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Friday, June 30, 2006
Over at The American Scene Ross posts about the conundrum that many couples face when having to discard their excess embryos in the context of in vitro fertilization. He states:
I have basically argued before that the axiomatic arguments made by both sides are a sham. I do not deny that pro-life individuals sincerley believe that life begins at conception, but, I do question why if abortion is a "genocide" equivalent to the "holocaust" they not take up arms in a just war against this murder? Yes, I know there are ways you can "reason" against such violence in the name of a good cause, but I find such reasoning as persuasive as "penumbras" which suggest a "right" to "privacy" in the American Constitution. Ross is correct to note that couples do not view embryos as a "clump of cells," but neither does this imply that such attachment is equivalent to that that they would feel toward a 3 year old child. I would argue that "pro-life" sentiment is roughly proportional to the degree of resemblence of the embryo/fetus to a conventional human physiognomy. And I do not believe that all such sentiment derives from socialization, much of it is hard-wired into us. Over the past generation cognitive science has suggested that there are powerful biases in our mental hardware which constrains and shapes how we perceive the world. For example, it seems clear that we have primed hardware geared toward facial recognition. And, this might have moral implications. I offer this research to illustrate the thrust of my point:
Two points:
My rough argument is that unconscious intuitional inputs shape how people "reason" about moral questions. I am certain that pro-life activists can give you rational, cogent and axiomatically precise1 reasons for why they stand and protest outside clinics which they consider dens of murder as opposed to entering and tearing the doctors away from their death devices, by force if necessary. But, I believe that mental subprocesses in regards to analyzing and categorizing inputs as "human" or "non-human" have a strong role to play underlying the persuasiveness of a chain of reasoning. This argument can be inverted, there are obvious reasons then why pro-choice people flinch and are offended when they see photographs of aborted fetuses. They may intellectually assert that they were just a cluster of cells, but clearly they are made uncomfortable by the resemeblence between the fetus and a nenonate. By logic alone I would hold that pro-life individuals should kill all those who deal in death in the name of a greater good (the lives of innocents), while those who argue that fetuses are just a "clump of cells" should have no hesitation in using such tissue for dog food and the like. Does this speak to Ross' implication that we need to look beyond intuition and rely on reason? I guess I would say that in this case the reasoning is rather specious, insofar as a plain reading of personhood beginning at conception would imply rather drastic action which only a few pro-life individuals are willing to commit. The rhetoric and averred positions are, I believe, far more distinct than what you would excavate from their moral guts. Addendum: It is well known that many pre-Christian European cultures practiced infanticide. This is a human universal, there is a tendency for genuine emotional attachment in cultures where infant mortality is high and infanticide not unknown to be delayed until a considerable time after birth and even into toddlerhood. Sometimes this is explicated in the idea that personhood only emerges at a fixed point after birth (e.g., at age 3). One might make an analogy to the common conventions of when individuals have free will and are responsible for their actions. In Mormonism that age is 7. Among many Muslims it is believed that small children are like angels and incapable of genuine sin because they know not what they do. But in any case, my point is that Christianity banished infanticide. Or did it? In the 18th century many poor families in France sent their children to "orphanages." The mortality rates at these "orphanages" by the age of 5 could be as high as 95% (source: Mother Nature). So clearly, the Catholic French, no longer pagans, and in fact subjects of the most Christian King, believed that their children had souls and that their lives were sacred, so they did not kill them when they could not support them. The simply sent them to the orphanage where they would almost certainly die of neglect. My point is that Christian ideals were enforced while the brutish realities of human "rationality" continued. Also, check out Ross debating Matthew Yglesias debating on abortion. Go 2/3 ahead, I liked that Yglesias didn't concoct a fake a priori chain of reasoning. Though I think he would look more seemly with a shorter buzz cut. 1 - Please note that I mean mostly Catholics here. By the time evangelicals "noticed" the abortion issue the Catholics had elucidated most of the reasoned arguments against abortion so there was no need for them to generate their own. Please note in the book Catholicism and American Freedom there is documentation of the fact that the evangelical flagship magazine, Christianity Today, an article was published in the late 1960s that was cautiously hopeful about the trend toward reproductive freedom in the United States. Remember, Ronald Reagan was the one who signed legislation which decriminalized abortion in California in the 1960s.
As of this morning the journal Intelligence has a positive review of Lynn's Race Differences in Intelligence, from behavior geneticist John Loehlin. One issue raised earlier was the reliability of the numbers Lynn reports. Loehlin writes:
Are the numbers accurate? I checked a sample of 40 of the 615 rows in the IQ tables against their sources. . . Result: 14 of the 40, about 1 in 3, showed discrepancies, although mostly minor ones. For example, there were 9 with discrepancies in Ns, such as using an overall N from the study instead of the actual N on which the particular IQ was based. In a similar number of cases, the ages or age ranges were a bit off. . . my [IQ score] estimates and the values in the tables were typically within a couple of IQ points. I only came across one large discrepancy - an IQ 14 points too high (in Table 12.1, row 20; due, according to an e-mail from Lynn, to a clerical error in adding instead of subtracting a Flynn correction). The citations and references were, on the whole, accurate. In short: Yes, the general trends in the tables are probably dependable, if the assumptions regarding Flynn effects, etc., are correct, but it is prudent (as always) to check with original sources before quoting particular results. Loehlin concludes in a manner similar to my review: Is this book the final word on race differences in intelligence? Of course not. But Richard Lynn is a major player, and it is good to have his extensive work on this topic together in one place. Future workers who address these matters under this or any other label will find that Lynn has done a lot of spadework for them. And they will also find that there is plenty to ponder over within these pages.
I have a post on my other weblog where I'm asking about why mathematical disciplines tend to more conservative in academia. I know there are many references in JSTOR but I'm strapped for time, so could people please dump references into the comment box? I am especially interested in the psychometric finding (I've seen it!) that shows high IQ individuals stronger in math than verbal skills tend to be more conservative while the inverse are more liberal. Thanks ahead.
When looking for genes or alleles involved in a phenotype, especially "complex" phenotypes where many genetic factors are involved, the most powerful approach is often an association study-- type a large number of variants in some cases and some controls (or just a bunch of people if you're talking about a quantitive trait) and see if a certain variant is present more often in the cases than the controls.
As it's currently impractical to sequence a large number of genomes (and thus genotype all the possible genetic variants in the genome), one has to pick and choose which sites to genotype. Nowadays, the markers that are used are Single Nucleotide Polymorphisms (SNPs). But even with chips that can now type 500,000 SNPs in parallel, there's no way to genotype them all (there are an estimated 10 million SNPs in the genome). Plus, there are deletions, duplication, inversions, etc-- there are plenty of ways that two genomes can differ. Luckily, some SNPs are correlated with others, so that the genotype at one gives you information about the genotype at the other. So by typing 500,000 SNPs in a person, you could theoretically have information about the genotypes at millions of sites. The HapMap Project is an attempt to identify all the common SNPs in the genome and map the correlations between them. But as I noted before, there are also stuctural polymorphisms in the genome. An important question is: are there correlations between SNPs and structural polymorphisms? If there aren't, then doing an association study using only SNPs might miss a lot of the potential variation in the genome. Previous studies have shown that common deletions and SNPs are correlated. This is encouraging. However, a new study takes a closer look at some areas where copy number polymorphisms (i.e. one person might have three copies of the region, another person only two) are common, and finds that the variation is not very closely correlated with SNPs. This is less encouraging, as it means that it would be possible to do a full-genome association scan without taking into account any copy number variation in the sample. The authors present some possible reason for this lack of correlation, and I'm inclined to be optimistic-- most of the copy number polymorphisms they identify are rare, while the SNPs in the HapMap (especially the first version, which they use) are generally common. The correlation coefficient being highly dependant on the frequencies of the variants, it's possible that the newest version of the HapMap, or directed sequencing, could find better correlated SNPs. That said, if it turns out that structural polymorphisms aren't well-correlated with SNPs, it will be important to keep in mind-- perhaps SNP-based studies could be supplemented with assays designed to detect structural polymorphism.
Thursday, June 29, 2006
Sex, Booze and Violence - Another tale from the Blank Slate
posted by
dobeln @ 6/29/2006 07:06:00 AM
The Swedish government, a world leader in gender equity, decided last year to ban bars and restaurants from enforcing different ages of admittance for men and women. Up until then it was commonplace to allow women to enter at, say, age 20, while the men had to wait until they were 22 or so to get in.
Now, I know this will shock you all, but according to local police this exercise in equality has led to increased levels of violence in Stockholm. According to "Stockholm City": We noticed that violence went up last autumn, that's why we launched an inquiry. It shows that when bars have dropped age limits for guys, they admit these younger guys who can't handle alcohol very well, and then you have a fight on your hands, says Lars Lehman. Why, it's almost as if men and women were different or something!
Wednesday, June 28, 2006
I can't get enough Dinosaur Comics. This might be my favorite site on the internet.
T-Rex on: HeLa Cells, Thermodynamics, Genetics, Philosophy, Intelligent Design, and Science vs. Religion (prequel, 1, 2, and 3). OK, enough. Get back to work!
The March 2006 issue of Cytogenetic and Genome Research was entirely dedicated to genomic imprinting. I know some of y'all cats are into this business. There's one by Haig entitled Intragenomic Politics, and several on regulatory mechanisms which are more my speed, including one about small non-coding RNAs.
Of course, the articles aren't free, but perhaps arrangements could be made for the really important ones.
Tuesday, June 27, 2006
Every once in a while I realize something with my conscious mind that I've understood implicitly for a long time. Such a thing happened to me yesterday, while reading a post on Stalin, by Amritas. It is this: S = P + E Social Status equals Political Capital plus Economic Capital Now, if someone were to have just shown me that equation, I would probably have been unimpressed. It seems like a definition, a tautology, a pseudo-mathematical formulation of the expression "socioeconomic status". What I suddenly realized, though, is that this formula has tremendous explanatory power. So much so, that I want to call it the "Universal Law of Interpersonal Dynamics". Now, I am not a psychologist, sociologist, or anthropologist, and I am not familiar with the literature, so I don't claim that it's an original idea. I'm sure that such a thing must have be expounded upon by someone before me. But I'm a fairly well-educated person, and I've never encountered such a thing in any popular forum. Assuming that it more-or-less stands after it is posted, it deserves to be popularized. Here's an example of its explanatory power: If we assume that a major human drive is to maximize S, we can predict that people with high P will attempt to minimize the value of E (since S-maximization is a zero-sum game). And so we see. Throughout history there has been an attempt to ennoble P while stigmatizing E. Conversely, throughout history, people with high E use it to acquire P. Thus, in today's society we see that socially adept people, who have inborn P skills, tend to favor socialism or big government - where their skills are most valuable, while economically productive people are often frustrated by the fact that their concrete contribution to society is deplored. Now, you might ask yourself why the reverse isn't true, why people with high P don't use it to acquire E, while people with high E don't attempt to stigmatize P? Well, I think that is true. But, while the equation is mathematically symmetrical, the nature of P-talent and E-talent is not. P-talent can be used to acquire E from the E-adept, but the E-adept are no match for the P-adept in the attempt to stigmatize P. Furthermore, P is endogenous to the system, while E is exogenous. In other words, the P-adept have the ability to manipulate the system itself to make P-talent more valuable in acquiring E, while the E-adept have no ability to manipulate the external environment to make E-talent more valuable in acquiring P. Of course not all people fall neatly into one of these two categories. Some people are naturally both P-adept and E-adept, while others, unfortunately, are neither. This, too, is asymmetrical in its implications, since the both-adept have a choice of pursuing either P-strategies or E-strategies (indeed, there are many real-world applications which leverage both), but the neither-adept have no choice but to support a P-strategy, since cooperation of this kind is itself a P-strategy (libertarianism, by contrast, would get them neither P nor E). Put another way: Socialism is all about taking the "economic" out of "socioeconomic status", meaning that gaining social status becomes a purely political game. Which is why it appeals to both the socially adept and the economically inadept. They both hate status that is based on dirty economics. Those boors don't deserve it. Now, I don't think that this is a new phenomenon at all. Back in hunter-gatherer times, I have no doubt that there were already people who gained social status through P-strategies. But the social systems were so small, and the harsh economic realities to obvious, that it probably took a lot of political-talent units to equal one economic-talent unit. Now, however, societies are very large and complex, and the sources of economic productivity are not well-understood. The playing-field has tipped dramatically toward the socially adept, the merely economically adept now often, endearingly, termed "losers". I leave it as an exercise to the reader to show how the Universal Law of Interpersonal Dynamics predicts the following:
(Cross-posted on Rishon Rishon.)
While I'm recommending weblogs, I thought I'd point readers to Clark Gobles' Mormon Philosophy & Theology. Now, I know that most readers here aren't religious, and there is probably a mildly anti-philosophical bias as well, but, if you want to sample an "Intermontane" flavor of Derrida discourse, Clark is your man. Think of him as the Napoleon Dynamite of philosophy and cognitive psychology.
If you're at all interested in long-term potentiation (LTP) and long-term depression (LTD), you're going to want to read this review/opinion by Govindarajan, Kelleher, and Tonegawa in July's Nature Reviews Neuroscience. This team has previously written one of the best comprehensive reviews of neuronal translation control mechanisms. They do a brief reprise on that business, broadly suggesting which signaling molecules are involved and emphasizing that protein synthesis happens local to the stimulated synapses. Then they turn their attention to synaptic tagging/capture experiments for the bulk of the paper.
