mice. They managed to get 142-fold induction of RAGE upon exposure of the cells to doxycycline. Not bad. They found something that works for their purposes, but this is also sort of representative of a problem with progress in the field. I can't tell from the paper what is the factor that mattered and whether that factor would be generally helpful to apply in any further manipulations I want to do. People find something that works for them, but there aren't a lot of papers comparing different 'optimal' systems. Beyond changing the nature of the DNA constructs and enhancers, there are also people tinkering with the amino acid sequence of the rtTA protein to perhaps make it more responsive or have different induction properties. For instance, one technique has been to use a version of Tet Transactivotor (TransSilencer) that actually silences tetO-controlled genes in the absence of doxycycline in conjunction with the rtTA. Now the trans-silencer is active in baseline conditions and turns down leakiness, but when you add doxycycline it both de-activates the trans-silencer and activates the trans-activator. There are also other inducible systems wherein the estrogen receptor (which can activate gene expression) has been mutated such that it is induced by tamoxifen.

One other area that isn't necessarily specific to transgenic issues is the production of new types of proteins worth expressing. Sometimes you want to do more than just make your cells glow. Miyoshi and Fishell have produced a table of interesting proteins worth expressing in neurons. They include proteins that glow only during synaptic transmission or during calcium influx, proteins that cross synapses and identify cell connectivity (tracers), and functional proteins that can affect neuronal physiology when expressed. As an example of a functional protein that you might want to express, there is a synaptobrevin fusion protein developed by Alla Karpova and Karel Svoboda that shuts down synaptic transmission in the cells in which it is expressed. You could use inducible expression of this protein to really dissect the contribution of a given neuronal population. If any of you protein-refiners are out there listening, might I suggest what I think would be ideal? I don't understand yet how you can make versions of GFP that are sensitive to calcium, pH, and voltage, but if its not too much to ask, why don't you just make an rtTA that is sensitive to these things? I'm dreaming of a transgenic mouse with, for instance, voltage-sensitive rtTA and a tet-controlled GFP. You could insert little tiny electrodes into this mouse's hippocampus and stimulate gene expression with minimal invasiveness but presumably greater temporal control than doxycycline going through the digestive system.

I have a couple mad scientist experiments dreamed up involving all of these inducible systems, but I think they would require making transgenic mice that carry 6 different constructs. The basic idea is to mark cells that were active during memory encoding by causing them to express rtTA. Then I could turn on any gene that I wanted just in the cells for a certain memory. Perhaps I could even reactivate the cells if I turned on the right gene (say a leaky calcium channel that greatly increased cell excitability). Would this reactivation cause the mice to perceive recollection of that particular memory? It just might and that could be used to achieve 'Marilyn Monroe' experiment in which you make a mouse remember something that never happened. I'll let you think on it for a while and post how I think it could be done next week.

Thursday, February 08, 2007

When is a synonymous sequence not synonymous?   posted by rosko @ 2/08/2007 06:28:00 PM

...when it specifies a different fold! At least that's the latest word from Kimchi-Sarfaty et. al., who reported in the Jan 26 issue of Science that a supposedly "silent" mutation in the multidrug resistance gene MDR1 changes the function of the encoded protein. If the authors' conclusions are correct, this result could radically expand the number of gene variants that have the potential to influence phenotypes, and that's why I chose to post this one on GNXP. To understand the meaning of this, you have to know something about the genetic code and the subject of protein folding.

As I'm sure most of you know, the amino acid sequence of a protein is specified precisely by the sequence of bases in the DNA of its gene. Each amino acid is specified by three consecutive bases, and since there four possible bases, there are 4^3=64 possible base triples (called codons). Considering that there are 20 amino acids found in proteins, and three codons that act as stop signs, that means there are on average three codons per amino acid. These duplicate codons often differ by a single base, which means that many point mutations even within the coding region of a gene will not alter the protein sequence. Different organisms have clear preferences for what codons they use to specify each amino acid, and while any known life form can recognize them all, the preferred ones are read a little faster (the mechanism for this involves the abundance of the tRNAs that actually do the recognition, though that doesn't matter for our discussion). It is a piece of cake to determine whether any two variations on a common gene sequence, for example, one from a healthy person and another from someone with a disease, will encode the same exact protein. Ones that do are routinely dismissed as being "silent", i.e. unable to cause a new phenotype, except in cases where the change is in a regulatory region that controls expression of the gene, splicing, etc.

That brings us to the question of protein folding. It is generally accepted that a protein's function is intimately related to the three-dimensional shape into which it folds, and that this shape is determined by the sequence of amino acids from which it is made up. Therefore, researchers have assumed (and typically rightfully so) that no matter how you make a given sequence of amino acids, under typical cellular conditions it will fold up into its proper shape and start functioning. The prevailing view also holds that the correct three-dimensional shape is formed because that one has the overall lowest (free) energy of any possible shape.

This energetic criterion cannot be the whole story, because a quick calculation (see Levinthal's Paradox) shows that a protein could never "visit" all possible shapes in any reasonable amount of time. Therefore, most people studying protein folding believe that protein sequences are optimized not only to dictate the correct fold but to specify a "roadmap" of how to get there, by setting up fast initial interactions among the atoms that "push" the folding in the right direction. However, there has been no good evidence that the final state isn't a unique energy minimum, regardless of how complex the journey to get there.

Kimchi-Sarfaty et. al. looked at a transmembrane pump called P-glycoprotein (P-gp) that is well-known in the cancer research community for being something that cancer cells turn on to expel the kind of toxic drugs we throw at them. P-gp tends to grab large, greasy molecules, without regard to their precise structure, and use ATP to power their expulsion from the cell, thereby allowing the cell to evade their effects. Several variants of the MDR1 gene, which encodes P-gp, can be seen to specify the exact same sequence of amino acids, except that one of these is encoded by a slightly different set of three bases in each variant. However, the change converts a codon that is common in mammalian cells to one that is rarer, and as mentioned above, the rarer one would be expected to create a slight pause at that point in the synthesis of the protein.

The very surprising result is that the proteins produced from the different variants show a bunch of functional differences, including the affinity with which they bind several drugs, even though they are expressed at the same level and their amino acid sequences were verified to be identical. The authors conclude that the pause induced by the rare codon causes the protein folding (which starts long before the protein is finished) to follow a different pathway. This implies that the rate at which a protein is allowed to fold, and not just the set of final states, is crucial for determining the final shape. For the geneticist, the take-home message here is that a change in a coding sequence should not be dismissed as a possible cause of a phenotypic trait just because it doesn't alter the protein sequence.

Seasonality of preterm births: A life history view   posted by agnostic @ 2/08/2007 03:09:00 AM

At his personal website, our co-blogger Matt recently posted on a conference presentation by Bodnar, Simhan, and colleagues -- details here -- which shows a seasonal pattern of preterm births in the US. Simhan suggests that this new study is the most rigorous such study in an industrialized country, but there have been several other such studies. Lee et al. (2006) review the literature on preterm birth seasonality in the developing and developed countries, and present a new study of their own that examined the London-area population (N=482,765). In any event, is there something adaptive about this pattern, as Matt asks? I think so, and the answer comes from life history theory (Roff 2002 provides an overview of the field, while Roff 2007 discusses how genomics can illuminate life history investigations). In brief, it is possible to view preterm birth as a facultative "desertion" strategy that mothers use when they perceive environmental cues that signal rough times ahead for their infant offspring.

But before developing an explanation, let's first review the relevant evidence. From the Lee et al. (2006, p.1282) summary on the developed countries:

Using secondary data analysis, two developed countries reported similar preterm birth seasonality.[14,21,22] In the USA and Japan, the pattern was annual, with the highest proportions and risk occurring twice a year: once in summer and again in winter. The lowest risk was observed in spring and autumn.

One study from the USA reported no seasonality of preterm birth.[23] This study compared preterm birth rates from May to October with those from November to April for 1983-85 in a northern Californian population and found no difference in spontaneous preterm birth proportions.

Add to that the new study by Bodnar, Simhan, and colleagues on the most risky season being Winter (though not Summer as well). Add also the novel study in Lee et al. (2006), which also found that preterm births were more likely among Winter (but not Summer) births in the London area. As for the developing countries (same page as above):

In the developing countries, all three studies that were located reported a seasonality of preterm birth using their own definitions of seasons. In Bangladesh,[24] the lowest proportion of preterm births occurred during winter (3.6%), followed by summer (5.5%) and monsoon (6.0%) season. The highest proportion of preterm births was observed in autumn (8.3%).