As some here must be sick of hearing by now, memories are likely to be stored as changes in synaptic weights. LTP and LTD are increases and decreases respectively in synaptic weight. The long-lasting (late) phases of LTP and LTD require protein synthesis. Govindarajan et al make the case that this is achieved by increased efficiency in general translation machinery. Synaptic tagging and cross-tagging experiments have shown that the proteins generated by a given L-LTP or L-LTD inducing stimulus can be captured by synapses that have only received E(early)-LTP or E-LTD inducing stimuli, thus producing late phase plasticity. Govindarajan et al note that transport speeds are known for important plasticity-related proteins, like AMPA receptor subunits, and that it would take them about an hour to move the length of your average dendritic branch. In tagging experiments, if L-LTP and E-LTP stimuli are separated by around this length of time, the capture of plasticity proteins does not occur. So they are suggesting that plasticity proteins are probably only shared within a dendritic branch, producing 'clusters' of synapses that have undergone long-term change. I'm not sure the transport speed issue is central to their theory or if you could simply argue that the generated proteins are degraded in that hour, but one prediction they didn't make that I think follows is that in cell populations with shorter dendritic branches you should see greater spread of these induced proteins or maybe a longer time window for capture, and vice versa. The clustered plasticity model carries advantages over a dispersed model where synapses are changed at more random sites across the neuron in part because stimulated synapses in the same dendritic branch sum supralinearly. The whole of the stimulation is greater than the sum of its parts. To get cells to fire in the dispersed model would take a lot more network activation than that in the clustered model. The authors argue that this has implications for ease of memory recall. I have an interest in trying to understand the relationship between broad-scale network activities like theta oscillations and sharp-wave ripples and the small scale on which plasticity is studied. There is a little bit about that in this review. ...assuming that connectivity between the set of presynaptic neurons and postsynaptic neurons is random, clustered plasticity would be advantageous compared with dispersed plasticity only if the density of active inputs is high enough to enable the setting of potentiation and depression tags at multiple synapses within at least one dendritic branch in the postsynaptic neuron. In support of this, 30-50% of hippocampal cells are active in a given environment, hippocampal activity resembles theta-burst stimulation, which has been used as a robust inducer of plasticity, and 45-75% of synapses are capable of undergoing plasticity. Therefore, in an episode (a sequence of related events; the hippocampus is important for acquiring memory of such sequences), it is probable that there is sufficient activation so as to result in many dendritic branches in the hippocampus containing multiple tagged synapses. The probability of this being the case is even higher when sharp waves are considered. In rats, it has recently been shown that sharp wave activity during exploration carries information about the environment explored by the animal. Furthermore, sharp wave-type activity would lead to high enough activity to enable activation of multiple synapses in a dendritic branch. I don't think this quite does it, but at least folks are starting to turn their attention to it. It's weird to try to make actual predictions about memory based on this hour timeframe of integration. Would a given dendritic branch represent events in about a two-hour window with a peak in the very middle? When a salient or unexpected event occurs that might drive neuromodulation and increase protein synthesis occurs, do events an hour on either side of that event benefit from the upregulation? How much time worth of events is integrated in a single sharp-wave ripple or compressed in a single theta oscillation? All I know now is about distances that are integrated and it seems like it is not an hour's of exploration.
Via Free Association comes a profile of Craig Venter, the so-called "maverick biologist".
1. Apparently Venter is going to be publishing his own genome sequence shortly and making it publicly available, which is pretty cool. If technically trivial, would you do the same? I'll go ahead and say I would--Venter makes the good point that we don't know what most of it does anyways, so GATTACA-like scenarios are far from being reality. And data is hard enough to come by as it is; I'd be happy to let other people play around with my genome sequence and see what they find. 2. The article makes some mention of the "race" to sequence the genome, and how it ended in a tie. I've explained before why that's BS: Venter and Celera published eventually published an independent genome sequence, but they didn't do it until 2004.
When I'm writin' I'm trapped in between the lines. I escape when I finish the rhyme. - Rakim
I wanted to go a little deeper into one of the new papers in the recent Cell. It is a set of findings in miRNA research that can be tangentially related to synaptic plasticity. For the field of miRNA research, this paper is important because it is one of the clearest examples of miRNA derepression. To date, in most examples of miRNA-mediated gene silencing the target RNA is moved to P bodies where it is eventually degraded. Why make all this RNA just to destroy it? Not to mention that the system would be a lot more flexible if new RNAs didn't have to be transcribed each time new proteins were needed. A couple papers have come out recently that show RNAs being released from repression in response to environmental signals, but this one proposes a distinct mechanism and examines the relationship with P bodies. Interestingly, the other two papers were both concerned with synaptic plasticity. The authors were able to find modular elements in the 3' UTR (untranslated region, a common area for regulatory elements in mRNA) of the cationic amino acid transporter 1 (CAT-1) mRNA that confer susceptibility to repression by a specific miRNA (miR-122) and derepression by interaction with a protein called HuR. These elements can act independently of the rest of the CAT-1 message. For instance, certain chunks of the 3' UTR can be attached to a glowy protein stolen from fireflies (luciferase) to make it a target for miR-122. They do a decent job mimicking the behavior of CAT-1 in a human hepatoma cell line in ideal growth conditions. Under less than ideal growth conditions, such as amino acid starvation, CAT-1 protein is upregulated within an hour while CAT-1 mRNA comes up in a range around 4 hours. So CAT-1 protein is regulated independently of the mRNA levels. The luciferase reporter constructs that only contain miR-122 binding sites are not affected in the starvation condition. Translation remains low. A further 1-kb of the CAT-1 3' UTR is needed for a protein increase in response to cellular stress. This chunk of UTR contains three adenine (A) and uracil (U) rich regions. These, like other AU-rich elements (AREs), interact with an RNA-binding protein called HuR. People have generally thought that Hu binding to AREs stabilized the RNA by blocking exonucleolytic degradation. The authors carried out binding assays and also measured the effect of each of these AREs independent of the others. They found that the strength of HuR binding to a particular ARE predicts the amount of stress-inducibility of a reporter with that ARE. Thus, the story so far is that miR-122 represses CAT-1 constitutively, but in response to certain environmental conditions, HuR becomes active and binds to elements downstream from the miRNA sites and derepresses CAT-1. Now, often when a miRNA binds its target they will both localize to cytoplasmic processing bodies (PBs). This is the case for CAT-1 and miR-122. Under normal conditions CAT-1 is found in PBs, but in response to starvation CAT-1 moves out of PBs and associates with polysomes (protein synthesis machinery). HuR binding to the AREs is necessary for this relocalization. The authors mention a preliminary finding that Ago2 (of Slicer fame) remains associated with CAT-1 when it relocalizes, but they show data that miR-122 abundance in PBs doesn't change. I find it a little difficult to square these two, as one would expect that the interaction of Ago2 and CAT-1 RNA would be mediated by the miRNA, but perhaps miR-122 is just so abundant that some of it can wander off with CAT-1 without making a dent. So HuR is little like a molecular Lee Marvin rescuing CAT from certain destruction (yes, I went there). The ability of HuR to do this even when the AREs are on a different RNA being repressed by a different miRNA makes the mechanism seem more general. HuR is part of a family of proteins called ELAV-like RNA-binding or Hu proteins, some of which (HuB, HuC, and HuD) are neuron-specific. Research into regulation of neuronal proteins by these Hu proteins goes back several years now and has focused on regulation of a protein called GAP-43. GAP-43 is associated with axonal growth during development and is phosphorylated by protein kinase C (PKC) in response to LTP induction. It is not entirely clear what GAP-43 does at a mechanistic level yet, but the vague impression is that when GAP-43 is involved axons are growing and establishing new connections. I find it interesting that PKC may be regulating GAP-43 at more than one level. PKC can directly phosphorylate GAP-43 which leads to a number of changes in intracellular and membrane signaling. PKC activation also leads to upregulation of all three neuron-specific Hu family proteins. These proteins in turn stabilize GAP-43 mRNA and lead to GAP-43 protein increase. Hu proteins and GAP-43 are regulated in response to hippocampus-dependent learning tasks too. Abstract: Increase of the RNA-binding protein HuD and posttranscriptional up-regulation of the GAP-43 gene during spatial memory The Morris water maze is one of the most common behavioral tasks used to assess hippocampal function in rodents. It is assumed that the animals are learning to navigate in a two-dimensional space using distal cues to create a cognitive map. All of this should make synaptic changes in the hippocampus. Others have shown directly using zinc staining that over-training on the water maze task can actually lead to axonal growth into new layers of the hippocampus, which is a major structural change that may well contribute to permanent memory storage. I guess what I'm saying is that GAP-43 is probably a good candidate for a memory-related molecule that is regulated by miRNAs. If I had the bioinformatics know-how I would go look up the potential miRNA binding sites in GAP-43's 3' UTR. Then I would look to see if they had similar distance from the AREs in GAP-43's 3' UTR as they do in CAT-1. Then I would stretch and see if other proteins that have similar function to GAP-43 and share conserved sequences such as MARCKS and Neurogranin also have these sorts of motifs. These guys are also regulated in response to synaptic plasticity, and I think it would be really cool if they were regulated in coordination by Hu proteins derepressing the same miRNA. MARCKS has a CU-rich element that is recognized by HuD and HuR. I'm really thinking that miRNAs, since they don't have to be specific, could regulate protein modules, so GAP-43 and MARCKS could share the same miRNA. Here are a couple other interesting things that I haven't really integrated. Recently, a SNP in a human neuron-specific Hu protein (ELAVL4) was associated with age-at-onset of Parkinson's disease. Also, HuD and HuR appear to regulate acetylcholinesterase through an ARE in its 3' UTR. 1 in 20 human genes have AU-rich elements, so just tying things together with AREs isn't going to be enough, but if things had AREs and similar miRNA-binding sites I could see room for coordination.
Monday, June 26, 2006
Well, pretty soon Craig Newmark's cherubic visage is going to be on Time. Craig's List is expanding and taking over the world.
So, the numbers of "personals" posted in Sweden's Craig's List: 131. Finland? 34. As for the debate about which is the "gay capital of Europe" between partisans of Stockholm & Helsinki: Men seeking men in Stockholm: 13 Men seeking men in Helsinki: 1 (and I think this is a bisexual individual?) Are Finns even terrified of the internet? It seems that they are proto-Solarians. (note, Finland's total fertility rate is a bit higher than Sweden's).
If you're a pseudo-intellectual such as myself who gets tired of reading all the time but still wants to be able to pretend to be familiar with the great thinkers and major political figures of our time, you may be interested to find that many episodes of Charlie Rose are available for free on Google Video right now.
I have thus far been entertained and educated watching Milton Friedman, Bashar Al-Assad (President of Syria), Salman Rushdie and Deepa Mehta, and Shirin Neshat.
Half Sigma has piqued my interest of late. He makes really bold claims, above and beyond what a cautious reading of data might imply, but, at least he consults the data. That's more than can be said for most political blogging, which seems to draw from the bullshit of the heart. Inductivist is worth a go too (seem's that he's Half Sigma's GSS dealer that started him on the habit). Some of the sample sizes are way too small for my taste, but at least they deal in samples which have an N you can criticize. Read them like you'd read Peter Gammons (I never liked Gammons actually, I was always a Dick Schaap Sport's Reporters kind of guy, but Schaap is dead and I don't have a TV).
Before you read this, check out Razib's excellent 10 questions with Jim Crow, which I am unfortunately knocking off the top of the blog.
So a little while back, I wrote about a paper describing the evolution of a bacteria over the course of an infection (Aetiology also had a post--a better one, truth be told-- on the same paper). I speculated that different individuals might present different environments for the bacteria, thus presenting slightly different selective pressures. Moving up one level, one could imagine two populations being different genetically, so a pathogen could in theory adapt differently to life being passed around in the two. But does this happen? A new paper suggests that the answer is yes. The authors analyse HIV sequences from a couple genes isolated from individuals in two different African populations. From the sequences, they determine which codons are under selection in the different populations, and come up with seven amino acid sites under differential selection. They link this to the different genetics (especially genetics of the immune response) of the two groups. I certainly find that plausible, but I think there's certainly another possibility here: essentially, there's more than one way to skin a cat. We're talking about differential selection at the level of a single codon and assuming that the differential selection reflects differential selective pressures in the populations. But maybe the different virus populations just came across different, yet equivalent, ways to adapt to the same selective pressures. That is, maybe we're just seeing an example of the stochasticity of evolution.
James F. Crow is Professor Emeritus of Genetics at the University of Wisconsin. A collaborator with Motoo Kimura on Neutral Theory, he remains an active member of the evolutionary genetics community.
1) In 2002 in "Perspective: Here's to Fisher, additive genetic variance, and the fundamental theorem of natural selection," you conclude, "is there any other quantity that captures so much evolutionary meaning in such a simple way?" in reference to additive genetic variance. And yet, what about other factors like statistical epistasis? Do gene-gene interactions pack enough of an evolutionary punch to be anything more than a footnote in God's Book? Have you seen Loren Rieseberg's work at Indiana which points to the importance of loci of large effect? The remarkable thing about additive genetic variance is that it predicts the effect of selection, even in the presence of dominance and epistasis. Nature seems to follow least-squares principles. The result is that the additive component of variance pulls out of dominance and epistatic variance those components associated with allele frequency change under selection. Of course the theory is not exact, but it is a very good first approximation. Fisher did not ignore epistasis, as some have said; rather he showed how selection can utilize epistatic (and dominance) components of variance. On a more technical level, Kimura showed that under selection with loose linkage the population rather soon attains a state in which the linkage-disequilibrium variance approximately cancels the epistatic variance. Thus, under this circumstance the effects of selection are better predicted by ignoring additive by additive epistatic variance than by including it. See my book with Kimura (1970, p. 217 ff). I am aware of Rieseberg's work on sunflowers. QTL mapping and various other molecular methods are indeed finding alleles with large effect in many species. It is inevitable that the first genes discovered will be those with largest effect, so I expect alleles with smaller effects to follow. How large a part genes with large effect have played in evolution is still up in the air, as far as I know. But they are getting more emphasis now than in the recent past. 2) R.A. Fisher is reputed to have aimed for an "ideal gas law" of evolutionary genetics (The Fundamental Theorem of Natural Selection?). In the paper above you state that you expect "mathematical theory" to become more "general and rigorous." How near are we to an "ideal gas law" for evolutionary genetics which takes the step beyond a qualitative heuristic, if such a thing is possible? It is not surprising that Fisher, who was trained in classical physics, would use physical analogies. Various mathematical geneticists, such as Tom Nagylaki of the University of Chicago, have found more general and accurate expressions, and I expect this to continue. I don't expect evolution to imitate classical physics in such things as an ideal gas law. For example, Fisher's analogizing fitness with entropy is better regarded as a metaphor than as rigorous science. 3) Computational methods have come to the fore within the past generation as an alternative to analytic modes for attacking theoretical problems. Do you believe this has been wholly a good thing, and if not, can you elaborate? Yes, I think it is a good thing. Many problems in population genetics cannot be solved by a mathematician, no matter how gifted. Although I expect improvements in the mathematical theory, it is already clear that computer methods are very powerful. This is good. It also permits people with limited mathematical knowledge to work on important problems; but I don't expect it to entirely replace mathematical theory. 4) The 1966 the Lewontin and Hubby allozyme papers reported a great deal more polymorphism than either the followers of Wright or Fisher expected (i.e., Balance School and Classical School). The work with Neutral Theory and its successors stepped into the theoretical breach. In hindsight, does it seem that Neutral Theory was plausible a priori, or did the evolutionary geneticists of the pre-DNA era simply miss the possibility (and ubiquity) of neutral substitutions because they did not have a good mental model of variation on the molecular level? The amount of variability disclosed by Lewontin and Hubby was more than some expected, although it did not seem particularly surprising to me. It is important to say, as Lewontin was the first to articulate, that the difference between the classical and balance schools does not lie in the amount of variability (variability is an observable and not a theoretical quantity). Rather the difference in the two schools was the way in which variability was thought to be maintained: mainly by mutation-selection balance or mainly be heterosis. I think neutral variability came as a surprise to almost everybody. Of course, it was an outgrowth of molecular methodology, which made possible the study of DNA itself rather than phenotypic traits. I don't think it was the absence of a mental model as much as not knowing in advance the enormous number of nucleotides in the genome, and how little of the DNA, especially in mammals, is protein-coding. 5) Do you believe that group selection (i.e., inter-demic selection) might have played a significant role in the evolution of H. sapiens sapiens? I'm sure it did, for our ancestors for many years had a tribal existence with competition, even wars, between groups. I suspect that group structure may be responsible for much altruistic behavior. In a small group everyone is related, so behaving cooperatively or altruistically toward members of a group is the genetic equivalent of kin-selection. Muller and others emphasized this idea. There is a level of relatedness in a group at which the welfare of the group prevails over the welfare of individuals. Egbert Leigh quantified this as did Aoki and I. 6) When your commentary on Arthur Jensen's infamous Harvard Educational Review article on the inheritance of IQ and racial differences was published in 1969, did you have any inkling that the issues raised by Jensen would remain largely unresolved over thirty-five years later? What kind of evidence do you think would decide these issues one way or the other? I did not expect the issues to be resolved soon, for there were no new methods that promised be more informative. Of course, the structure of DNA had been discovered, but the powerful methods now available had not yet been developed. I think further identification of individual genes, usually by molecular methods, and a combination of statistical and molecular methods are pointing the way toward a solution. I don't expect racial differences to be either entirely genetic or entirely environmental, but of course I don't know the relative amount; it is likely to be different for different traits and different human groups. 7) In you recent review of "Genes in Conflict" you state in reference to Robert Trivers' papers published in the 1970s that, "They were ignored by most social scientists, who were reluctant to consider natural selection as a cause of human behavioral traits, and they were bitterly attacked by marxists for reasons of doctrine." Recently the University of Chicago evolutionary genomicist Bruce Lahn has come under fire (as profiled in The Wall Street Journal, June 16th edition) for his study of ASPM, a locus implicated in brain development, from both geneticists and non-geneticists because of the sensitivity of the possibility of intergroup variation due to differential evolutionary forces within the past 40,000 years. Last year the paper put forward by Gregory Cochran, Henry Harpending and Jason Hardy that argued high Ashkenazi IQ was due to recent natural selection also ignited a firestorm. It seems that we are entering a new era of human genetics as a great deal of data will soon be available for theorists to analyze (e.g. the HapMap and its successors). Are "controversial" questions still going to be off limits, or will the science compel the political and cultural taboos to step aside? I hope that such questions can be approached with the same objectivity as that when we study inheritance of bristle number in Drosophila, but I don't expect it soon. There are too many strongly held opinions. I thought Lahn had a clever idea in thinking that the normal alleles of head-reducing mutants might be responsible for evolution of larger heads in human ancestry. Likewise, I think that Cochran et al. are fully entitled to consider the reasons for Jewish intelligence and I found their arguments interesting. In my view it is wrong to say that research in this area -- assuming it is well done -- is out of order. I feel srongly that we should not discourage a line of research because someone might not like a possible outcome. 8) If a budding evolutionary thinker had to read one book or paper that excluded Charles Darwin's body of work, what would you recommend? I would recommend Fisher's "Genetical Theory of Natural Selection". But the reader should be prepared to find it tough going. Fisher's elegant obscurity has left many of us baffled, but entranced. Your "budding thinker" might want to stop before the last four chapters, which are more dated than the rest of the book. And by all means, read the 1999 variorum edition. It's appendices explain many of the book's obscurities. 9) You've defended "bean bag genetics" (Nature, 2001). Lynn Margulis has complimented you personally, but seems to dismiss the whole endeavor of theoretical evolutionary biology as trivial and irrelevant when set next to the concrete realities of molecular and cell biology. Over the past generation molecular biology has dethroned physics as the "Queen of Sciences" in regards to prestige, and many young biologists seemed to take the work of Fisher, Wright, Haldane, Kimura and yourself for granted and do not concern themselves with the abstract "big picture" when mechanistic details on the DNA scale needed to be elucidated. Do you believe that over the next generation more young people will begin to look once more at evolutionary biology in its grandest abstract reaches as the "low hanging fruit" in molecular biology is exhausted? Lynn Margulis is a long-time personal friend and has done important work on the origin of cellular organelles, but I disagree with her on this issue. It is true that the elegant theory of Fisher, Wright, Haldane, Kimura, and Malécot was less useful than might have been expected, because of lack of good data to whieh the theory was applicable. But that is no longer true. Molecular evolution has provided an abundance of data and the theory now has plenty of important applications. In particular, the neutral theory of molecular evolution has had great heuristic and predictive value, and it owes a great deal to Kimura's earlier theoretical work, which built on the foundations of the pioneers. Lynn might change her mind if she looked at some of the striking results gotten by combining molecular measurements with population genetics theory. Maybe I should ask her! 10) If you had to have one last glass of beer, and your drinking partner was going to be either Fisher, Wright or Haldane, who would you choose, and why? I would choose Haldane, for his uninhibited willingness to speculate, his enormous erudition, his interest in almost everything, his irreverence, his wit, and his enjoyment of conversation. I am told that much of the good biology in Huxley's "Brave New World" is the result of his drinking partnership with Haldane. Labels: 10 questions
Gary Steinman is the researcher who published the findings that diet may modify fraternal twinning rates. I just listened to him giving an interview on the radio, and he made the following points:
Sunday, June 25, 2006
Below the fold is a map which shows where our Ozzie readers hail from....
 So what's up with Alice Springs? Is it just a nodal point for all the IPs from the great outback? Or are my posts about blonde aboriginals driving this?
...so what does equal causation?
A long article in The New York Times Magazine comes out the same week as a Pew Global Attitudes survey which suggests that British Muslims are by and large nuts. The interesting point is that continental European Muslims are less nuts than British Muslims. Too bad American Muslims weren't included in this survey, as my general impression is that they are less nuts than most European Muslim groups (though the bar here is really low).
Update: A nice little survey of "American" Muslims. Quotation marks because it seems the methodology used (looking at surnames) is likely to be skewed toward immigrants and the children of immigrants, leaving out converts. Addendum: In the comments: I think this is wrong to the first approximation, and my reason is this: more Muslims = more segregation = more distinct communal boundaries. Reduction in the number of Muslims coming in though would lead to less hostility from the mainstream/majority and the eventual reduction of alienation as the threatening counter-culture is eventually swallowed. Basically, this is simply the "a little anti-semitism is good for the Jews" style of argument. It is arguable that what is good for minority communities and self-styled leaders is not good for individual minorities. Similarly, a little patriarchy is good for the health of feminism and feminist organizations, even if it isn't good for individual women. Update: Jim Bender assumes that my assertion (implied) that continental Muslims are more rational has to do with jihadism. No, over half of British Muslims believe that the 9/11 hijackers weren't Arabs. This might be true, in which case the world I see and experience isn't the real world but a vale of lies. When individuals disagree on the basic fundamental aspects of reality as we know it there is no room for genuine discourse. This is the case with Creationists, they live in a fantasy-land and to them I surely do as well. In such a battle at the end of the day only one idea, one reality, can stand and breath within the ring (in this case, within national polities), it is a zero-sum game. Of course, victory is won if an illusion is driven into the private domain. Update II: Gay American Muslims & faux-hetero marriage.
Saturday, June 24, 2006
Ruminations on the relationship between religion and evolution at the Conservatives Against Intelligent Design website.
Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells:
Update: Previous commentary on ASPM.
The Trivers-Willard Hypothesis was proposed a generation ago, and there has been some empirical support for it. Now, Anna at Sepia Mutiny pointed me to this story who goes toward suggesting that different nutritional regimes can effect sex ratios. How would this work?
Well, some assumptions.... 1) Among mammals the conception rate of male zygotes is going to be higher than female zygotes because the Y chromosome is smaller than the X chromosome. 2) Because of lethal unmasked sex-linked traits, and immune suppressive impact of testosterone, the rate of spontaneous abortion of male fetuses should be higher than that of female fetuses 3) Ergo, the 104:100 ratio of males and females at birth in the United States is a reduction from a higher ratio at conception. Obviously data from other mammalian groups should be relevant for human beings. If we assume that more male fetuses are marginal than female fetuses (their fitness being reduced by non-lethal recessives unmasked because of operational haploidy) then stress during pregnancy might be assumed to disproportionately effect male fetuses. So you have a mechanism here to equalize sex ratios in a facultative fashion in stressed environments, or, bias toward males in an environment of abundance. Does this work for humans? Here is a list of sex ratios by country. I'll leave it to others to generate the appropriate regressions and correlations (obviously some data points, like China, should just be discarded)....
Friday, June 23, 2006
Steve Sailer has been on a rampage about the Donme recently. There are two overall lessons that the Donme can teach us.
1) The truths of human psychology. The Donme make the Millerites seem as credulous as Pyrrhonian skeptics. To say the Donme illustrate the depth of human credulity and irrationalism is trivial, but, that is certainly the start of any subsequent analysis. 2) As Steve points out, cultures are complex. As Americans, and citizens of an imperial nation, it would behoove us to appreciate this complexity and take it into account in making our decisions. But the reality is that time is finite, and representative government relieves us of the tedium of such things...in theory. As for the Donme specifically...well, I've tried to find literature on this group in college libraries, and there isn't much. Google print results in 17 and 19 hits respectefully for "Donme Turkey" and "Donmeh Turkey." What I think is something that we can spread the word about is the presence of Alevis in Turkey, which goes unnoticed by many. I recall a few years ago that a representative of Turkish origin in Germany a few years back had problems speaking to the greater Turkish community in that nation because of his Alevi background. As sage an authority on all things green as Ikram Saeed simply couldn't believe that 10-30% of Turks might not be Sunni. In any case, here's a map from Wikipedia (this concords with what I've read in the literature): 
Thursday, June 22, 2006
Adam K. Webb is the author of Beyond the Global Culture War and a lecturer at Harvard College. His specialization is world political thought, liberalism and antiliberalisms. Below are 10 questions....