In Gambia, two seasons were reported.[13] Preterm birth proportions were found to peak twice a year: once at the beginning of the hungry season in July and again towards the end of the hungry season in October.

Harare, Zimbabwe, was reported to experience four seasons.[25] Births in the early dry season were three times more likely to be preterm compared with those during the late rainy season (OR 2.9, 95% CI 1.65-5.2). No other seasonal differences in the risk of preterm birth between seasons were found.

The common denominator appears to be that when environmental quality predictably becomes much worse, preterm births become more common. In the developed world, we know that Winter is the flu season when infection is more likely. Studies of seasonality of disease in Bangladesh suggest that the low-point for preterm births in Bangladesh occurs with the low-point for nasty infectious diseases such as malaria (Rahman et al. 2006; free text), cholera (Alam et al. 2006; free text), and diarrhea (see the abstract of this study), all of which reach their nadir in Winter. Each of these diseases peaks in various non-Winter seasons, but both malaria and cholera appear to peak in Autumn just like preterm births. As for variable environmental quality in Gambia, the name of "the hungry season" speaks for itself.

Why might something like an infection cause the mother to deliver a preterm baby? Consider that if the mother is infected, it's also likely that the fetus will become infected as well, either in the womb, on the way through the birth canal, or what have you. An offspring that has been parasitized before even being born is clearly of lower quality, so perhaps once the mother's body recognizes it has been parasitized, it decides to in effect abandon the child -- since delivering it preterm, in the absence of superior medical care, is tantamount to aborting it -- and start over again. Note that humans are capable of mating, conceiving, and giving birth to offspring year-round, so the benefit from a mother cutting her losses and beginning anew would not be outweighed by a large cost. Assume a mother in the developed countries essentially aborts the child in Winter; if she mates right away, she can deliver another child by the coming Autumn, before the worst period of risk of infection sets in. Alternatively, she could wait just 6 months, mate in Summer, and deliver a child by the following Spring after the worst period of risk of infection had passed.

Hunter-gatherers tend to space their births four years apart because their way of life cannot sustain a family of, say, 10 offspring. Even among most agricultural populations during most of human history, you figure 4 or 5 offspring would have been on the high-end of average -- thus, forgoing child-rearing by waiting just 6 months is not going to impinge much on the mother's lifetime fecundity, and will certainly boost the fitnesses of the surviving offspring with respect to coping with pathogens. So, making the switch to desertion of her offspring will not likely incur substantial costs, which in any case would likely be outweighed by the benefit of having non-parasitized offspring.

But is there any independent evidence that this sort of thing happens? For birds, at least, the answer is "yes." Roff (2002) cites a study by Oppliger et al. (1994) which demonstrated that great tit mothers were more likely to desert their nest if it had been infested by an ectoparasite (the hen flea). Something similar occurs among bird species subject to brood parasitism, whereby the mother of another species places her own egg(s) in the nest of the host bird species, which clearly imposes costs on the latter since she expends energy and resources in raising an unrelated offspring. A review by Hosoi & Rothstein (2000) shows that species that have spent longer evolutionary periods of time with the parasitic cowbirds are more likely to desert their nest after being exposed to a particular cue of parasitism than are those who have been more recently troubled by the cowbirds' ways. There are some important details that are, however, irrelevant to the discussion of human desertion: for example, it seems that the host bird mothers pay more attention to the presence of cowbird mothers nearby, rather than discriminate between "self" eggs and "other" eggs. The point is simply that nest desertion shows signs of being an adaptive response to parasitism. Also, one strategy available to birds is to eject the "other" egg from their nest, but humans cannot so easily purge their body of pathogens.

So, does the seasonality of human preterm births permit an adaptive explanation? The evidence could certainly be stronger, but based on a consideration of the predictable seasonal patterns in environmental quality, the trade-offs involved in "deserting" an infant by delivering it preterm, and evidence from other animals such as birds subject to various types of parasitism, the hypothesis seems on the right track, at least sufficiently so that future studies should incorporate more of a life history perspective. For example, Pike's (2005) discussion of life history and preterm births shows how such theoretical approaches can clear up confusion in the field of medicine, in which evolution tends not to occupy a central role.


Alam, M, NA Hasan, A Sadique, NA Bhuiyan, KU Ahmed, and others (2006). Seasonal Cholera Caused by Vibrio cholerae Serogroups O1 and O139 in the Coastal Aquatic Environment of Bangladesh. Applied and Environmental Microbiology, 72, 4096-104.

Hosoi, SA & SI Rothstein (2000). Nest desertion and cowbird parasitism: evidence for evolved responses and evolutionary lag. Animal Behaviour, 59, 823-40.

Lee, SJ, PJ Steer, & V Filippi (2006). Seasonal patterns and preterm birth: a systematic review of the literature and an analysis in a London-based cohort. BJOG, 113, 1280-88.

Oppliger, A, H Richner, & P Christe (1994). Effect of an ectoparasite on lay date, nest-site choice, desertion, and hatching success in the great tit (Parus major). Behavioral Ecology, 5, 130-4. Cited in Roff (2002), p. 415.

Pike, IL (2005). Maternal stress and fetal responses: Evolutionary perspectives on preterm delivery. American Journal of Human Biology, 17, 55-65.

Rahman, A, F Kogan, & L Roytman (2006). Analysis of malaria cases in Bangladesh with remote sensing data. The American Journal of Tropical Medicine and Hygiene, 74, 17-9.

Roff, DA (2002). Life history evolution. Sunderland: Sinauer Associates.

Roff, DA (2007). Contributions of genomics to life-history theory. Nature Reviews Genetics, 8, 116-25.

Bad for boys and good for girls   posted by dobeln @ 2/08/2007 12:38:00 AM

The two genes MAO-A and 5-HTT have drastically different effects on male and female behavior, according to Swedish researchers at Uppsala University. Major Swedish daily "Svenska Dagbladet" reports:

Gene variants that in a given environment lead to alcoholism, depression or antisocial behavior in boys have the opposite impact on girls. And vice versa.

In the study, 5000 swedish youths completed a behavioral survey. From this sample, 200 youths were selected for further interviews and blood tests. Teachers and parents were also interviewed. According to SvD:

The results were clear. A short version of the gene MAO-A for boys and a long variant for women in combination with a problematic social environment meant for example an increased risk for alcohol-related problem behavior. When boys had the long variant and girls the short one, the results were reversed.

"The impact is very small when only looking at environment or genes in isolation. But there is a tremendous increase in the effect when they are combined", says Lars Oreland. "

Results have been published in several journals, among them American journal of medical genetics and Journal of biological psychiatry.

Media-related side note: This news is splashed all over the news in Sweden, with zero "anti-genetics" jibes in sight. Which is interesting.

Previously on GNXP about MAO-A.

Wednesday, February 07, 2007

World Haplogroup Maps   posted by DavidB @ 2/07/2007 12:33:00 PM

This link has almost certainly been posted here before, but it's still pretty cool, and we do have new readers from time to time.

It's a pdf file with maps of major haplogroup distribution: the World and Europe for Y chromosome haplogroups, and the World for mitochondrial haplogroups.

I came across it having read Razib's post below about Bryan Sykes's 'Blood of the Isles' theories, and I wanted to see what info was available about the distribution of haplogroups in contintental Europe, for comparison with the British Isles. The maps aren't really detailed enough for this purpose, but it does seem to my uneducated eye that the distribution in England is closer to that of Denmark than to that of Ireland or Wales, which rather goes against Sykes's thesis. The major difference is that the Y-haplogroup J (light green on the map of Europe) is moderately common in Denmark but rare or absent in the British Isles. But it is also absent in Iceland and rare in Norway and Sweden, while being quite common in France, Italy, Greece and Turkey. There seems in fact to be a definite gradient of increasing frequency from NW to SE Europe, so it can hardly be presented as a specifically 'Nordic' marker.

Tuesday, February 06, 2007

Scientists discover: science is hard   posted by p-ter @ 2/06/2007 05:33:00 AM

Ever since 1996, it has been a foregone conculusion that the linkage study would be de-throned in favor of the association study as the preferred method for searching for genes involved in common human diseases[1]. New technologies and the availablity of resources like the HapMap have now nearly made that foregone conclusion a reality. Large-scale association studies are no panacea, of course--they certainly have their limitations, and perhaps some members of the human genetics community have been too bold in their promises of what they will bring. But a new paper lauches a puzzling attack on the entire field, all in the service of demolishing a straw man.

The paper is entitled "Are genome-wide association studies all that we need to dissect the genetic component of complex human diseases?" The authors apparently think the answer is "no", and I'm certainly not going to disagree with them there-- this is the straw man. It would be nice if they could give an example of one person who thinks that genome-wide association studies are all that is needed to understand complex disease-- a dumbass grad student, a dotty old professor, anyone. But the best they can do is to quote a HapMap press release as saying that the HapMap -- and the association studies it allows -- are a "new tool that will accelerate the discovery of genes related to common disease". This statement is, well, true. Even the authors think so: several pages later, perhaps having forgotten what they wrote in the introduction, they opine that "the availability of [new] tools and information are a valued and welcome addition to the armamentarium geneticists can use to identify and characterize the genetic component to complex diseases". Frankly, it's a little unclear what inspired the writing of this paper.

But perhaps they were just trying to make a splash with their title-- a little rhetorical excess is always forgivable. Their arguments against large-scale association studies are centered around two questions-- first, will most genetic variants involved in complex disease be detectable by association, and second, even if an association is observed, where will that eventually get us? Both of these questions are legitimate ones, yet I find their answers to both disappointing.

I. Will most genetic variants involved in complex disease be detectable by association?

For reasons I'm not going to explain, linkage studies generally have only the ability to detect rare alleles that greatly increase succeptibility to a disease. Association studies, on the other hand, have the ability to detect more common alleles that only moderately increase succeptibility. The authors note a number of successes in which an association study has identified such alleles. They then give a laundry list of problems with expanding these studies-- rare variants are important and missed by the association approach, gene-gene or gene-environment interactions as well, multiple testing is an issue when scanning the entire genome, genetic heterogeneity is likely when comparing populations, etc., etc., etc. All of these things are relevant, but honestly, this isn't news; these arguments have been around for quite a while.

Ultimately, after raising an issue, most scientists generally try to address it. These authors don't. The inital results from genome-wide association studies are promising, and it's perhaps ironic that, while they were busy writing this paper, other papers were published on clever new study designs and strategies for dealing with gene-gene interactions. The methods for ideally addressing the issues raised by the authors don't exist yet, it's true. But for some, that means there's still an opening to make a big discovery or develop a groundbreaking new tool. For the authors, it's almost like they don't see the point in doing human genetics research anymore. Indeed, their answer to the second question strengthens that suspicion.

II. Why bother finding genes that are involved in complex disease?

The goal behind finding genes involved in disease, any biotech CEO will tell you, is to gain insight into the disease mechanism and ultimately to disrupt it. In the wake of the sequencing of the human genome, companies were founded by the boatload to do just that. Most of them wasted away, as documented in a Slate article from 2005 subtitled "Why genetics is so far a bondoogle". But even that writer (presumably not a geneticist) had enough sense of perspective to realize that pronouncing the uselessness of genetics research after a few years of disappointments might be a little premature.

The authors of this paper aren't going to announce the death of genetics research either, but they don't seem to hold out much hope for it going anywhere. A comprehensive review of companies that have tried to make the path from genetic association to treatment would have been appropriate here. However, the authors give only one example-- their inability to figure out the role of the immune system in auto-immune disease. Genetic mapping has consistently associated the HLA region of the human genome, which codes for proteins important in the immune system, with diseases like Type I diabetes and Crohn's disease. But no one has really figured out how this genetic succeptibility works, or much less developed a treatment based on this knowledge. This is all true, but to generalize from trouble understanding the intricacies of the immune response to an impotency in all other aspects of understanding human biology is unwarranted.

If it were warrented, the entire discussion of the best approach to studying the genetic basis of human disease would be moot. It's obviously a waste of time to find disease genes if eventually they don't lead to any medical advances. The authors' point can't be that understanding the genetics of disease isn't worthwhile, otherwise they wouldn't have devoted pages to debating the best approach for doing so. Yet their sole example in this section makes the outlook appear somewhat bleak (again, I'm not sure what the goal was in writing this section). So I'll present a few counter-examples:

1. In the '70s, a devastating disease marked by early heart attacks and high cholesterol was mapped back to its causal locus-- a receptor for high density lipoproteins. This was an important insight into how cholesterol levels are controlled in the body, which eventually played a role in the development of the most popular cholesterol-lowering drugs on the market today-- the statins.

2. In 1960, cytogeneticists noticed a curious chromosomal abnormality in patients with a certain type of leukemia, which they dubbed the Philadlphia chromosome. As the decades went on and technology improved, closer and closer looks were taken at this chromosome, which was eventually shown to always be a translocation bringing together two genes, one of which was actived by this translocation. It was hypothesized that inactivating this gene could be a plausible treatment, and indeed, in 2001, Gleevac hit the market.

3. More recently, DeCode Genetics has turned an association between variants in a gene and risk of heart attack into a successful clinical trial. The drug isn't on the market yet, but it could prove to be the first big success of the post-genome era.

Yes, the successes I've noted have taken time (even decades) to go from a genetic association to a usable drug, but large-scale association studies promise to accelerate that process by allowing researchers to directly find relevant genes in an expedient fashion. Nothing happens overnight, even, believe it or not, solutions to the most prevalent diseases in Western society.

So the pessimism of these authors, while perhaps understandable, is unwarranted, nor does it make for a particularly good paper. I'm reminded of a another, perhaps more clever, paper with similar conclusions...ah yes, here it is:
National Science Foundation: Science Hard

INDIANAPOLIS-The National Science Foundation's annual symposium concluded Monday, with the 1,500 scientists in attendance reaching the consensus that science is hard.

"For centuries, we have embraced the pursuit of scientific knowledge as one of the noblest and worthiest of human endeavors, one leading to the enrichment of mankind both today and for future generations," said keynote speaker and NSF chairman Louis Farian. "However, a breakthrough discovery is challenging our long-held perceptions about our discipline—the discovery that science is really, really hard."
"I guess there's cool stuff about science," Watanabe continued, "like space travel and bombs. But that stuff is so hard, it's honestly not even worth the effort."

[1] See here for a primer on the difference between linkage and association.

IRES rising, raising ires   posted by amnestic @ 2/06/2007 02:39:00 AM

I first became interested in internal ribosomal entry sites (IRESs) upon reading this paper by Pinkstaff and colleagues. They used a reporter system, which I will describe shortly, to suggest that five dendritically localized mRNAs could be translated via internal ribosomal entry. This provided a novel twist on the role of protein synthesis in synaptic plasticity. Presumably, those mRNAs are trafficked to dendrites so they can be translated rapidly and locally when the time comes. An IRES allows the protein synthesis apparatus, the ribosome, to connect with an mRNA and start translating without the normal rites of initiation. Messages containing these elements could keep translating during times when global protein synthesis has been downregulated and initiation factors are scarce. At least two of the IRES-containing mRNAs reported by Pinkstaff are known to be rapidly translated upon induction of synaptic plasticity. An intriguing scenario thus emerges in which global protein synthesis is actually inhibited at the initiation step during synaptic plasticity. This leaves excess ribosomes and only a few special mRNAs with the ability to use them, so specific plasticity proteins are upregulated while most proteins are turned down. One could imagine all sorts of scenarios to flesh this story out. The conditions for synaptic plasticity induction include a large calcium influx, activation of several enzymes, and a relatively large amount of energy to put things (like calcium) back where they came from. Maybe this is interpreted as a type of cellular stress necessitating a metabolic shutdown. This would be a way of locally coordinating expression of the necessary subset of synaptic modification proteins.

To be clear, translation is the final step of the central dogma of genetics. This is the step where the triplet genetic code of nucleotides is read off into the new language of amino acids. A tRNA carrying an amino acid matches up to three nucleotides of the mRNA chain, and the ribosome attaches this amino acid to the growing chain. The dynamic mechanism by which all these factors and RNAs and ribosomes actually get to the point of starting a new protein is called ribosomal scanning. Canonical translation initiation involves a series of recruitment steps bringing together initiation factors, the initiator tRNA carrying an amino acid, the mRNA to be translated, and the ribosomal subunits. The initiation factors bind the mRNA at the very end and assemble with a ribosome carrying the initiator tRNA. Then the whole complex slides down the mRNA looking for a start codon (AUG). The AUG sequence is sticky for an initiator tRNA because it matches the tRNA's anticodon. The machine tarries there, allowing time to bring in a second tRNA and start the chain. Imagine everyone's surprise and delight when it was reported that, in some viruses, translation can start without any of this process. None of the initiation factors, no initiator tRNA; the ribosome just jumps on to the RNA in the middle and starts synthesizing proteins. The idea of an IRES (internal ribosomal entry site) is that the mRNA carries a complex three dimensional structure that mimics many of these factors and provides a platform for translation to start. In fact, recent crystal structures have provided insight into the mechanisms of action for two viral IRESs. I'm not gonna play around and pretend that I understand structural papers (or even summaries of them), but it seems to me that, unless you can just force RNA into whatever conformation you want by crystallizing it with the right co-factors, these structural papers provide a new level of evidence for the concept of internal ribosomal entry. The RNA folds up in a way that appealingly explains how ribosomes could join and synthesize without initiation factors.