Update: Adam K. Webb responds to criticisms and questions on the message board. 1) Dr. Webb, I have read your book, Beyond the Global Culture War, but I suspect few of my readers have (yet), so can you offer a succinct summary of your argument for us? The book traces the rise of liberal modernity and the global culture war it has sparked. You might call me a traditionalist with a deep commitment to social justice. I share the misgivings that many thinkers and movements around the world have about the flavour of the emerging global culture-consumerist excess, an obsession with markets, the erosion of traditional ways of life, and the like. But I fear that resistance today, whether from the fundamentalists, populists, nationalists, or other such folk, isn't going to do much to roll back what so many of us find objectionable. For one thing, it's too insular. The Islamists, the Christian Right, the indigenous activists-none of these are offering an alternative vision that speaks to humanity at large, rather than just to (some of) their own people. They fight against the liberal "end of history," but they're going to keep losing because they're not fighting on the same global scale. And the visions they do offer their own societies are off-putting to many, for obvious reasons. They're too defensive and too rigid. They claim to speak for some great and now defunct premodern civilisations, but they're hardly representative of the many layers of human experience and human aspirations that those civilisations really included. In the book I try to explain how liberal modernity gained ground, even though it doesn't really satisfy the deepest human needs. And I suggest a way out: a way to fight back against it in a kind of grand cross-cultural alliance of exactly the traditions it has put on the defensive for the last century. 2) In Beyond the Global Culture War you express some concern that the raw cultural material for resistance to liberal globalism is being diminished by the day, and we are facing the possibility of the "dark night" of the end of history passing over us. Forever is a long time, but do you imagine then that a liberal global culture can truly attain a steady equilibrium 'climax' state which suppresses cultural change in any "ethical" direction for a sustained period? No culture can remain in equilibrium for hundreds of years, in the sense of not changing at all. But a liberal global culture could remain dominant long enough to erode much of what inspires real resistance to it. That doesn't mean it would reach an equilibrium in the sense of satisfying people's needs. In the deepest sense, once one probes below the glitter of high living standards, I think liberal culture is intrinsically unsatisfying. That would still be true even if it delivered an iPod to every pocket and a Lexus beside every olive tree a century or two from now. Something would still be missing. But people in an unsatisfying culture aren't necessarily always aware of what they’re missing, or of real alternatives to it. In the developed West today, we see some of that directionless alienation. Stronger resistance lingers elsewhere in the world precisely because there are still lived practices, communities, and memories that inspire it. Once they're gone, all cultural change is likely to be from within, as variations on a theme. As I explain in the book, an atomist can be a libertarian, a social democrat, even an evangelical of the more individualistic sort. So there might still be changes within liberal culture, but the basic contours of the new global civilisation would be set. That is what is really at stake today: the shape of a future global civilisation, while we're still in the century or so when things are in flux. It's a time of rapid change, even vertigo, and will be for another couple of generations. But as many times in history, vertigo will give way to stability. I'd like that stability to be a global version of the great civilisations of the past, not the kind of self-indulgent technocracy that is now trying to lock in its own vision. 3) You allude to ethics and principles derived from religion and philosophy. Against this you set the models of the rational self-interested actor, which seems to derive in large part from neoclassical economics, though I suppose you would assert that the roots can be found in the general 'atomist' worldview. And yet it seems to me there is another alternative, and that is the model derived from cognitive psychology which contends that our minds are shaped by a particular biological architecture which results in biases and tendencies, a refutation of the behavioristic paradigm which rejected discussion of aspects of psychology beyond the empirical domain of inputs and outputs. In its application to economics this often implies that 'rationality is bounded,' or at least strongly constrained by the fact that our actions are often contingent upon non-reflective influences. Have you considered this dimension in regards to your meta-narrative? I think my overall argument about ethics is quite compatible with any insights we might get from biology and psychology. The former is about how people understand their place in the world, and what demands they place on themselves. The latter is about impulses that work on a less than conscious level. A culture can channel those impulses in better or worse directions. The human impulse to protect one's kin, for example, can be a building block of a larger culture of social responsibility in one time and place. In another time or place, it can take the form of what Edward Banfield called "amoral familism": a cutthroat disregard for everyone outside one's immediate circle. The fact that cultures vary shows that ethical commitments shape how deeper impulses play out, and even that there is a point where biology stops and conscious ethical agency really comes into its own. I focus on ethics in the book because we can do something about what is conscious, in a way that we can't do much about unconscious human nature. 4) My understanding is that the attitude of the Chinese mandarin class toward Xunzi, the early Confucian who most emphasized ritual as opposed to heart, was ambivalent because of the fact that it was his students who became the base for Legalism. On the other hand, some scholars contend that State Confucianism as it emerged under the Han dynasty owed a great deal to Xunzi and Legalism even though rhetorically it reviled them. What is your attitude toward Xunzi? Do ritual, heart and piety stand shoulder to shoulder, or do you emphasize one in your personal constellation of values? I's true that some of Xunzi's students became the founders of Legalism. But I suspect he would have frowned on the path they took. The Legalists were hard-headed pragmatists who tended to scoff at ethics. (They're eerily modern-sounding....) Xunzi was no soft idealist, but he was deeply committed to Confucianism. He was much like Aristotle in appreciating that living an ethical life required being habituated to good practices first. People needed to learn how to be good, through ritual and custom and law, rather than just relying on an innate goodness to come out, as Mencius tended to stress. While the later Confucian high culture elevated Mencius over Xunzi, perhaps because he seemed more idealistic, all the stress on custom and study smacked of Xunzi. Premodern China spoke Mencius but lived Xunzi, and benefited from doing both. Speaking for myself, I tend to think heart is more important than ritual, as you put it. That's probably because I see rituals varying across cultures, while the bettering of the heart at which they aim is more universal. I’m interested in common ground, and that often seems the easiest place to look. That said, I'm very aware of how important habits, instilled by a culture, are in forming people and sustaining their better natures. It's very easy to talk about one's heart as the most important thing, and then slide into a kind of shapeless complacency, especially if a society on the whole is not very hospitable to virtue. Rituals can fortify. I imagine Xunzi would agree: rituals are important, but they're important because of where they lead, which is to the heart. 5) You express the hope that a cosmopolitan international 'virtuocracy' may emerge in your World Commonwealth (or, more accurately, it will be the cause of the emergence of that polity). This virtuocracy would be an expression of unity in diversity, not erasing differences of outlook between traditions, while at the same time reaching a respectful understanding of various visions and their common goal. I can see this in the case of a Hindu or East Asian virtuocracy, but I am somewhat more skeptical of the participation of Islamic or Christian civilization in the sense that it seems that 'Abrahamic' traditions have come to emphasize an exclusive and almost tribal attitude toward the other streams of human culture. While 'orthodox' Hindus and Confucians seem to be able to express an attitude toward pluralism which is not hostile, it seems to me that fundamentally what we term 'orthodox' followers of the Abrahamic traditions, as opposed to liberal revisionists and accommodationists, can not fundamentally accept pluralism as anything more than a temporary compromise in the ideological Forever War. What is your opinion in regards to this issue? It's true that in some ways we can contrast Christianity and Islam, on the one hand, with Hinduism and Confucianism, on the other. The two pairs handle encounters differently, and see the boundaries between "inside" and "outside" differently. But we should be careful about saying that the two Asian traditions are more pluralistic than the two Abrahamic ones because of that. The real difference lies in how they see their beliefs as being transmissible to outsiders, and how they see beliefs interlocking when they meet. Take one example. When the Jesuit missionaries went to China in the late 1500s, they developed a rapport with some of the mandarins and even gained a few converts. The Jesuits saw Christianity as universal, as something any human being anywhere could embrace quite easily, alongside a lot of local cultural practices that could persist because they were worthy in their own sphere. The mandarins saw Christianity, much like Buddhism, as offering a kind of spiritual supplement to the worldly social ethic of Confucianism. It wasn’t a matter of one belief system losing out to another. Different kinds of beliefs could interlock, in a division of labour, so to speak, because they addressed different levels of human experience. Now I admit that not all encounters work that way. A Christian and a Muslim would have to seek common ground on another level, perhaps in parallel understandings of God even though they differ on other details. It doesn't have to be easy, and some people will never reach out to others that way. But as I argue in the book, there are enough ways to find common ground across traditions-certainly enough to make common cause today against a lot of pressures that tradition-minded folk everywhere find troubling. A common political project, at the global level, does not require deep theological agreement. But it does require realising that likeminded people are better off casting their lot with each other in a time of crisis. If you don't hang together, you’ll hang separately, as Benjamin Franklin said in a different context. 6) I have spoken of 'tradition' a few times here, I am curious, are you at all influenced by the school of 'Traditionalism' which ultimately derives from Rene Guenon? His overall approach to spirituality was rather eccentric and esoteric. He hasn’t been a direct influence on my thinking, unlike some of his contemporaries. But I suppose there are some parallels in his misgivings about the modern society of his own time, and his effort to take multiple traditions seriously and find overlaps among them. 7) In Beyond the Global Culture War you admitted holding metaphysical beliefs, but stated that exploring them would only distract from the thrust of your argument because of its scope and intent. May I ask what metaphysical beliefs you hold? The short answer is that I'm a theist. I believe in a divine presence, and that human spirituality reflects a deep-seated impulse towards it. I believe that the virtues have foundations, and that they're not just subjective values conjured up out of thin air. I believe the state of mind that one acquires through living virtuously is, universally, more deeply satisfying than any external rewards one might get through vice or subterfuge. I believe that the world's traditions of wisdom all have some degree of higher inspiration behind them, and that they're the first place one should turn for guidance on how to live, today as in the past. 8) You hold out the hope for pluralism of belief and life in the future. And yet it seems that your world must also be constrained by some common standards, common boundaries of what it means to be human. What is your attitude, or, more precisely, what do you believe the attitude of the potential virtuocracy would be, toward bioengineeringand cybernetics? In other words, is a full expression of humanity a set of ideas and ethics resident within the mind irrespective of the form in which in resides, or is their something essential to the organic unity of body which we possess that should be respected and held in stasis? The distinctly human, in the sense of what sets human beings apart from animals, is the ability to have these kinds of ethical ideas and to act on them in a sustained way. To be fully human obviously requires being sentient, and having the sort of consciousness of oneself to act ethically. Or to shift the language a little, it means having a mind and a soul, and living among other beings who also have minds and souls. As long as that is the case, I don't think the organic constitution of the creature matters much. An intelligent extraterrestrial, if we imagine such a creature, could be said to have a mind and a soul (and, I strongly suspect, would have traditions of wisdom analogous to our own). So I suppose one could change the organic features of humanity without changing the essence of a higher consciousness. Whether one should is another matter. There's a temptation to hubris in doing so. But beyond that, there’s also the problem of what one changes and to what ends. A cut-throat capitalist society values very different human impulses and capacities than, say, mediæval Christendom did. Genetic engineering could have very different effects on the ethical climate and the cultural balance of power in a society, depending on who dominates that society and what they're trying to accomplish. Imagine someone who had been genetically engineered to have a razor-sharp intellect, a relentless competitive instinct, and an imperviousness to emotion. That poor fellow would still be an ethical agent, but he’d have an uphill battle against the temptations from within and without. And society would be worse off for it, even if he might increase GDP. The lesson? If I’d trust anyone with the ability to tweak "human nature," it surely wouldn't be the sort of people likely to be paying for it and directing it in the near future. 9) I will admit that myself, I do admire some aspects of Confucianism. But, at the end of the day I am an empirical man, and it seems to me that Confucians held an idea of human nature which leaned strongly toward the 'tabula rasa,' or 'blank slate,' which assumed that the possibility of perfectability of all men (and women presumably). But the reality, to my eyes, is that behavior genetics and other modern biosocial sciences show us that there is variation across our species, and some people have strong biases against being 'perfected' in various directions. That is not to say that biases are destiny and that expectations of society should be contingent upon the expectations of statistics, but do you believe that a virtuocracy should avail itself of the findings of the modern empirical sciences of human nature? Premodern civilisations were very attuned to the variety of human capacities, temperaments, and aspirations. And their social structures reflected that wisdom, albeit often in very imperfect ways. Even Confucian China, while urging all people to improve themselves, recognised real differences in practice. Modern liberal society downplays human diversityexcept the superficial kinds-for a variety of reasons. One ill effect is that, despite its loudly proclaimed freedoms, society today does not really provide the many institutional spaces for different worthy ways of life that traditional societies did. Try being a world-renouncing mystic or a devout villager today, and you'll have problems. The broader culture will disdain you and bring all kinds of subtle and non-so-subtle pressure to bear. Modern society is not structured for many kinds of human flourishing, according to people's inclinations and capacities. It's structured for efficiency and uniformity, with enough room for a pedestrian kind of self-indulgence so people can let off steam. If behaviour genetics sheds light on inborn temperament, then it's simply telling us with more scientific detail what we've always known. The lesson, given some ethical reflexion, seems to be that a postliberal society would have to get away from just professing an empty tolerance of individual choices, and instead restore the spaces and the cultural signals that allow multiple ways of life to flourish and complement one another. In the book I talk at some length about what this might involve. Lessons at the level of public policy on how one treats individuals are rather more complicated. Prodding individuals along different paths according to their supposed inborn temperaments gets quite messy, even dangerous. It may work quite well just to create the diversity of spaces, send signals about the many different aspirations we value (and mean it!), and then let people do as they wish. 10) A common assertion of Creationists is that if you believe that humans derive from pre-humans, and so share a kinship with animals, then we will behave as animals. What is your opinion of this contention? Does evolutionary biology strongly imply amorality to you? Not really. People may try to read amorality into evolution, some because they want an excuse for amorality (social Darwinism, for example), and some because they find evolution unacceptable and think all bad things must go together. I don’t think the link makes much sense. Evolutionary biology, if true, is an account of certain mechanisms by which the organic features of human beings developed. That account, taken at face value, doesn't have any obvious point of contact with the world of ethics. It tells us at most how the physical platform for consciousness was assembled, and perhaps why some impulses put pressure on the mind and soul. I am not a Creationist in the narrow sense that those you mention are. But even to them, I’d point out that the basic framework of evolutionary biology says nothing about the origin of the cosmos, about any non-obvious external influences that might have influenced evolutionary developments, or above all about the nature of ethics and spiritual experiences once consciousness has emerged. Labels: 10 questions
Wednesday, June 21, 2006
I really want to celebrate my main man Shaq Diesel's fourth championship, but I'm not sure that I feel right about it. Like everyone else, my first thought upon the whistle at the close of Game 5 was, "Who touched him?" See here for Sports Guy's take on the mind-boggling fact that a 2-guard could average 17 free throw attempts per game in the NBA Finals. Now, in fact, the foul call every time someone even breathed on D-Wade is representative of the rule changes and officating style geared toward the generation of more offense. If you look at the replay of the last play, you see GP's arm draped around Jason Terry's waist--not a foul in the old days, in fact it was how MJ and Pippen guarded John Stockton and kept the Jazz scoring in the fifties one Finals game. (Why didn't the refs call it here though? Well, the forearm the Mavs probably wouldn't have wanted called, because it would have sent Terry to the line for two when they needed a three. But what about GP tugging on Terry's jersey right afterword? That is definitely a foul. If they had wanted to, they could have called in the act and given Terry three free throws!) The league now wants none of that. But this was still painful to watch. I have never seen the officials giving greater deference to a player.
The last time I felt this way was after Game 6 of the 2002 Western Conference Finals, when the refs decided that a Game 7 was absolutely in order. Game 7 itself washed out the bad taste, as the Lakers showed guts and the Kings choked. I don't know about here. The Heat played harder in Game 6, but I'm not sure they played better, given their atrocious number of turnovers. Guys, what do you think? Are the Heat champions in your eyes? Please tell me that I'm being weird. I'm also curious: has being a sports fan made HBD more plausible to any readers? It has to me. I always knew that any red-blooded American male would sell his soul (if such a thing existed) to be out there on the field or the court. To tell me that the differential outcomes right in front of my eyes were entirely the result of superficial cultural differences ... that made we inwardly cringe even at the height of my young and naive leftism. I mean look at these guys! D-Wade could be a model for a statue of Adam. And there are tons of guys like that in the NBA and NFL. Does anyone seriously think that you could find even one six-four guy like that among China's billions? Update: Maybe I'm wrong. See this from TC. Update II: I see that some readers want to call me out on my rhetorical question. I don't remember anymore what I really meant. If I meant "Are there any tallish, buffish Chinese guys capable of competing with blacks in a black-dominated sport?" then clearly I'm wrong. But if I meant "Is there a single Chinese guy who (a) is 6-4 or taller, (b) is ridiculously jacked, (c) can jump out of a gym, (d) can handle the ball like a Globetrotter even while wearing work gloves, (e) and shoot 65% against the Detroit Pistons" then I like my chances. GC mentions the "method of thresholds." This comes from our friend La Griffe du Lion, who has written a piece that gives much insight into this question.