Why am I so nervous about whether IRESs exist? While I was searching for information on RNA structure and IRES activity so I could explain noncanonical RNA interactions and structure to you, I came across the reviews of Marilyn Kozak (2001, 2001 exchange, 2005, and 2006). Kozak has made major contributions to the understanding of translation initiation. To give an idea, the consensus sequence that determines whether an AUG start codon is really going to be the site of translation initiation is called a Kozak sequence. She has been arguing for a rigorous re-examination of the evidence for IRES-dependent translation for the last 15 years or so (or perhaps longer and I haven't gotten to that review yet). Her critical 2001 review of the evidence for IRESs in cellular mRNAs drew accusations of unscholarliness, false statements, and misrepresentation of others' data in a strident letter to the editor with 87 signatories including names I recognize as eminent in translation control studies. Nahum Sonenberg, for instance, is an editor of the recently released Translational Control in Biology and Medicine monograph from CSHL Press. I'm a sucker for a clever contrarian, so of course I think this section from her rebuttal letter is worth quoting:

"I will save the curious reader the trouble of counting the names appended to the Letter to the Editor: there are 87 votes in favor of cellular IRES elements and associated phenomena. Some of the signers (e.g., Drs. Farabaugh, Filipowicz, Goldman, and Krug) work on subjects completely unrelated to the content of the minireview; they must have studied hard to qualify as judges. The letter was composed and circulated by Drs. Schneider and Sonenberg. Many of the signers have close links to Dr. Sonenberg, either as coauthors or members of the same institution.

It is obvious that the organizers worked hard to collect all those signatures, but to what end? A single voice suffices to present a logical argument. I might be alone in refusing to believe a story with so many flaws, but that does not mean I am wrong. Counting the votes determines the answer in politics (Florida excepted) but not in science."

The jury will disregard the Florida comment. We shall now proceed to her substantive arguments.

The model system for study of IRES-dependent translation has been the dicistronic vector, a DNA construct that contains two protein-coding genes (open reading frames) separated by the putative IRES. The first gene in the sequence should be translated by the normal scanning mechanism. The amount of the second protein product indicates the degree of IRES-dependent translation. The vector of choice for a large number of studies contained Renilla luciferase as gene 1 and Firefly luciferase as gene 2 (the pRF vector). These can be detected independently, so you can compare IRES and normal translation. The arrangement of this vector is similar to the dicistroviruses in which IRESs were first reported. These viruses mostly carry structural, coat proteins in the first open reading frame and proteins important for replication and integration in the second one. After transcription and translation the protein products are further cleaved to produce the mature pieces needed to build a new virus. Here is one of the first reasons to be suspicious of the proposed IRES mechanism. There are a number of examples of viruses that look dicistronic, but they achieve the two protein products through RNA splicing or protein cleavage. Kozak cites a string of virus families whose downstream genes are silent until they are moved to the front of the line by removal of the upstream open reading frames.

A second issue is that there is little to no conservation between proposed IRES sequences. This is not necessarily a problem, given that IRESs are supposed to work at the level of 3D structure rather than primary sequence recognition, but it is unsettling. There are some ways of inferring an important RNA structure. For instance, nucleotides that pair in stem-loop structures may not be conserved, but their ability to pair is (i.e. a G and a C are mutated to a C and a G). The recent structural studies may provide some more criteria for how an IRES should look, but these are for the simplest proposed IRES mechanism. Other reported IRESs bear little primary sequence-level resemblance.

One of Kozak's major themes is to criticize the efficiency of expression from IRES reading frames. This is her real feat. She goes over dozens of papers claiming to demonstrate IRES-dependent translation with a fine-toothed comb and comes up with no credible example of a strong IRES. It really matters what you compare efficiency with. Insertion of an IRES may represent an impressive-sounding increase compared to a vector containing no IRES, but still look dismal compared to regular cellular translation. Viruses need to make proteins. They can't really just screw around with some new mechanism and make a little of this and that. Any translation mechanism proposed to be important for viral life cycles or, for that matter, cellular protein synthesis better be efficient enough to support the observed efficiency in a natural setting. Instead, even the strongest putative IRES doesn't come close to the efficiency of regular translation. It does bring synthesis up higher than if there were no IRES at all, but Kozak has answers for that as well. This is a part of her position that is vulnerable to attack though. At what point would an IRES be efficient enough to please her? She repeatedly uses phrases such as "IRES X only increased efficiency X amount." Why the 'only'? She is emphasizing the smallness of the number, but we don't really know what a meaningful level of translation should be. Is it necessary for the IRES to reach efficiency as good or better than normal cellular translation? Do viruses really need that much replication machinery? She does make a strong point regarding negative controls though. The pRF vector with no IRES at all produces variable results:

"There is always some translation of the 3' cistron, and this unexplained background expression is not constant. Background translation of the 3' firefly luciferase (Fluc) cistron varied >10-fold when three different negative controls were tested by RNA transfection [Figure 5C in Ref. (9)]. When tested in vitro, translation of the 3' cistron increased 10-fold upon simply lengthening the intercistronic domain [Figure 9 in Ref. (64)]. Whatever the reason for this background, its variability would seem to set a lower limit on what level of expression constitutes a credible positive result when a candidate IRES is tested."

Not only that, but people have occasionally used negative controls in which structured RNA sequences that actually decrease efficiency are inserted between the Renilla> and Firefly genes.

What if we do find a sequence that can be placed between two open reading frames and lead to a major increase in accumulation of the product form the second frame? We have a pretty good IRES candidate now, right? Nope. You need to do RNA analysis. Here's the problem. You don't really know what you are putting in between those two DNA sequences. There are two creatures you might be inserting instead of a real IRES. First, there is the possibility of a cryptic promoter: the increased product is due to independent transcription of the downstream reading frame, so ribosomal entry really isn't internal at all. You just have two mRNAs; nothing mysterious. This mechanism has been detected for the reported IRESs in p27-Kip1, VEGF, and c-sis/PDGF2. I'm getting this information directly from this table in Kozak's 2005 review (free). Also, the first open reading frame in the fully transcribed dicistronic mRNA could simply be removed during RNA splicing (the step in mRNA maturation in which introns are cut out from between the protein-coding exons). This would leave a fully intact second open reading frame mRNA that needs no IRES to be translated. This mechanism has also been detected in three reported IRESs. The cryptic promoter idea can be circumvented by injecting RNA directly into the cells (or in vitro translation system) rather than a DNA construct. The splice site problem is less easily removed. You have to use the most sensitive possible assay and look for the spliced RNA. The problem is that the only citation given for a sensitive-enough assay reports spurious splicing caused by the candidate IRES. What constitutes proper RNA analysis is left uncertain.

Now let's look back at the exciting findings of Pinkstaff et al. 2001. They found IRES-dependent translation associated with the mRNAs of Arc, CaMKII, neurogranin, MAP2 and dendrin. Did they run these experiments well enough for Kozak's standards? First, they used the pRF construct. We know that baseline firefly luciferase expression in this dicistronic system is variable. Unfortunately, we can't tell how variable it is in these experiments because all results are expressed as a ratio of Renilla to firefly levels normalized to the negative control baseline vector. Kozak defines as 'weak' any increase of less than 5-fold compared to the control vector. CaMKII and dendrin never cross this threshold, so it would be crucial to make sure these aren't varying at the level explained by baseline fluctuations. The initial RNA analyses for neurogranin turned up two small RNAs, indicating that a splice site had been inserted. After removing this issue, neurogranin still had some of the highest IRES activity. In a further test, when a construct containing the neurogranin sequence controlling both reading frames (this time yellow and cyan fluorescent proteins) was injected into neurons, IRES activity could be up to 15% of the level of normal translation. It's not super strong, but the story goes that this type of translation should be reserved for special times. It remains to be explained why the IRES activity is 15-fold better than control in a rat neuronal tumor cell line but only 3-4 fold better when injected into hippocampal neurons. I'd have a hard time strongly rejecting the idea of IRES-dependent translation for these mRNAs. Yes, CaMKII and dendrin are weak, but the error bars are shown on a beta-globin control and they are well out of that range. The difficult part is the RNA analysis. It was sensitive enough to catch one inserted splice site. Does that mean it is sensitive enough to catch any and all? It is just a Northern blot. On one hand, this goalpost is one of the most easily moved. On the other, it would be nice to see some a more exhaustive search. Also, the efficiency of the second gene can be enhanced in some cases by simply increasing the space between open reading frames, so an appropriate control vector needs to equate this parameter between control and experimental constructs.