Darth Quixote recently pointed out (below, June 15) that Francis Galton's celebrated book Hereditary Genius has recently been reprinted in a cheap paperback edition. This welcome news prompted me to check, on Amazon.com and Amazon.co.uk, what other books by Galton are currently in print. I was pleased to find that most of them are, though some are very expensive.
The following are all available from Amazon.uk. Some but not all are also available from Amazon (US). Apart from Hereditary Genius, Galton's fascinating book The Art of Travel is in print in several editions. The book gives practical advice to travellers and explorers in 'wild countries', on matters such as selecting a camp site, finding water, and disciplining native servants. One to be enjoyed from the armchair! Inquiries into Human Faculty and its Development, which contains most of Galton's researches in psychology, is available as a print-on-demand paperback, either separately or combined with Hereditary Genius. It might be expected that print-on-demand would be a lengthy and expensive process, but I have used it for a few other books, and it is not bad at all. Human Faculty is also quite easy to find second-hand, as it was published for many years in the Everyman's Library series. Natural Inheritance, Galton's most substantial theoretical work on heredity and statistics, is in print but only as an expensive hardback. Likewise, English Men of Science, their Nature and Nurture, is in print but expensive. Essays on Eugenics, a late book containing most of Galton's specific writings on eugenics, is available in paperback. But my biggest and nicest surprise was to find that Galton's 1892 book Finger Prints has recently been published as a Dover paperback, the first book by Galton to appear in this major imprint. This classic work is the foundation of the forensic use of fingerprints, but also has interesting remarks on heredity, evolution, and other matters. Go and buy it, if only to reward Dover for reprinting it! These leaves only a few of Galton's books not available in print at all: notably his early book of exploration in South Africa, and his delightful late autobiography Memories of my Life. But don't forget that all of these, and hundreds of articles, pamphlets, and other short works, are available as on-line downloads, from Gavan Tredoux's remarkable Galton.org website here. There is also a permanent link under the section 'Other Sites of Interest' on the sidebar at the right.
Tuesday, June 20, 2006
Bloggers Half Sigma and Inductivist are having ongoing fun with the General Social Survey data set: ethnic, gender, and religious comparisons galore! Half Sigma looks at the relationship between the GSS mini-IQ test and religious belief, and finds what we already knew.
Labels: IQ
John Derbyshire reviews Before the Dawn. Something is rotten in science when National Review publishes a piece about a book which deals in human evolution that is more positive than what Nature produces. Of course, Derb likes the book, while the physical anthropologists who reviewed Before the Dawn didn't, but, the important point is that Derb actually reports on the substance of the book and its central arguments accurately, instead of mischaracterizing Wade in an attempt to mock him. On another Derb related note, blow-by-blow at my other weblog about what went down in the The Corner over the past few days between Derb & the pundit-pods.
Right on the heels of Razib's ten questions for David Haig comes this (free) paper proposing an extreme imprinted brain theory of autism.
The theory is based off the fact that paternally and maternally inherited alleles are expressed in different parts of the brain. Given a species where the father contributes less parental investment than the mother, we have a classic setup for genetic conflict: the father hedges his bets, so to speak, by wanting more resources for his offspring at the expense of the mother and her other children (who may have different fathers). This is achieved through the control of his "territory" in the brain: the limbic system and areas controlling basic drives and appetites. The mother, on the other hand, looks out for herself and her other children (all of which are equally related to her). The authors put it like this: Her maternally active genes will be expressed in all her children and should further the mother's interests by building a cortical brain capable of integrating mental activity in the greater interests of her whole family. Her genes will control the parts of the child's brain that can be educated by verbal instruction and practical example. She will be able to use the speech centres of the cortex to teach her child its mother tongue and the inhibitory and prioritizing functions of the frontal lobes to control behaviour in accordance with her commands and instructions. Here a top-down, contextual, holistic and empathic cognitive style might be particularly useful in influencing a child's social interaction with its siblings, peers and parents. This would make a child much more likely to see things from its mother's point of view and perhaps less likely to act impulsively on the promptings of its paternal brain.Their description is obviously a little self-serving, as on reading it one wants to take the logical next step and hypothesize that autism is caused by an underperformance of this maternal part of the brain or an overperformance of the paternal brain. Which is exactly what the authors do. They think of the brain as a "social placenta" (their term, which I dig) in which alleles with different interests compete for resources. This is an extention of Baron-Cohen's "extreme male brain" theory of autism, but the authors claim it does a better job explaining the data-- for example, the sex ratio in severe autism is not nearly as skewed as the sex ratio in "mild" autism, which is puzzling in the context of Baron-Cohen's theory: shouldn't the sex ratio become more skewed the more severe the symptoms? In the imprinting theory, a decreased activity of the maternal brain would cause severe autism, while an increase in the activity of the paternal brain would cause "autism spectrum disorders", the less severe cases. In this framework, one could argue that males are more succeptible to increases in paternal brain action, while both sexes could be equally affected by decreases in maternal brain action. This is a hypothesis, of course, and they make three main predictions: 1. "The primary causes of autism should be alterations in imprinted genes, genes regulated by imprinted genes, and genes associated with the regulation of imprints, via their application and removal." 2. "Autism may be caused by diverse genetic, epigenetic and environmental factors that cause paternal–maternal brain imbalance." 3. "The behavioural changes involved in autism should reflect extreme manifestations of general, evolved mechanisms for mother-offspring and among-sibling competition over resources." The rest of the paper presents their evidence; I'm no autism researcher, so I've got to take them at their word. The idea of the brain as a "social placenta" is what I particularly like; it wouldn't surprise me if other mental phenotypes were controlled in a similar manner. Labels: disease
Monday, June 19, 2006
David Haig is the editor of Genomic Imprinting and Kinship. You may find many of his publications on his website. Below are 10 questions....
1) Reviewing your work on genomic imprinting I detect some frustration with those who suggest that monandrous mating systems imply symmetrical expression of "madumnal" and "padumnal" (for readers, inherited from mother or father, respectively) copies of a particular gene. Your basic argument seems to be is that in pure monandry madumnal and padumnal copies should agree on overall expression levels, but how they get there is irrelevant (i.e., the proportion of a gene product contributed by each). This seems trivially clear once pointed out, so my question is: did the researchers to whom you were responding really read your original papers? Or were you simply unclear on this issue? It is my experience that the majority of working biologists do not read theoretical papers closely and, when they do, often do not put in the effort to really understand the arguments. I can understand this, given that this is not their specialty and given the pressures on all our time. Things are not helped by 'silly' statements by a few theoretical biologists who do not have this excuse. 2) R.A. Fisher and Sewall Wright disagreed on the important of statistical epistatic interactions (i.e., those that result in variation across a population) in evolutionary process. Fisher seemed to assume they were as irrelevant as population substructure and random genetic drift, while gene-gene interactions played an important role in the adaptive landscapes in Wright's Shifting Balance Theory. 1) Is this argument relevant today? (in the post Neutral Theory and postgenomic world) 2) Do you have an opinion on the importance of epistasis in evolutionary processes? Discussion about the role of 'epistasis' is complicated because the term has different meanings in biochemistry/molecular biology and in population genetics. Biochemical epistasis occurs when two genes have products that interact in a single pathway. Population-genetic epistasis occurs when two loci are polymorphic and there is a statistical interaction between alleles at the two loci in their effects on fitness. One can have one sort of epistasis without the other, and it is not always clear which definition people are using. There is no question that biochemical epistasis is important in evolution. There is still controversy about population-genetic epistasis. This is not my area of expertise but I suspect that the answer may change depending on an individual's implicit time-scale. I have had a particular interest in fitness interactions between genes in mothers and genes in their offspring. Such interactions have the property that mothers treat offspring differently depending on which genes they inherit. If the loci in mother and offspring are tightly linked, then such interactions can have the properties of genetic 'self-recognition' or green-beard effects. 3) Do you believe most biologists, even evolutionary biologists, appreciate formal theory? Most biologists do not appreciate formal theory. Theory is more respected by evolutionary biologists as a group. 4) You note that there is some evidence that related species of mice with alternative reproductive strategies, polyandrous vs. monandrous, exhibit different levels of genomic imprinting confirmed by hybridizations. What is the general time scale of how fast genomic imprinting can evolve? My understanding is that sexual dimorphism emerges rather slowly because of its peculiar sex contextual nature, would genomic imprinting be similar? I do not know how rapidly such divergences in imprinting can evolve. We really need more data on more cases of closely related species with different mating systems. 5) You make it clear that one would expect monandrous species to exhibit a wide range of madumnal and padumnal expression on imprinted loci. But, it seems to me that in regards to a monandrous species that had "relaxed constraint" upon imprinting one could ascertain an expectation of the distribution of expression ratios between the two copies across loci. In short, could this be a way to infer aspects of sexual natural history of a monandrous species? (e.g., the length and extent of monandry) I think there may be information of the kind you mention in the pattern of imprinted gene expression. For example, it is possible that maternally-expressed and paternally-expressed genes will react differntly to changes in mating system and that this may leave an evolutionary trace. 6) In your review of Narrow Roads of Gene Land: Volume 2, you addressed the late William D. Hamilton's attempt to apply evolutionary biology to humanity and our present state. In particular Hamilton was an unabashed eugenicist. My general impression is that though you did not question Hamilton's heart, you were skeptical of the particular plans he forwarded to implement his solution to the problem of deterioration of the human genome through the lack of selection against deleterious alleles. Now, seeing as how there are about 6 1/2 billion humans on this planet, is there any plausability that 'mutational meltdown' could be an issue for our species? And in regards to our health, is not likely that since our effective population is so large there should still be a wide range of realized variance in mutational load so that a small percentage may carry the torch of "genetic health" into the future even in a scenario where our technological civilization can no longer prop up the health of the genetically suboptimal majority? These are very complicated questions about which I am wary of giving an ill-considered answer. Hamilton was a great proponent of the importance of sexual selection in keeping the gene-pool free of deleterious mutations (survival makes no difference if you do not reproduce) but he does not appear to have given this much thought with respect to humans. Selection on reproduction may have been less relaxed than selection on survival. Personally, I think that we should be worrying foremost about the environmental problems of having 6.5 billion people (these problems are here now and will get worse soon) rather than worry about the very long-term danger of a mutational meltdown. 7) In a follow up in regards to accumulation of deleterious alleles, in The Cooperative Gene Mark Ridley suggests that spontaneous abortions are purging the genetic load from our population. If survivability and reproductive value of individuals who carry a high load of deleterious alleles in elevated in our modern population, that seems to imply to me that spontaneous abortions would be elevated as well, perhaps serving as a check on the accumulation of load. Is this possible? It is possible. 8) In Genes in Conflict Austin Burt and Robert Trivers point out that a large number of the loci in mice which are imprinted have behavioral and neurological implications. This seems born out by Prader-Willi Syndrome in humans. Do you believe that many cognitive traits or biases will show the effects of imprinting? I must await the evidence on this but I would not be surprised if this were true. Theory does predict that genes evolve imprinting because they have effects on relatives. 9) Do you have an opinion in regards to the data emerging from the HapMap project which implies a great deal of positive selection on the human genome within the last 10,000 years? I have not given this much thought, but I would not be surprised because natural selection never stops. 10) If you could change one thing about your educational path, would that be? I would have learnt more linear algebra as an undergraduate. Labels: 10 questions
I imagine regular readers of GNXP are pretty familiar with Hardy-Weinberg Equilibrium (HWE): if a population is in HWE and we have a two allele locus with allele frequencies p and q, then the frequencies of the two homozygote genotypes and the heterozygote genotype are p*p, q*q, and 2*p*q, respectively. To maintain HWE over time, textbooks generally list five necessary conditions:
1. Random mating 2. Large (read: infinite) population size 3. No mutation 4. No gene flow 5. No natural selection Obviously, these conditions aren't met in any population, but a lot of times we can say "eh, close enough". But it turns out the first condition is actually not necessary at all. That is, certain non-random mating patterns lead to equilibrium as well. This was brought to my attention by this paper, which shows that, in a single round of non-random mating, HWE can be achieved in a population without a change in allele frequencies. In it, the author references another paper by Li, which derives several patterns of non-random mating that maintain HWE. So, as the author says, "thus Li's contribution and this one completely remove the necessity of random mating as a requirement for the establishment and maintainence of HWE". The practial import of this? Probably close to null. But an interesting fact nonetheless, and a revealing look at how slightly incorrect (random mating is still sufficient for HWE, just not necessary) information can get passed through the generations.
John Derbyshire, the firestarter extraordinaire of National Review is at it again. This time, it's a pretty conventional rerun of the good ol' genetics vs. environment parenting cagematch. What is less conventional is the candidness of the Derb's opponent: Jonah Goldberg.
Derbyshire states: To take your last point first: Are you suggesting that if I hold a certain opinion about politics and society, and if I then read a sheaf of research studies that seem to me to be sound, but that contradict my opinion, then I should hold on to my opinion and ignore the science? Sorry, no sale. Pretty conventional "truth always comes first" boilerplate. Meh. Now, Goldberg on the other hand dares to be different: Derb - Let me take your first point first. Yes, to a certain extent I am asking you to have your politics shape your opinions and frankly, I am at a loss to see how you should think otherwise, let alone why you should be so boastful about it. Update from Razib: Keep an eye on The Corner, it be buzzing.... Update from Rikurzhen: Informative comments from the Haloscan thread for the sake of Google: Jason Malloy - 06.19.06 - 6:14 pm writes: It takes years or even decades to move a theory from "vague speculation" to "established fact." From that link, here's the data for income and adoption:  Jason Malloy - 06.19.06 - 6:21 pm writes: Derbyshire is wrong that peer socialization has much support too. The Nurture Assumption simply raised it as a theory. Later research is mildly supportive, but genetics and nonshared (unique to the individual) environments describe the grand share of individual differences. (Derb leaves out nonshared but it's a huge and important part - most of what you are comes from your own unique and random experiences. Not exactly something encouraging for our would-be social engineers) Jason Malloy - 06.19.06 - 6:49 pm writes: One thing Jonah's right about is that culturally specific traits are transmitted in the family. Read the Alford paper from last year on political orientation and genetics. To summarize, your* propensity to be political at all has a modest genetic component (.36), but no family component (.02). Your actual political opinions have a medium genetic component (.32) and a modest family component (.16). But the actual party you affiliate with has a nontrivial family component (.41) and a small genetic component (.14).