The debate rages on although I'm not sure everyone is listening. The chapter on cellular IRES activity in Translational Control in Biology and Medicine by Elroy-Stein and Merrick cites Kozak (2005) but also cites several cellular IRESs that Kozak doesn't accept (including XIAP, which has been shown to undergo splicing!) and argues that these protein products are "biologically effective at rather small concentrations" in an attempt to get around her 'ineffeciency' arguments. Even if cellular IRES activity turns out to be true, researchers need to apply more rigor and transparently report their data in the initial characterization of these mRNA elements. IRESs are certainly intriguing if they work, but it is currently too early to say. Here's one more dead-on Kozak zinger for the road - "Is the "scholarly" review the one that repeats the premature claim or the one that explains why it is premature?"

Monday, February 05, 2007

Fluctuating Asymmetry: honest truth and ballyhoo, part 1   posted by agnostic @ 2/05/2007 02:39:00 AM

To kick off GNXP's contribution to the Week of Science, during which participating bloggers will write only about science rather than fend off creationists and the like, the present entry will discuss the reality and hype surrounding the concept of Fluctuating Asymmetry (FA). Basically, it is the random discrepancy from perfect symmetry in a trait that is expected to be symmetrical, e.g. the length of your left ear compared to your right. FA excludes Directional Asymmetry, whereby individuals tend to depart from symmetry in a certain direction; for example, the right testicle tends to be larger than the left one in humans. FA also excludes Antisymmetry, whereby a population approaches bi-modality, with one sub-pop departing from symmetry in one direction and another sub-pop departing in the other direction: for example, handedness in humans.

I'll restrict my discussion here to FA, the random minute variance in values of a trait between the left and right sides (though there is also radial symmetry), which some researchers believe reflects Developmental Instability (DI), or random perturbations in development that prevent the developmental system from reaching its target phenotype in the individual. As I see it, researchers interested in this FA-DI relationship fall primarily into three camps: 1) ecologists studying environmental stress, who investigate whether greater levels of stress are reflected in greater levels of FA in the population; 2) quantitative geneticists who investigate the genetic architecture of FA; and 3) evolutionary biologists studying sexual selection, who investigate whether individuals use a prospective mate's FA to infer the extent of said mate's DI, typically on the assumption that individuals desire those who have "good genes" and who can thus better resist DI. Others are interested in the topic, to be sure, but I believe these three groups constitute the majority.

You could spend the rest of your career studying just one aspect of this phenomenon, but part of the value of a blog like ours is -- I hope -- that we can cover the main points of an interesting issue, with pointers to the literature, without requiring weekly attendance at a seminar. And unlike literature or book reviews in journals, you don't have to pay us $30 just to read it! (Although you're certainly welcome to.) This clearly is no replacement for studying the material in detail, but it's a better way of letting a target audience know what important other ideas there are outside of their narrow specialty, in the interests of cross-fertilization of ideas. In this spirit, I've summarized 4 important take-home lessons from my reading of the FA-DI literature. In brief, they are: 1) the link between FA and DI is far from clear; 2) the heritability (h^2) of FA is very low, though epistatic effects may be non-trivial; 3) FA is likely of minor importance at best in matters related to sexual selection; and 4) it can reveal environmental stress. I'll write about the first two today and the second two at a later date in the Week of Science.

Before moving on, it's worth providing links to two great websites on the FA and DI literature by leading participants in such research: Palmer's website on FA is pretty diverse and has a great bibliography section, which includes many free PDFs of the author's work (including a nice satirical review -- Palmer & Hammond 2000); and Leamy's website also has several free PDFs of his work. Reading the review PDFs there will give you a good hint of what the consensus is, though if you're really interested in this topic, Polak (2003) is required reading since its chapters cover the topic from a variety of angles (measurement of FA, the quantitative genetics of FA and DI, and so on).

Point 1: The FA-DI relationship, if it exists, is very poorly understood

If readers take away only one point, it must be that claims that FA is a reasonably precise measure of DI, or that the relationship between FA and DI is suitably understood, or even that DI exists, should be taken with a large grain of salt. We know FA exists, and as long as we're very careful -- i.e., take repeated measures, since FA is typically within the range of measurement error -- we can actually measure it. But as for accurately measuring DI, here is one phrasing of the consensus, from Leamy & Klingenberg (2005, p. 3; free PDF):

Because FA is calculated from only two sides (one degree of freedom) of a bilateral character in a given individual, it is a rather imprecise estimator of DI variability. Thus, sampling variation should result in many FA values at or near zero (the expected mean for FA) even in individuals with very high levels of DI. The correspondence between FA and DI has been parameterized by the hypothetical repeatability, [R], which expresses the degree to which differences in FA reflect differences in DI. Theoretical formulas for calculating [R] that are based on variation in FA have been derived by Whitlock (1996, 1998) and Van Dongen (1998), and estimates of [R] from a number of FA studies have averaged about 0.08 (Gangestad & Thornhill 2003). This very low value serves as an important reminder of the difficulty of obtaining good estimates of DI in populations from measurement of FA in various characters.

(NB: I've replaced the typographically awkward R with a normal R in brackets. Their list of references is contained in the free PDF linked to above.) So, when we read statements such as the following from Thoma et al. (2006, p. 1457), we should be aware that the qualitatively true statements are misleadingly omitting any mention that FA is a poor measure of DI, a phenomenon whose existence remains muddied:

A common marker of DI is obtained through the measurement of fluctuating asymmetry. . . As a marker of DI, fluctuating asymmetry reflects the interaction of stabilizing developmental processes with disruptive, random environmental (i.e., exposure to toxins) and genetic (i.e., nonadaptive mutations) processes. . .

In two separate studies, Furlow et al. (1997) showed fluctuating asymmetry to be negatively correlated with a measure of fluid intelligence, the Cattell Culture Fair Intelligence Test. Several recent studies have replicated and extended these results (Bates, 2004; Prokosch et al., 2005; Thoma et al., 2005), supporting a link between DI and performance on standard intelligence tests and g estimates. This perspective raises the important possibility that genetic variation in susceptibility to early (perhaps prenatal) environmental influences adversely affects the development of human intelligence.

Hold on there! Now, if this had appeared in an article geared toward those already somewhat familiar with FA and DI, the omission of qualifiers might be justifiable, but this article is geared toward psychologists (it appeared in a neuroscience journal), so all of the qualifiers should appear. Not only is FA a dicey measure of DI, but we don't know that DI is non-trivially heritable either, and our best guess for the heritability of FA is that it's close to 0 (see Point 2 below). The murkiness of the issues surrounding FA and DI should temper the exuberance typified in the quoted text above. One of the reasons I've selected this topic for the Week of Science is that those unfamiliar with the consensus in the FA and DI literature -- such as most professional psychologists and anthropologists, as well as close to all journalists -- could be easily seduced into believing that FA offers far greater explanatory power than it truly does for their object of inquiry (e.g., human intelligence). Given that the article quoted from above was published in 2006, it is clear that non-specialists must still be wary of confident claims that FA is important in explaining some property they're interested in.

Point 2: Additive genetic variance in FA is very low

If I, as a non-expert, had to guess what event set off the "spring cleaning" in the FA-DI literature that culminated in an edited volume (Polak 2003), I would say it was a controversial meta-analysis of the heritability of FA (Moeller & Thornhill 1997*), which elicited a large number of articles in reaction just within the issue in which it was published. The authors claimed to have found a modest h^2 of 0.19, although later meta-analyses and literature reviews pointed to an h^2 surely less than 0.1, and typically around 0. For example, Table 11.1 of Fuller & Houle (2003) is a review of the literature on the heritabilty of FA and (by adjusting that by R) the heritability of DI. They found a mean h^2 for FA of 0.026, and for DI of 0.255, although the interpretation of the latter result must reflect the fact that the estimates of R were pretty erratic, commonly resulting in an h^2 for DI that lay outside of [0, 1], which is meaningless in context. Thus, there is likely something inappropriate about calculating h^2 for DI in this way.