As most of you know I'm involved in the Donors Choose program over at Science Blogs to raise some $benjamins$ for various public school projects. Here is the tally so far:
Pharyngula $4257.80 Good Math, Bad Math $878.23 stranger fruit $663.19 A Blog Around The Clock $582.52 Terra Sigillata $579.45 Afarensis $578.91 Sed Sic Sic $455.00 Adventures in Ethics and Science $435.00 Uncertain Principles $395.00 The Scientific Activist $330.00 Gene Expression $180.00 You can check the latest here. Since SEED is matching us dollar for dollar all that's raised is good. Of course this isn't a competition, but I know that many readers of my two weblogs have some disposable income. Right now Gene Expression is well under an order of magnitude under the #1 fundraiser, but it would be nice to close the gap just a little. Anyway, I'm hoping that if kicking in some moollah (the green, not the turbaned kind) out of altruism isn't doing it for you, perhaps competition might.
Sunday, June 18, 2006
I just discovered a news service called Brightsurf that collects science press releases. At the same time, I was irritated to discover that my RSS feeds for Cell and Neuron don't update immediately when the new issues come out. So the new Neuron has been out for 4 days, and I was in the dark. Mainly I wanted to point out that the new Cell came out, and it has a bunch of cool articles in it, three of which are accompanied by press releases.
I hope to have time to dissect some of these articles in detail. One shows a change in a certain allele in the lineage of HIV-1 that used to inhibit T-cell death. This is apparently why SIV in most cases is harmless. I know absolutely nothing about this, but it suggests to me that one route to treatment might be rather than trying to block viral entry into cells to attempt to mimic this lost viral function by knocking down the gene that the virus used to knock down on its own, called TCR-CD3. Two papers, that didn't get press releases, discuss RNA regulation pathways in detail. One dissects the pathway by which RNAs that were transcribed wrong get targeted for destruction in P-bodies, while another shows how sometimes RNAs that get targeted to P-bodies don't get destroyed at all. This latter has been foreshadowed in the literature for a while. This would provide a more flexible control of translation by miRNAs, so they could just trap their targets for a while and release them at the appropriate time (much faster response to environmental inputs than having to transcribe the whole thing again). Another paper showcases a fancy technique known as an "optical trap" whereby single molecules can sorta be frozen in place, so we can take a look at them. Nanotechnology is really starting to pay off in the molecular biology world, so it's probably time I start wrapping my head around how this stuff actually works. They use the technique to discover specific DNA sequences that induce RNA polymerase 'pausing'. RNA polymerase turns out not to read DNA seqences off all smooth-like, but instead coughs along in fits and starts, more like Fozzy Bear's jalopy than a new Caddy. Until now, it had to be chalked up to "noise", but now we can start actively pursuing the physical mechanisms. And finally, I have to point out how egregious this press release is. Compare the headline to the article title: Headline: Cure found for Huntington disease in mice offers hope for treatment in humans Article: Cleavage at the Caspase-6 Site Is Required for Neuronal Dysfunction and Degeneration Due to Mutant HuntingtinCure found for Huntington's disease?! Awesome! Oh wait, it's just a really cool paper discovering more about the mechanisms by which abnormal huntingtin protein leads to neural pathology. Huntington's disease is one of a few that has been traced down to abnormality in a single gene. The gene has a big chunk of sequence added to it that causes the protein to contain a long string of glutamine residues. I was unaware that mutant huntingtin gets chopped up by cellular proteases and that these cleavage products accumulate early in the disease process. The article shows that, at least in mice, blocking this cleavage step blocks the rest of the disease. This does provide a target modification we might like to make in the genes of Huntington's patients, but we had one of those already (remove the polyglutamine sequence). The hard part is going to be getting a gene therapy vector to neuronal populations and changing the sequence without negative side effects. I'm not discounting the importance of the paper, this may prove an easier change to make, but it might almost be considered cruel to start a headline with "Cure for Huntington disease.." when it is really only one more incremental step in the long process. Am I being too demanding/nit-picky? Anyway, Brightsurf looks like a good resource for those that didn't know about it already. Lots of interesting stuff coming out. I'll get back to packing info into ye olde noggine now. Probably won't be starting in on a novel this week.
Mendel's Garden is out!
Saturday, June 17, 2006
I take a guilty pleasure in reading the work of creationists and intelligent design proponents. I can't really get worked up over them, even if I try - I just find it a relaxing pastime. Perverted, I know. (Make no mistake, I use Darwinism as one of my litmus tests for reasonableness, but I can't really work up actual anger with creationists.)
Still, seeing Intelligent Design poster boy Bill Dembski in action is quite something. Here is an exchange over bird evolution over at his Blog, "Uncommon descent": You're mis-construing the importance. It's not "we've found a missing link, therefore evolution is proved", but rather "we've found a fossil ancestor that tells us something interesting about how birds evolved". Here is the answer from the always-friendly management: Wanna see me turn YOU into a missing link? -dt Gotta love that spirit of open scientific debate! PS. Bill appears to have some trouble with mathematics too... DS.
Friday, June 16, 2006
Shelley Batts has some interesting commnets about the new finding which suggests that blacks and women have better hearing than whites and men, respectively. Shelley goes on to support the idea that melanin might have a protective effect on hair cells because of physiological factors by drawing from her own research. It seems that there is a way to test this: find the correlation between index of reflectance (skin color) and hearing loss. Do comparisons on sibships, especially in populations with lots of skin color variation. If this phenomenon is due to the effect of the phenotype, that is, the end product of melanin, as opposed to pleiotropy on one of the skin color genes then the covariation should work across populations. On the other hand, if this is pleiotropy of some sort coupled with one of the genes which controls skin color, then you would see variation across populations for the correlation because different populations of the same skin reflectance have different genetic profiles (i.e., East Asians and Europeans are pale for different genetic reasons, or, more precisely, a different combinations of alleles on the same loci).
Additionally, if memory serves it seems that humans have had very dark skin for something on the order of 200,000 years if the "fur loss" research pans out. That is, unexposed skin color in most primates is depigmented, and the implication is that dark skin emerged after we lost our hair and were exposed to the full force of solar radiation. Simulatenously, if the FOXP2 research program is confirmed we might have gained speech around the same time frame, or, at least fully articulate and recursive speech. This facility would require greater auditory capacities, so the two concomitant transitions might have fed back into each other. Addendum: Background for those of you who are a bit perplexed by my allusions re: skin color. The short of it is that very dark skin is generated by a constrained "consensus sequence." Black skinned the world over, from Africa to southern India to Melanesia tend to exhibit this consensus sequence (for example, a particular form the MC1R gene). In contrast, light skin has no consensus sequence, but is characterized by variation. In Europeans MC1R is very polymorphic (i.e., Peter Frost's sexual selection/frequency dependent hypothesis), while in East Asians it seems to be subject to positive selection which is pushing it toward fixation on an alternative consensus sequence. The locus which controls around 1/3 of the variation between Europeans and Africans in regards to skin color is shared between Africans and East Asians.
We'll have to wait and see, but it seems his interest in intelligence is wavering at present, so suggests a recent WSJ profile of his situation post-ASPM-MCPH1 (available below the fold).
Head Examined: Scientist's Study Of Brain Genes Sparks a Backlash Labels: IQ
Brain-derived neurotrophic factor (BDNF) is very busy around the nervous system affecting things like cell survival, synaptic transmission, immune responses, and plasticity. It's been discussed around here before in a number of contexts. New articles come out fairly frequently concerning the effects of the Val66Met polymorphism in human BDNF on risk for various psychiatric conditions and also cognitive function in general. I will leave discussion of those to someone more qualified. It is becoming clearer how these more global effects occur at a basic level. Here's one, for instance, in Nature Neuroscience where experience-dependent plasticity in humans is affected by the polymorphism. I'm going to go down even further into the nitty-grit with this article (Rao et al. 2006) that came out at about the same time in the same journal concerning the mechanisms by which BDNF affects levels of a protein called activity-regulated cytoskeletal protein (Arc). The article provides a thorough examination of the interaction between BDNF, synaptic transmission, and gene regulation and provides a novel role for what is normally considered just a reliable workhorse of excitatory transmission (the AMPA-type glutamate receptor).
Arc is a favorite among memory researchers because it has all these nice properties that make it look like a good final effector for synaptic plasticity. The RNA and protein both increases in response to plasticity-inducing stimuli and experience in novel contexts (possibly the plasticity involved in creating a cognitive map). The RNA is localized in dendrites where it could be rapidly translated to make changes to post-synaptic properties. One of the most compelling findings is that even within the same dendritic field the protein is translated in an input-specific manner. Imagine a long dendrite with synaptic inputs up and down it's length. Tetanic stimulation of a pathway that only inputs to the distal regions of the dendrites will cause increases in protein just out there and not in portions of the dendrites more proximal to the cell body. This is important because learning is presumed to involve very fine-tuned changes at specific synapses rather than wholesale whole-cell changes. It is kind of funny given all this evidence that no one is really sure what Arc is doing once it gets synthesized. It is associated with the cytoskeleton... maybe it affects actin polymerization, but no one has really conclusively shown what its function is. There is a model in the making that BDNF is released in response to tetanic stimulation and may act on the pre-synaptic side to increase neurotransmitter release or on the post-synaptic side to make changes to synaptic signaling pathways or receptor content. If you block BDNF, synaptic plasticity is impaired. If you apply BDNF to neurons, Arc levels will increase. One of the first questions addressed in this paper is kind of a chicken and egg problem. Does synaptic activity increase BDNF and thus lead to Arc expression or is it that BDNF increases synaptic activity and that is the Arc synthesis cue? The data points to the latter scenario since sequestering BDNF with a fake BNDF receptor molecule didn't affect activity-dependent Arc increases while blocking neural activity with an ion-channel blocker inhibited the Arc increases elicited by direct BDNF application. So at least in this in vitro system BDNF leads to synaptic activity which then leads to Arc RNA and protein increases. So which sort of synaptic activity are we talking about here? Excitatory transmission is primarily a function of ionotropic (ion-channel) glutamate receptors. There are three major subtypes differentiated by their susceptibility to certain synthetic agonists: AMPA, NMDA, and kainate. Everyone ignores kainate which I'm sure is gonna come back to haunt us in the future, but for now we'll focus on AMPA and NMDA receptors. NMDA receptors are much loved by memory researchers because they provide a nice molecular analogue of the requirements for memory. They are usually blocked by a magnesium plug, but when a the post-synaptic membrane is depolarized (excited) the plug pops out. Normally glutamate binding to NMDA receptors won't do much of anything, but when the magnesium plug is gone calcium can pass into the cell and start initiating this or that signaling cascade and doing things that we think are important for changing synaptic strength. Since these changes are supposed only to occur when there is a coincidence between post-synaptic depolarization and pre-synaptic neurotransmitter release, the NMDA receptor has been labeled a "coincidence detector". While there are exceptions, one common requirement for classical conditioning is that the conditioned stimulus occur close in time to (coincident with) the reinforcing (unconditioned) stimulus. See the analogy? You can get these two levels of analysis a lot closer in a reduced system like the sea slug and really hammer home the link between learning and NMDA receptor activation. The AMPA receptor on the other hand is usually thought of as less of a mover in synaptic plasticity and gene regulation and more of a movee. The final outcome in synaptic strength changes is often presumed to be trafficking of AMPA receptors into the post-synaptic membrane where they have the effect of producing greater neural activation in response to the same amount of neurotransmitter. So it was rather surprising to find AMPA receptors playing an active role in supressing gene expression in this paper. As expected, BDNF-induced Arc increases were inhibited to some degree by NMDA receptor antagonists. However, when the authors tested out AMPA receptor antagonists, they found a really striking increase in BDNF-induced Arc levels. I usually just think of AMPA receptors as allowing some sodium into the cell everytime they get glutamate. Sodium isn't supposed to be any big signaling second-messenger or anything, it is just supposed to change the membrane potential. It makes one really curious about the way that AMPA receptors could control the level of a given gene. One relatively simple way out would be to blame the regulation on calcium-permeable AMPA receptors. Certain configurations of AMPA receptor subunits allow calcium in and that could be initiating some sort of regulation, but the authors eliminated that possibility early on using a drug specific to these subunits. Instead it appears that AMPA receptors are having their effect through associated G proteins. I'm guessing that it isn't so much the sodium influx as it is the conformational change associated with ion-channel opening that may trigger activation of these G proteins that go on to inhibit the cyclic AMP signaling pathway. By altering these intracellular signaling pathways, AMPARs could be affecting all sorts of cellular processes. Which one's really matter for Arc regulation? The authors found that rather than directly antagonizing the immediate downstream effects of BDNF (certain kinases phosphorylated and whatnot), AMPARs must be working less specifically against BDNF and more directly on Arc expression processes. They also examined at where in the process of Arc synthesis this regulation is occuring. Protein and RNA levels increase in response to BDNF, but this could be because of reduced degradation of either one, increased synthesis of RNA and followed by protein increases, or independent increases in RNA and protein. The verdict is that AMPAR antagonists are no big deal when it comes to protein synthesis or degradation pathways. Rather, the majority of AMPAR impact is on Arc transcription. This data is fairly consistent with a model of plasticity that relies heavily on nuclear signaling to stabilize long-term changes in synaptic strength. Especially interesting that G proteins and cAMP have popped up again. Everyone's favorite learning and memory related transcription factor is called CREB (cAMP Response Element Binding protein). Since AMPAR transmission activates a G protein that should inhibit the production of cAMP, one could imagine a simple scenario in which CREB is just held at a lower activation level and is less capable of positively regulating Arc transcription. This puts NMDA receptors at odds with AMPA receptors in terms of their downstream effects. The way I'm thinking of it for now is that AMPA receptors may act as negative feedback. I'm envisioning something like NMDA receptors initially increasing Arc production and plasticity which entails trafficking of AMPARs into the synapse. These would allow the synapse to be more easily depolarized and could potentially lead down a positive feedback track. But instead, along with their depolarizing properties AMPARs also limit the amount of plasticity-related proteins that can be created at once and therefore keep the cell from building synapses bigger all willy-nilly.
I recently came across an article about the 5% Nation and its place in the rap world and thought some of you might be interested in seeing what beliefs some of the core of the original NY hip-hop scene (Busta Rhymes, Wu Tang Clan, Nas, Rakim, Big Daddy Kane) are espousing. I was really unaware of the origin and specifics of this particular sect. Read the article. Some choice quotes below the fold.
Seven is the number of perfection. It stands for the seventh letter of the alphabet, G, and for God. (Five Percenters originated the homeboy expression, "'sup [what's up], G?"; originally "G" stood for God, not gangsta.) According to Jah-Z-Allah, keeper of the 5% website, "The God sees in cycles of 7 colors of the rainbow and hears in 7 cycles of notes on the musical scale."17 According to Farad's lessons, the Original (Black) Man has 7 1/2 ounces of brain, the (white) devil, only 6 ounces (Farad, Lost Found Muslim Lesson No. 2). The 85% are those without the knowledge, the mentally blind, deaf and dumb who are bent on self-destruction. The 10% are the bloodsuckers of the poor, those who have knowledge and power but who use it to mystify and abuse the 85%. The 10% include the "grafted" white devil (created, according to Farad's teaching, by the evil scientist Yacub approximately 6000 years ago) as well as the orthodox Muslims and Christian preachers who preach that god is a "spook" or a "mystery god." I realize you could fill the entire internet with the bizarre beliefs of this or that religious sect, but I thought this one was particularly interesting given the potential impact of these artists on pop culture and because I generally enjoy the work of a lot of these folks. I wonder though how much other fans actually take to heart?
A number of people have pointed out that a post from my old site was quoted in a New York Times piece on recent results in behavioral genetics and the response of John Q. Public to the those results. The quote is this:
... to summarize, want to live until a ripe old age? Have parents that live long. Think you're a friendly, peaceful guy 'cause your mom raised you right? Think again. Able to try drugs just a couple times and never good hooked because of your strong will? Nope. Now, lest anyone think I've gone completely nuts, I'd like to point out that I was quite conciously being hyperbolic, and the rest of the post puts that quote in context. Also, Amy Harmon (the journalist who wrote the article) notes that "biologists are also quick to emphasize the role environment plays in activating genetic dispositions that might otherwise never be expressed, or mitigating those that are." I'd like to include myself in that group. Here's the response I gave to a comment of hers that it seemed like I embraced "rather cheerfully" that genes determine our destiny: But genes don't "determine" our destiny nor who we are, at least in the commonly understood sense; they play a role (or "merely" play a role, depending on how you want to frame it). There's a lot of room for personal responsibility and simple random chance. So there you go. Overall, the article is well-written and fair, and her conversations with non-academics show how research is being interpreted out in the world. Do you think it's frustrating to read about somebody saying, essentially, "I can't quit smoking. Probably got a 'smoking gene'. Ah, well, such is life"? I do. But if that's how people are going to react, it's good to know. And hopefully we'll be able, eventually, to inform people about the statistical nature of any association or, barring that, at the very least convince them to be skeptical of companies trying to sell genetic personality tests.
Thursday, June 15, 2006
On the heels of the asinine review of Before the Dawn in Nature, I see Carl is linking to some recent papers that are coming out in regards to positive selection in our own storied lineage. I must say that the new one in Science is quite phat in its broad sweep. Pictures below the fold....
     Show me the money honey, you can sneer about incomplete evidence for selection on human lactase persistence, but saying it just ain't gonna make it so. Labels: Human Evolution
Readers know that I don't have a totally positive opinion of Before the Dawn, but this hatchet job in Nature is out of control, it stinks of "The Sociobiology Study Group." Full text below the fold, I'll let readers point out the issues....
In Your Own Image Labels: Human Evolution
Bruce Lahn was interviewed by Chicago as one of the 10 most eligible bachelor's in the Second City. Pretty amusing. "The secret lives of scientists" and all. Also, the full list has two browns (though the dude looks like a tool).
Related: Bruce Lahn profiled in The Scientist, and of course, his evil genius.
I've done this before, but over at my other weblog I'm asking for 10 or less words to describe evolution to the public.
This shit is hilarious. Achondroplasia is an dominant Mendelian condition, though most individuals who carry the mutant allele seem to be the result of de novo mutations.
Wednesday, June 14, 2006
Browsing through the MIT Open CourseWare page, I saw some courses that might be of interest to hardcore GNXP readers:
Cognitive and Behavioral Genetics (from Stephen Pinker) Computational Functional Genomics Quantitative Genomics Computational Evolutionary Biology I haven't looked too in depth at any of them, but a couple have reading lists that might be worth a look.
Over at Genetics and Health, Dr. Hsien Hsien Lei had an interview a little while back with Dr. David Moskowitz, Chief Medical Officer of Genomed. It's an interesting read, but I hope Dr. Lei doesn't mind if I say what at least one of the commenters on the thread was thinking: this guy is full of it. My evidence:
1. Here's a quote from near the end of the interview: Perhaps because I'm the only genomics company CEO who sees patients, I feel that the world of genomics runs on a fuel of 99.9% hype, 0.1% clinical medicine. A clinician understands in their guts that the patient seeing them needs a practical solution right now, not 20 years from now. Fair enough. Here's a quote from near the beginning: Q. What do you think we can expect in the genome revolution? Pot, meet kettle. There's nothing wrong with being ambitious; I'm all for it. But it will take a lot more basic advances in science, using technologies that don't exist now, before we can even think about getting to what he's suggesting here. Of course, Dr. Moskowitz isn't that big on technology, either... 2. Here he is talking about the X Prize-like competition to reward people who develop technologies for cheap genome sequencing: I've spoken to them, and they're obviously hooked on technology. They have no appreciation of clinical medicine or the scarce resources available for healthcare on this planet. This is a striking example of a non sequitur: some cancers can be predicted with a limited number of SNPs, thus genome sequencing is a waste of money. It does not follow. Low cost sequencing will not only be a boon to medical researchers, who use genetic information to find new drug targets, but will lead to a sea change in our understanding of the genome, its organization, and its relationship to disease. And better understanding will have vast clinical consequences. Dr. Moskowitz probably agrees with me here; he says at one point, "you can't beat disease without knowing its pathways". Well, low-cost genome sequencing will greatly help towards that goal. 3. Did you notice he cured atherosclerosis in 1994? Well, here's something else: I first found out how to prevent 90% of kidney failure in 1994. But I'm still the only person in the world using my protocol. Here, I went to PubMed. What I found was a 2002 paper on preventing renal failure. The abstract (no access to the full text) claims that, "as a group, the outcomes are superior to what is available in the literature". Nothing about preventing 90% of renal failure, though perhaps that's in the full text. And note there's nothing in PubMed on artherosclerosis. Perhaps his cures haven't caught on because he's keeping them to himself (he is the CEO of a biotech company, after all). 4. Here's his last comment on genomics: The field can continue to follow the lead of Craig Venter, Francis Collins, Eric Lander, and other pediatric geneticists who have yet to solve any adult, polygenic diseases, but who consume enormous amounts of time and money in the process, or it can focus on what needs and can be done. This I'm going to have to chalk up to jealousy. I mean, honestly, "pediatric geneticists"? These are the people who are interested in the basic research, who sequenced the human genome, and who fund the HapMap Project. They're at the forefront of the field, and did the work that inspired his company: It suddently became possible to scan the entire genome for disease-associated SNPs, instead of looking at one SNP at a time, as we had been doing. Since we were in a global competition to find disease-predisposition genes, I was unwilling to give up the race. I started Genomed These people inspired his career and made his company possible, and now he thinks they're worthless? I've definitely noticed that a "genomics is hype" meme has caught on among a lot of scientists that don't really seem to know what to do with a lot of data, but this is a particularly egregious example.
Uhh.. No time to sleep cos if ya sleep ya don't eat... Gotta hold heat just to make ends meet.. - T3
I got to thinking about flies again, partially because Ron Davis came and gave a talk at our department and partially because I saw a couple papers in Nature showing sleep regulation is mediated by protein kinase A (PKA) signaling in the mushroom bodies. You may be surprised to find out that flies sleep, but they at least do something like sleeping where they sit very still and it's harder to arouse them. Then once I started digging in I found yet another paper in Current Biology that came out within two days of the Nature papers implicating serotonin 5-HT1A receptors in the mushroom bodies. 5-HT1A receptors and PKA are linked through the cyclic AMP (cAMP) signaling pathway. PKA is also referred to as cAMP-dependent protein kinase. Where else have I seen all these cats before? Ah yes. Here they are inititating memory formation in Kandel's Nobel lecture about the mechanisms of long-term facilitation in another invertebrate (the sea slug).  In fact, the PKA signaling pathway in the mushroom bodies is known to be of major importance for memory formation in fruit flies as well. Two of the earliest discovered fly memory mutants, rutabaga and dunce, ended up lacking PKA pathway proteins, and at least the rutabaga memory phenotype can be rescued by inducing the missing protein just in adult mushroom bodies. I keep talking about mushroom bodies. Mushroom bodies are a bilateral tripartite structures found in the insect brain. Most of the mushroom bodies are made up of the axons of Kenyon cells. The Kenyon cells are all collected together in a big round hunk of tissue positioned to the dorsal-posterior. A tract called the peduncle shoots down and forward and a little lateral and then abruptly splits into lobes. For simplicity's sake I will pretend that there are only alpha, beta, and gamma lobes. The alpha lobe shoots straight up from the branching point producing a vertical lobe. The horizontal offshoot from the branching point goes medial and consists of beta and gamma lobes which skilled fly neuroanatomists can tell apart using arcane fly researcher magic. Actually I think the gamma lobe is just like in front of the beta lobe or something. Mushroom bodies are known to be important for memory (especially long-term memory) because of things like the aforementioned rutabaga rescue experiments and because you can screw up memory by cooling them or ablating them with hydroxyurea. Also, they are kind of in a good spot to encode the type of memory most people study in fruit flies (aversive olfactory conditioning). They are two or three synapses from the olfactory receptors and they receive neuromodulatory input from transmitters proposed to be involved in shock representation. All of these papers use the Gal4-UAS system, so I ought to lay it out. If fly researchers want to affect a gene's expression in a cell-type specific fashion they can just pull a fly Gal4 line off the shelf. Gal4 is a transcription factor that has been inserted in multiple spots in the fly genome producing flies that make Gal4, say, just in certain Kenyon cells or in the antennal lobe, or in the protocerebrum, or wherever. This happens because the Gal4 sequence is being driven by some other gene's regulatory region (promoter). A lot of times, they don't even know which gene's promoter is being co-opted, but hey it works. Gal4 has the property of activating transcription of genes that are controlled by an Upstream Activating Sequence (UAS). So you have to make a fly that has whatever gene you're interested in controlled by a UAS. Then you grab a Gal4 strain that has expression in the cell-type you're interested in and cross'em. Gal4 + UAS = your gene expressed solely in the tissue of interest. Pitman et al. started out by inserting a temperature-sensitive inhibitor of neurotransmitter release (shibire) after a UAS and trying it out in different Gal4 lines to find sleep centers. They found a few lines with reduced sleep (short-sleep lines, SSLs), and then looked to see where Gal4 was being expressed by using the same Gal4 lines but crossing them with UAS-GFP strains instead of the neural silencer. They mostly found expression in the mushroom bodies, so they tried out a couple more known mushroom body lines (c309 and 30Y), and these showed short-sleep phenotypes too. The overall idea here is that mushroom body activity is sleep-promoting. Interestingly, a c309-PKA line also reduced sleep. So turning off neurotransmitter release seems to have the same effect as turning up PKA activity. Also, sleep-reducing changes were associated with a reduction in lifespan. I will use this finding to cynically sensationalize any further findings regarding sleep regulation by making them seem a matter of life or death. Since the sleep regulation machinery overlaps so much with synaptic plasticity and memory pathways, I will use this as an excuse to say things like "Learning can kill you!" or "Learning can save your life!" depending on which way I interpret the rest of this data. Joiner et al. did a similar set of experiments, but instead of turning off neurotransmitter release in certain Gal4 lines, they expressed a constitutively active version of PKA. They found sleep phenotypes in two lines: 201Y and c309 again. It's rare to see an experimental result independently replicated period, let alone on the next page of the same journal, but here we have it. c309-PKA flies showed reduced sleep in Joiner et al.'s hands too. 201Y-PKA flies showed an increased sleep phenotype. The authors of this paper were a little more subtle with their histology and determined that c309 and 201Y did indeed both have mushroom body expression patterns, but they have a complementary pattern within the alpha and beta lobes. 201Y is found in gamma lobes and the core region of the alpha and beta lobes while c309 is found in the gamma lobes and not in the core region of the alpha and beta lobes. These folks also have a mushroom body Gal4 line with similar expression pattern to c309 that can be turned on in response to a drug (RU486), so they could isolate the adult contribution rather than the developmental contribution of PKA activity. This manipulation was also associated with reduced sleep. Tissue and time-specifically expressing potassium channels to inhibit mushroom body activity or sodium channels to activate led to increased and decreased sleep respectively. But didn't we just learn that mushroom body activity is sleep-promoting? In fact, this paper also contains the finding that mushroom bodies leads to less sleep, but they note that other manipulations can produce much larger changes. Mushroom bodies probably contain populations that do both and when you ablate them you are canceling out a little bit of both. I got interested in this idea and started looking for indicators of what might be different between the two populations. The major distinction seems to be that PKA activity (and thus more activity?) in the core of the alpha and beta lobes is sleep promoting while PKA outside of the core is sleep reducing. I found one paper that shows a GABA receptor subunit is primarily found in the core of alpha and beta lobes. GABA is normally an inhibitory input, so having GABA receptors throws a minus sign in the equation, but these are receptors not neurotransmitter, so this only explains a differential response to external stimuli between core and non-core. Another paper shows that calcium/calmodulin-dependent kinase II (CaMKII, an important synaptic plasticity molecule) is mostly non-core, as are two important PKA signaling molecules, Leonardo and Rutabaga. This indicates to me that it is a little unnatural to be expressing active PKA in the core (and thus promoting sleep). This leads me to believe that endogenous PKA activity is probably sleep reducing. Finally, there's this Yuan et al. paper from the same lab as the Joiner et al. paper. In this paper the focus is on serotonin receptor subtypes. The authors produced disruptions in each of the drosophila 5HT receptor subtypes and looked for sleep phenotypes. Only the 5HT-1A receptor disruption had an effect on sleep, producing a short sleep phenotype. Reinstating 5HT-1A using a pan-neuronal Gal4 driver and UAS-5HT-1AR, rescued sleep. Also, expressing the receptor using the Gal4 MB-Switch driver (the one that can be turned on with RU486) just in adult mushroom bodies rescued sleep. This pretty much ruins my core versus non-core theorizing because the aforementioned "pan-neuronal" driver has more intense expression in the core while the MB-Switch driver is preferentially non-core, but the outcome is the same for expressing 5HT-1A receptors in both. When I read all of these at once I had hoped to come up with some grand overarching theory of memory, sleep, and cyclic AMP signaling, but, alas, the data isn't that neatly sewn up. It seems like serotonin and PKA are having opposite effects. The story would fit more neatly into my scheme if PKA activity in the mushroom bodies was sleep promoting, and it is in certain neuronal populations. If I combine this with Pitman et al.'s general finding that mushroom body activity seems to be sleep-promoting and ignore the inconvenient data points from Joiner et al., then I could say something like "learning induces signal cascades that produce greater mushroom body activity and promote sleep." Then I could tie it in with theories about the role of network activity (like sharp-wave ripples) in the mammalian brain during sleep. Turns out it isn't that simple. Any ideas? How do you like reading a blog post without the answer at the end?