That is not to say that genetic variation plays no role -- indeed, QTL research by Leamy and colleagues has shown that, at least for FA in the jaw morphology of mice, statistical epistasis contributes substantially to FA differences (Leamy et al. 2005; free text). Nevertheless, our imperfect but best guess is that FA probably will probably not respond to selection due to such low additive variance, a point to which we return when discussing the use of FA as a "fitness indicator" in sexual selection theories. Since we know so little about how to fruitfully infer DI from FA, the former may end up showing an h^2 in the modest or strong range, which would facilitate response to selection. Again, the enthusiasm will have to wait until our understanding of DI rises above the level of head-scratching.

In Part 2, I'll address the uses that FA has in studying sexual selection (including hunting for "fitness indicators") and environmental stress on natural populations.

*I spell the surname as "Moeller" for typographical ease, although the first syllable's vowel is just the o with a slash through it.


Fuller, R & D Houle (2003). Inheritance of developmental instability. In M Polak (Ed.), Developmental instability: Causes and consequences. New York: Oxford University Press, pp. 157-183.

Leamy, LJ & CP Klingenberg (2005). The genetics and evolution of fluctuating asymmetry. Annual Review of Ecology, Evolution, and Systematics, 36, 1-21.

Leamy, LJ, MS Workman, EJ Routman, & JM Cheverud (2005). An epistatic genetic basis for fluctuating asymmetry of tooth size and shape in mice. Heredity, 94, 316–325.

Moeller, AP & R Thornhill (1997). A meta-analysis of the heritability of developmental stability. Journal of Evolutionar Biology, 10, 1-16.

Palmer, AR & LM Hammond (2000). The Emperor's codpiece: A post-modern perspective on biological asymmetries. International Society for Behavioral Ecology Newsletter, 12, 13-20.

Polak, M (2003). Developmental instability: Causes and consequences. New York: Oxford University Press.

Thoma, RJ, RA Yeo, S Gangestad, E Halgren, J Davis, KM Paulson, & JD Lewine (2006). Developmental instability and the neural dynamics of the speed-intelligence relationship. NeuroImage, 32, 1456-64.

Sunday, February 04, 2007

Cultural change   posted by Razib @ 2/04/2007 09:31:00 PM

In the thread below Ingo Bading made a few comments which I'd like to address real quickly before "The Week of Science" kicks off and we move away from this sort of material. Ingo says:
And: I think Augustine is more or less representative for the IQ-elite of Rome. A lot of smart people went into the monasteries in those times, because the former roman ethic and polytheism failed to convince people.

There are two points I would like to make. The first is more meta, and that is that intellectuals are the ones interested in the details of history and they are the ones who record it. What we know of ancient Rome we know through the lens of Cicero, or Caesar's propoganda about the Gallic Wars, or St. Paul and St. Augustine, elite Christians who were firmly ensconsed in the Roman elite (remember that Saul of Tarsus was a Roman citizen). When it comes to high culture we have a pretty good sense of what was going on because the people who were writing down their sense of the times would be from the literate and elite slice. In the modern world with near ubiquitous literacy, and a relative disenagement from the world of pure subsistence the concerns and worldview of Roman aristocrats, steeped in philosophy and rhetoric, is not wholly alien to us because more or less all Westerners are persons of some leisure. This does not mean that intellectual pursuits are modal, but, those of us who might reflect upon the arc of human history are the sorts who would privilege intellectual pursuits in any case.

But aside from this elite level there is the daily life of the masses of humans. The bronze age peasant, the classical peasant and the medieval peasant, are fundamentally detached from this elite stream of thought. Their daily concerns are focused subsistence and status within their own social circle. Gruels made from cereal and fish sauce were far more consequential to the Italian peasant for thousands of years than the theses of Pythagoras or the conflict between the followers of Aquinas and Occam within the Church. When we talk about evolutionary changes we need to keep in mind gruel and fish sauce, because this is what was of consequence in the lives of the modal human, not the theses and propositions which were of some concern for around 0.1% of the population. This does not mean the propositions are irrelevant, people kill each other over these propositions because the elite uses these ideas to coalesce around factions, and these factions have mass supporters who will kill in the name of a word. But that doesn't mean that the theses and propositions themselves have any societally deep traction as internalized memes.

The second point I want to make is more specific, and this is the idea that ancient Romans and Greeks turned away from polytheism because they found it intellectually unappealing compared to Christianity. This is a common idea, and one until recently triumphantly proclaimed by the Christian Zeitgeist, as the winners do write history. Now that an anti-Christian streak is powerful in the intellgensia materialist narratives make Christianization a conspiratorial affair which resulted in the death of classical civilization (this counter-tendency starts with the
Renaissance). The reality, I believe, is more subtle.

First, if you read books like The Making of a Christian Aristocracy, you see that the transition from a pagan elite to a Christian one was a slow affair. In fact, until 400 the Western Senatorial elite was almost entirely pagan, as attested by the anti-Christian rebellion which Theodosius the Great defeated at the Battle of Frigidus. A powerful locus of anti-Christian feeling remained in the intellectual elites, especially around the Academy in Athens, which was closed in the early 6th century by the devout Christian Emperor Justinian. Augustine's City of God was written in part as a response to pagans who criticized Christianization as leading to the fall of the Empire (the Christian Goths has just sacked Rome), and the historian Zosimus could make an anti-Christian conservative case as late as 500. Why did the elite eventually become Christian? Consider that early in the 5th century officers who were pagan were banned, that as time passed public officials had to be Christian, and pagan temples were divested, torn down, and private pagan worship was banned. The point is that there were some very powerful inducements to becoming Christian, and the process at the elites where we can document it took about 2 centuries to complete (Emperors were still being deified as late as the late 5th century, though they were official Christian themselves).

Additionally, there is the reality that elite pagan opinion was not crassly polytheistic, but monistic. St. Augustine himself drank from the Neo-Platonic well of religious philosophy, and the ascetic outlook of Stoicis and Neo-Platonists likely influenced early Christian thinkers.

Finally, there is the reality that mass Christian worship in the countryside was operationally pagan for quite a long time, and some Protestant thinkers would contend that Christianity as a conscious profession of faith and values was not internalized into the European peasantry until mass literacy after the Reformation. During the 6th century requirements for an understanding of Christian doctrine were waived as mass conversions of peoples occurred via elite mediation (e.g., the king would convert and nominally bring over his nation). This resulted in an operational paganism among many Christans, even among the illiterate barbarian warlords, who focused on the cult of saints and relics to a far greater extent than the abstract philsophy of the Triune God. There is also the reality that psychological studies strongly suggest that the cognitive model of the divine in the minds of polytheists and monotheists is operationally the same, so on the non-semantic level (i.e., how a believer conceptualizes their divine entity) there might have been no change between the transition between paganism and Christianity.

OK, that's a lot to throw at you. But, I wanted that to get out there because if we're to talk about the past, and how it intersects with our understanding of evolutionary dynamics, we need a clear and distinct concept of how the past was, not how we view it because of the limited sample space of documentation and our own personal biases.

Just Science   posted by Razib @ 2/04/2007 07:16:00 PM

A Week of Science starts tomorrow. I've loaded up an aggregator blog at, but the best place to follow things will be via RSS,

The love connection   posted by p-ter @ 2/04/2007 11:09:00 AM

The explosion of online dating sites, some of which are free and require no registration, has been a boon for psychologists studying the deception and mind games of the dating scene. Scientific American has an article on what they're finding-- nothing that will really surprise GNXP readers:
For men, the major areas of deception are educational level, income, height, age and marital status; at least 13 percent of online male suitors are thought to be married. For women, the major areas of deception are weight, physical appearance and age.
My research assistant Rachel Greenberg and I have examined the age issue by plotting a histogram of the ages of 1,000 men and 1,000 women selected at random from the national database of, arguably now the largest of the online matchmaking services. We speculated that from age 29 on--the point at which people in our culture tend to become sensitive about growing older--we might see some distinctive patterns in the distribution of ages. For men, a small spike appeared in the ­distribution at 32 and a large one at 36. The number of men calling themselves 36 was dramatically higher than the average frequency of men between the ages of 37 and 41.

For women, we found three clear age spikes at 29, 35 and 44. The difference between the number of women claming to be 29 and the average frequency of women claiming to be between ages 30 and 34 was nearly eight times larger than we would expect by chance. Apparently women at certain ages are reluctant to reveal those ages--and certain numerical ages are especially appealing, presumably because our culture attaches less stigma to those ages.
(via Matt)

That women find socioeconomic status attractive is unsurprising; in my experience, though, there are even more subtle things that affect interest levels. For example, telling someone I'm a "geneticist" always gets a better reaction than saying I'm a "biologist" (people who know me are laughing, because they know neither is technically true. Whatever). I've never really understood this-- does genetics sound more impressive than biology?

Saturday, February 03, 2007

Blood of the Isles   posted by Razib @ 2/03/2007 10:59:00 PM

Since there was some talk about Saxons & Celts in posts below, I thought it would be worthwhile to reproduce some data from Saxons, Vikings and Celts, Bryan Sykes' new survey of British archeogenetics. The table below is of male lineages only, but it gives a general sense of the overlay of various demographic movements over British history. Don't put too much weight in specific proportions, rather, focus on the relationships between them. No matter the extact percentage of "Anglo-Saxon" which emerges out of any given survey, it is almost certain that East Anglia will exhibit the modal value and other regions of England and Wales will have decreasing proportions as a function of distance....

NorthumbriaNorthCentralEast Anglia LondonSouthSouthwestAll England North WalesMid Wales South Wales All Wales
Oisin ("Celtic") 68.362.865.851.257.657.778.26478.586.584.283.2
Wodan ("Anglo-Saxon") 15.925.121.331.223.236.412.622.
Sigurd ("Viking")
Eshu (Misc. West Eurasian/North African)
Re ("Neolithic")

Related posts.

Romans in China   posted by Razib @ 2/03/2007 03:33:00 PM

The Daily Telegraph has an interesting article titled Roman descendents found in China? The girl to the left is one of many individuals in the city of Liqian who exhibit more conventially European features (e.g., londe hair) mixed in with a typical Han phenotype. The article floats the idea that these individuals are derived from a settlement of Roman soldiers, who were originally captured during the defeat of Marcus Licinius Crassus at the Battle of Carrhae. At this period the soldiers in the Roman army were generally from Rome proper. The article notes that researchers have taken DNA samples from 93 local individuals, so if these traits are evidence of Roman ancestry we'll find out pretty easily because Italians carry West Eurasian haplotypes which should stand out pretty easily.

Of course, I think a more plausible guess is these individuals are simply part of the normal range of variation on the Western borders of China, which was inhabited byEuropean looking peoples like Tocharians until relatively recently. Additionally, during the rise of the Mongol Empire whole villages were transferred from the west to the east, and whole contingents of groups like the Alans (from the North Caucasus) were to be found in the Mongol ruled cities of North China. So, it is also possible that as opposed to ancient Romans, these individuals descend from transplants who arrived during the period the Pax Mongolica.

A final point which I would like to emphasis is that the East Asian ecotype which we recognize as dominant in that region of Eurasia is actually a relatively recently phenomenon. The expansion of rice and wheat farmers from the North China plain, or the settlement of Japan from Korea within the last 2,000 years, as smothered (I suspect) a great deal of morphological variation in Eastern Eurasia, and "atypical" peoples and individuals might simply be remnants of the ancient range of variation before the demic expansion of "Classic Mongoloids" starting about 8-10,000 years ago.

The Galton Institute   posted by DavidB @ 2/03/2007 12:58:00 PM

Readers may like to know that the Galton Institute in London now has a much improved website, accessible here.

The Galton Institute was originally founded in 1907 as the Eugenics Education Society, with Francis Galton as its first President. In its present form it does not explicitly promote eugenics, but it encourages research and discussion of a wide range of issues in human genetics and medicine. Membership is open, for a modest fee, to all who support the aims of the Institute. The benefits of membership include a newsletter, a free copy of the proceedings of the annual conference, invitations to lectures and conferences, etc. Back numbers of many of the newsletters are available from the website.

The Institute and its website should not confused with, which is concerned primarily with the work of Francis Galton himself and provides free downloads of most of Galton's works.

Cancer and race   posted by p-ter @ 2/03/2007 12:30:00 PM

Yann points to a news feature in Science on research by Olufunmilayo Olopade into the genetics behind racial differences in the aggresiveness of certain cancers. Olopade calls the field the "science of disparity", which doesn't have the same ring as "human biodiversity", but hey, you take what you can get.

The research itself is fascinating:
In more than a dozen studies, they've documented that breast tumors in African-American women tend to be more aggressive, less responsive to treatment, and more likely to strike before menopause than breast tumors in whites and other ethnic groups. The differences persist even when statisticians adjust for every variable they can think of, from body weight to education to the cancer treatment given.
But of course, this line of thinking isn't exactly encouraged:
[T]he "science of disparity," as Olopade likes to call it, remains on the periphery of oncology research. Oncologists worry that by focusing on it, they'll be perceived as dismissive of the very real gulf in access to care. And they're generally reluctant to seek physiological distinctions between races. "It's such a contentious issue, and it causes people so much stress to conclude there may be a difference" in biology, says Wendy Woodward, a radiation oncologist who treats breast cancer at M. D. Anderson Cancer Center in Houston, Texas
Honestly, I find it amazing that intelligent people will still go on record to parrot old arguments like this:
But in tackling the genetics behind breast cancer disparity, researchers must also address what race, a crude construct, really means. "Race is not a scientific category," says Harold Freeman, a cancer surgeon and medical director of the Ralph Lauren Center for Cancer Care and Prevention in New York City. While he praises Olopade's work, he is skeptical about performing research on populations whose distinctions he considers socially determined. And even if biological differences are relevant, Africans and African Americans "come from the most genetically diverse continent in the world," says Lovell Jones, who conducts health disparities research at M. D. Anderson Cancer Center.
On GNXP, the question, "What's the harm in telling the public we're all the same?" has often come up. Here's the problem: researchers end up believing it, and people like those quoted above end up "skeptical" of legitimate research. I'm inclined to think Dr. Freeman was perhaps misinterpreted-- maybe he never really said that the distinctions between Africans and Europeans are socially determined (an absurd statement, and very different than arguing the definition of race has a social component), but people are capable of extensive self-deception, so you never know.

In any case, there seems to be some lingering animus towards this work, even when done by an African woman with the goal of devloping treatments for a previously overlooked population of patients. That, frankly, is astounding, and I can think of no better "liberal" argument for leaving behind the opposition to the study of human differences.

See also: Race, the current consensus.

Gay sheep revisited   posted by p-ter @ 2/03/2007 11:20:00 AM

Over at Slate, William Saletan takes a look at the gay sheep story. It starts:
Just up the road from Brokeback Mountain, closeted away in their own private Idaho, the gay sheep were getting it on.

Well, it wasn't exactly private. They were doing it in front of scientists at the U.S. Sheep Experiment Station near the Idaho-Montana-Wyoming border. The scientists arranged the trysts. It's called "sexual partner preference testing."

According to an article by researchers involved in the project, here's how it works. In a 15-by-10-foot "arena," a young ram is offered four choices: two ewes in heat and two rams. "The four stimulus animals are restrained in stanchions so that they can only be approached from the sides and rear." For 30 minutes, the unrestrained ram does as he pleases. The scientists count his "anogenital sniffs," "mounts," and "ejaculations."

The science of natural variation in sexual preferences is actually pretty interesting, standing as it does at the intersection of neurobiology, behavior, and genetics. Of course, the reason it's getting attention now is because of the backlash from those who worry that altering a ram's sexuality is the first step towards eradication of teh gay. Once any process is well-understood, there is the opportunity for controlling it; the development of sexual preferences is certainly no exception. But it's seriously bizarre to assume that if homosexuality is eliminated in rams (for economic reasons), the next step must be to eliminate it in humans. PETA's unintentionally funny* press release makes it clear this is how they intend to interpret it: "the experimenters plan to extrapolate the test results to humans-with the insidious implication that homosexuality in people can be 'cured.'"

You can't have it both ways: it is generally taken for granted that if homosexuality is shown to be largely biological, which seems to be the case, this would be a blow to homophopia the world over (why this is, I've never understood. Skin color has always been biological, and people still get all worked up about it). But on the other hand, once the biology is understood, of course it might then be possible to alter it. Whether this (hypothetical) understand of how to control sexuality in humans should be used is a much more interesting question; the science has nothing to say about this.

* This sentence literally made me laugh out loud: "Navratilova-who has won nine Wimbledon Women's Singles championships and, with a record 167 titles in singles and 174 in doubles, holds more overall tennis titles than any other player in history-adds, 'For the sake of the animals who will die unnecessarily in these experiments and for the many gays and lesbians who stand to be deeply offended by the social implications of these tests, I ask that you please end these studies at once.'" Juxtaposition of utterly irrelevant tennis statistics and moral outrage gets me every time.

Friday, February 02, 2007

Where nature leads   posted by Razib @ 2/02/2007 07:10:00 PM

I noted a few weeks ago I read The English Civil War. This passage struck me:
All beholders, said a Dorset draper visiting London, shed tears. There were ironies in all this hero-worship. According to the Catholic Sir Kenelm Digby, the godly [Puritans] were, hilariously, keen to gather relics of the martyrdom, the bloody sponges and handkerchiefs: 'you may see how nature leads men to respect relics of martyrs'.

The key point is to note that the Puritan Protestants indulged rather quickly in the same idolatry for which they upbraided the Catholics! In the chapter on "The War Against Christmas" the proto-Benthanmite inclinations of Puritan rationalists is on full display, as the divines inveigh against saints days and other accretions upon the plain and simple Biblical faith, and not for the first time place the quasi-pagan festival of Christmas in their sights.

And yet let us recall the ascetism on display in the Letters of Paul, and the "unnatural" lionization of celibacy common in the early Church (and shared with pagan intellectuals in the Neo-Platonic tradition), which persisted down to the days of the Reformation. Though the Protestants rebelled against human nature, the love of the beautiful, elegant and the mixing of the sacred and material, the bleeding of the divine into the corporeal, they were also willing to concede to the necessity of human nature when it came to carnal inclinations.

An important consideration is understanding particular cultural manifestations of human universal tendencies, whether it be toward religion, social stratification or art, is that they tend to be "canalized" by our cognitive biases toward particular optimal (and familiar) states. Nevertheless, there is variation in human predispositions, and I believe that one of the tensions common in "elite" religious traditions is that the professionals who shape the exoteric formulation of the religious doctrine and the proper forms and rituals are often somewhat atypical in their emphasis on rationality and logical consistency, and their distance from common tastes and inclinations. During initial stages of cult formation, whether it be "primitive Christianity," or the initial stages of the Muslim community, a self-selected Elect establishes the norms and conventions which define "orthodoxy" and "orthodpraxy." But over time as the religion spreads and succeeds in being a mass movement these idealized forms must compromise with the reality of human religious sentiment, and the canalization toward recurrent religious motifs and forms found in all cultures becomes ever more powerful. In short, religions may be initated by common and recurrent socio-historical forces (e.g., a messianc leader taking advantage of economic dislocation), but they eventually converge upon common cultural truths.

In regards specifically to the tendency for religions to throw up a cult of relics, and a counter-tendency of rationalist "Puritans" to denigrate this sentiment, consider a object precious to your beloved. Even an atheist materialist, who sees in the universe around himself simply organized atoms, would be hard pressed to deny the sentimental value in keepsakes once in the possession of those who have now passed from this world. Fundamentally it is these banal psychological tendencies which can transmute into imbuing a bloody shroud with divine miasma.

Genghis Khan on In Our Time   posted by Razib @ 2/02/2007 07:05:00 PM

The podcast of Genghis Khan on In Our Time is up.

Why agriculture?   posted by Razib @ 2/02/2007 06:25:00 PM

The post on the thrifty gene hypothesis made me reconsider an issue I've mulled over the past few years: if a transition to an agricultural lifestyle increased the median life misery index, why did it supplant hunter-gathering? (and in most cases, nomadism as well) I think the easiest way to understand how farming could spread despite its relative misery is to use something from the contemporary world as an example. Consider two sisters. One is very bright, and pursues a professional career track and becomes a pillar of the community by 40 as an independent and successful woman. The other isn't bright enought to finish college and becomes pregnant by her boyfriend. I think the expectation might be that someone with career satisfaction, economic freedom and social status might be "happier" than someone who lacks these things. That being said, the structural necessities of being a professional woman mitigate against reproduction. Over the long term the choices which will become normative will be those that amplify fecundity. The hunger-gatherer lifestyle, in general, is constrained in regards to average increase of a population. Mobile groups simply can't support larger numbers of small children. In contrast, sedentary farmers have a bit more freedom in this regard. Over time, no matter the differences in misery index between farmers and hunter-gatherers, the future belongs to those who are most fecund. Eventually other factors will also come into play, the higher densities of farming communities will likely result in the incubation of more lethal pathogens than possible at hunter-gatherer densities, so the "wave of advance" of farmers would also likely be foreshadowed by the die off of hunting & gathering communities who come into contact with the farmers. Cultural diffusion can also work simply through differential reproduction of indigenes who are "adopters" and those who are not. The record shows that farming took thousands of years to spread from the Middle East to Northern Europe, so the process was likely very gradual and undiscernable in many locales (in many areas farming and hunting and gathering were facultative activities, as attested by the eventually closing off the "King's Woods" by elites).

Addendum: In After the Ice Steven Mithen argues that agriculture was in part a response to harsher conditions after an initial expansion of hunter-gathering sendentarism in the Middle East 10,000 years ago. Mithen argues that farming was the only way for communities to support the higher population densities when ecological changes resulted in a decrease in the numbers of the game animals which they had previously depended on to maintain a relatively luxurious lifestyle with a local elite which consumed surplus production. The details are, to me, fundamentally irrelevant. The key point is that farming need not be the acquisition of a "superior" cultural practice on a conscious level, rather, its somewhat higher long term natural increase would inevitably result in "waves of advance" in demographics so that hunter-gatherers would be marginalized. I think it is instructive that traditionally hunting was the passtime of leisured elites, and no nomadic peoples exhibited any inclination to settle down and farm unless forced to by military defeat.

Reference Scan is back   posted by Razib @ 2/02/2007 08:15:00 AM

Just in time for A Week of Science Aziz is back with his magnetic resonance blog, Reference Scan. Neuro types should check it out.

Thursday, February 01, 2007

Earnings and skin color among immigrants   posted by p-ter @ 2/01/2007 07:02:00 PM

Shelley Batts links to an interesting study looking at skin color and wages among recent immigrants to the US. On a scale of skin color, a single point lighter was good for about a 1% increase in wages, about equivalent to the effect seen for an additional inch of height.

The statistical analysis is pretty standard; nothing atrocious pops out at me (the obvious parameters-- country of origin, ability to speak English, occupation, etc-- were all included in the model), though they didn't control for IQ. But let's assume the effect is real. The hypothesis generally mooted for the association between height or attractiveness and wages passes through some sort of personality effect-- tall people are more confident, or more outgoing, or something along those lines. Is it possible there's a similar thing going on here?

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Resolving the hotspot paradox   posted by p-ter @ 2/01/2007 03:26:00 PM

When, a while back, the topic of the "hotspot paradox" came up, I imagined a number of fairly straightforward analyses that would be important first steps in the resolution of said paradox. As a new paper suggests that others have very similar ideas (and I don't have the time to get into a new project right now), I figured I'd throw my thoughts out there.

First, a simple formulation of the hotspot paradox-- recombination hotspots are places in the genome the are particularly likely to be involved in recombination during meiosis. In the first steps of recombination, one allele initiates the entire process; you could imagine a particular sequence being more prone to this initiation than others. However, during recombination, the initiating sequence is replaced by the other sequence (on a very small scale, see this figure). Thus, if there are two alleles-- a "hot" allele and a "cold" allele, eventually the "cold" allele will become fixed and there will be no recombination. The paradox, then, is that recombination still occurs (read the post linked above and the links therein if this doesn't make sense).

Personally, I don't find this so paradoxical-- it just simply means that there are factors other than local sequence variation that determine the location of a recombination event. So to resolve the paradox, one would just need to identify those factors and find out how they do whatever they do. Simple enough.

To find these factors, one could just use genetic mapping, treating hotspot intensity as a phenotype just like any other. The key for this approach is that there is variation in the population you're using-- if everyone had the same hotspots with the same recombination rate, mapping the intensity of a hotspot just wouldn't work (mapping the variation of a phenotype only works, obviously, if there is indeed variation). The paper I linked to above demonstrates exactly that-- people differ in where their recombination events occur. Note that the authors of the study are the same ones who first characterized variation in gene expression in humans, variation then then mapped, leading to a number of high profile papers. There's no doubt that they would love to map this phenotype as well.

But there are also some hints that the publicly available data set they're working with doesn't have everything they need to do the mapping. First, each parent has "only" 8 children on average, which means there aren't so many recombination events you can look at. They're forced to combine events into "recombination jungles", which are much larger (5 Mb) than recombination hotspots (a couple hundred bases) and presumably less robust.

To map the determinants of recombination in the genome, then, you'd need a pedigree with more children per family (I can think of only one off the top of my head). Alternatively, you could take a different approach and look only at a couple hotspots with high resolution using sperm typing. If you could look at the intensity of a few hotspots in a large number of men, it would be trivial (assuming you also have genome-wide genotypes for those men) to map the intensity back to causal loci in the genome. Any independently wealthy readers are encouraged to do this experiment and resolve the paradox.