Tuesday, June 13, 2006
This story in today's UK Independent describes a paper by archaeologist Paul Mellars which attempts to explain the sudden expansion of homo sapiens around 60,000 years ago. No doubt there are other reports, but I thought I would just note this one while it is fresh.
Added: There is a similar report in the UK Times. This mentions that Mellars's paper is in Proceedings of the National Academy of Sciences of the USA, online. I checked out the PNAS website, but couldn't find it yet. If anyone has better luck, please mention it in Comments. Added #2: Dienekes has an abstract of the PNAS article.
Monday, June 12, 2006
MC Coffee Mug, a recent contributor to this weblog, posted this comment below:
Dinosuars and "Hobbits" are not evolutionary genetics, they are paleontology. The last phenomenon, well, I don't know what it is, but it isn't evolutionary genetics either. Here is a rough sketch of pre-postgenomic evolutionary genetics, here is the future that has been prophesied. Here is a great evolutionary geneticist from the 20th century, and here is a profile of a young evolutionary genomicist. Repent heathen! Evolution + genetics = evolutionary genetics Evolution + geology = paleontology Evolution + atheism = rants Get your systematics in order! We believe in mutation, the maker of all We believe in selection, the shaper We believe in drift, the divider And we believe migration, the unfier In these parameters do we believe, four natures of one essence And so shall evolution be glorified in the eyes of Creation
I've never been big into carnivals, but RPM pointed me to a new genetics focused one, Mendel's Garden. I've actually always wished something like this was around, so hopefully I'll be submitting (one of the submission categories is "gene expression")...pass the word. Looks like you just got "scooped" Lei (though this won't go biweekly probably). The current host is Paul DeCelles.
Readers of this weblog might be interested in the comment thread spawned by my post over at my other weblog, Why genetic determinism is inevitable in a meritocracy. Several GNXP principals are getting into it....
Friday, June 09, 2006
NB: Extensively updated
Hell, at this blog, the point is probably taken for granted, but often the non-population geneticists (including me) can lose sight of just how confusing the realm of human beings is when left unilluminated by its basic insights -- and therefore, just how easily fooled you can be if you don't know squat. Elsewhere, DavidB and Greg have pointed out that when one crunches the numbers, sexual selection generally takes a hell of a lot longer than your garden variety directional selection (by roughly an order of magnitude). So, if the change is recent, then most sexual selection accounts of it will be more dubious than those whose premise is that the cause affects males & females roughly equally. But I'd like to take a closer look at a different concept of pop gen that's widely misunderstood and inappropriately applied in my own area of interest, which is psychology -- namely, assortative mating as an account of autism. [1] The theory was developed by Simon Baron-Cohen, an eminent autism researcher who has advanced our understanding of the condition considerably. In brief, the idea is that there is an essential difference b/w male and female brains: males tend to be more systemizing, while females tend to be more empathizing. Still, there is variance in both groups, so you can find females who score high on systemizing; if they mated w/ fellow high systemizing males, then surely their children would be on average high systemizers as well. On Baron-Cohen's view that autism represents an "extreme male brain" (i.e., highly systemizing), children w/ such a brain are likely to result from two high systemizing parents, say two technology-oriented people from Silicon Valley. As more and more high systemizers pair up w/ each other (i.e., as we see more positive assortative mating), we should observe more and more children w/ autism. Now, as far as it goes, the argument is fine (not to mention clever). However, it makes a crucial prediction about the pattern of autism at the population level which turns out to be just wrong. Assortative mating only means that "like pairs up with like," which is to say that w/ time the population becomes increasingly segregated into two groups of homozygote genotypes, thereby reducing the proportion of heterozygotes. Now, if we view an individual allele (like A or a) as a marble, and a genotype (like AA, Aa, or aa) as a bin, then assortative mating only moves the A marbles from the hetero bin to the AA bin, and the a marbles from the hetero bin to the aa bin. If we label the aa bin as the "autism" bin, then we've produced proportionally more autistic individuals by assortative mating, since it now contains more marbles -- but we've also produced proportionally more individuals who are the opposite of autistics, whatever they're to be called. So, assortative mating doesn't tell us anything about the change in frequencies of the alleles (number of marbles of one type divided by all marbles), only of the genotypes (how full the bins are, from 0-100%). Assuming there is no difference in fitness b/w homozygotes of type AA and of type aa, then the allele frequencies remain unaltered. Importantly, when two AA (anti-autistic?) individuals pair up, they won't have an aa child, so we should see autism decreasing among the sub-population whose marbles are drawn from the AA bin. But in reality, autism is on the rise across the board, not just among Silicon Valley nerds; lots of relevant info available on the CDC website for autism. Under assortative mating, that can only happen if aa individuals were more fit -- i.e., got more copies of their genes into the next generation -- compared to AA. But given how crippling autism is in the search to find a mate & raise children, or to raise one's nieces & nephews, this is not a plausible explanation. Less severe but still high levels of nerdiness / systemizing in the latter half of the 20th C West would have resulted in fewer children than average. So, if there is assortative mating on the dimension of empathizing-systemizing, this should have tended to purge alleles implicated in autism from the genepool. Therefore, we can safely conclude that autism cannot be a genetic condition in the sense that Sickle Cell is. The purported mechanism (assortative mating) would've had the opposite of the observed effect (prevalence increasing across the board). The lower bound of the estimate of current prevalence is about 1 per 500, which is greater than what could be produced by random mutation (about 1 per 10,000 at most), so it cannot be a freak mutation. Thus, we have two broad classes of explanations: 1) the diagnostic checklist has changed, artificially raising the estimates, or perhaps the detection methods have gotten better; and/or 2) environmental insults. If it's 1), then we have nothing more to worry about than before, and if 2), then we've narrowed down the list of where to look for the culprit. True, this wouldn't tell us which environmental insults were the culprit, but still, if you're a policeman looking for a burglar on some street, just knowing which side of the street he's hiding out on will significantly reduce the time, effort, and resources you expend in apprehending him. So, lack of knowledge of the most basic concepts in pop gen can not only lead one astray scientifically, but can also have very real consequences as far as public health and individual suffering are concerned. [1] I noticed this post from the GNXP archives on this exact topic, but I felt some more flesh on the skeleton was necessary, especially for those of us who aren't practicing population geneticists. Also, the idea is not interred yet, so it bears reiterating. Extensive Update: There's a good bit of discussion in the comments, the three main points of which I'll try to distill. The first is the complaint that my model is Mendelian, whereas a more realistic model would be polygenic. The reason I chose the simplified Mendelian model is that it preserves the relevant property of the polygenic model: namely, under assortative mating, we expect an increase in the phenotypic variance, not necessarily an increase in the mean or median. This is the relevant property b/c I claimed that empirical findings suggest that autism is on the rise across groups, not just among high systemizers / nerds. More on that in one second. Now, there are additional wrinkles that come w/ the more realistic polygenic model -- namely, a change in the mean or median could happen due to the non-additive effects of the genes involved. The effect that assortative mating has on the dominance variance is typically small enough that we can ignore it. That would mean, then, that though we wouldn't expect autism to rise among the left half of the "nerd curve" given the additive effects of the separate genes, nevertheless the interaction between these genes (i.e., epistatic effects) might produce something unexpected. I searched PubMed for 'assortative epistasis' and 'assortative epistatic' and found nothing on unusual conditions, diseases, etc. -- just the expected articles on how assortative mating complicates calculating heritability, and so on. I also Googled ' +"assortative mating" +disease +epistasis' and likewise with 'epistatic' and again found no data points. So, while possible, there appears to be little precedent for such a scenario -- although I'm not a student of diseases and welcome any corrections to the effect that assortative mating plus epistatic effects result in a mean / median increase in some human genetic disease. By contrast, there is ample documentation of diseases similar to autism in prevalence & crippling-ness that are due to environmental factors. The second big issue is: is autism really on the rise across all groups? The relevant group here is social class. There is an obstacle to overcome: studies which show that risk of autism rises as SES increases could reflect better access to health care services (diagnoses & treatment) among the more affluent, their higher IQ allowing them to better spot potential problems in their children, higher IQ making them more frantically concerned over their child's future, and so on. So what we want are data sets that can tease these variables apart, or that at least are exhaustive enough that selection bias in reporting will be minimal. Here follow six extensive enough studies that cast doubt on the putatively high link b/w parental SES and autistic children. 1) The most recent large, national study on the risk factors of autism analyzed data from Denmark (done by researchers at University of Aarhus in Denmark, and at Johns Hopkins and CDC in the US). Because health care is free and easy for all in Denmark, because only publicly hired people can diagnose autism, and because these data along w/ other demographic data on patients are collected into national databases, these researchers had access to essentially all cases of diagnosed autism in the country where the child was born after 1972 and was at risk of developing autism before 2000 -- a nice longitudinal study, rather than a snapshot.
2) Staying within Scandinavia, this study looked at SES factors of parents of autistic vs non-autistic children in Goteburg, Sweden, who were born from 1962 to 1973 -- so, before the autism epidemic, and before the expanded circle of definitions that included less severe forms, and thus representing what are now called "classic autistic" cases. The distributions of social class were almost identical in the infantile autism group and in the random group. With respect to some other social circumstances the two groups were very similar. Thus, the present results lend no support for the view that autistic children tend to come from high social classes. 3) Moving next to France, this 1997 study identified autistic children born between 1976 and 1985, so also probably classic autism pre-epidemic. One hundred seventy-four children (mean age: 11.6 years) with autism were identified. The prevalence rate was 5.35/10,000 (16.3/10,000 if other pervasive developmental disorders are included), with no difference according to geographical area or social class. 4) Suspecting a selection bias in studies claiming parental SES is a good predictor of bearing autistic children, Lorna Wing (who popularized the research on Asperger's Syndrome) examined the profiles of parents of autistic children in London in 1980, so as w/ the Swedish study, probably representing classic autism pre-epidemic. Children with typical autism, other early childhood psychoses and severe mental retardation without autistic behaviour were identified in an epidemiological study in an area of South East London. The social class distribution of their fathers was examined and no significant differences were found between the groups, nor in a comparison with the general population of the area. Fathers of children with autism and related conditions referred to an out-patient clinic with a special interest in autism, mostly at their own request, and fathers joining the National Society for Autistic Children, were of higher social class than both the average for England and Wales and the fathers of the study children. Joining the NSAC during its early years, and keeping up membership were also linked with higher social class. The findings supported the view that reports of a social class bias in autism may be explained by factors affecting referral and diagnosis. 5) Not long afterward, in 1982, Tsai, et al. did the same thing w/ parents of autistic children in Iowa. The social class distribution of fathers with autistic children attending a locally well-known and state-supported modern autism program was examined and was compared to the social class distributions observed in a nonautistic, mentally retarded population, in children with other psychiatric disorders, and in the general population from which the present autistic sample was drawn. No significant differences were found among the groups. The findings supported the view that if studies are not biased by certain selection factors outside the autistic child's clinical picture and diagnosis, and if services become better known and readily available, then no differences in social class distribution between autistic and nonautistic groups occur. The results suggest that social class is not an important factor in the origin of autistic syndrome. 6) A 1999 meta-analysis concludes that, "Social class and immigrant status did not appear to be associated with autism." I think these studies suggest that the link between parental SES and autism is exaggerated, almost certainly in the case of classic autism -- the crippling, from-another-planet version -- and likely in the slightly less severe forms as well, if not in perhaps the highest functioning versions where the child appears to be simply "really nerdy." The perception that autistics are more likely to come from nerdy parents is likely mostly a reflection of such parents having better access to health care to diagnose and treat their child, having the requisite higher IQ to recognize problems w/ their child and to obsess over its well-being, and having better access to the popular media by which to broadcast their concerns. Third, and lastly, is the contention that, even if ultimately due to an environmental insult of some kind, the fact that genetics play a strong role argues in favor of considering autism a (perhaps partially) genetic condition. See the references here, but most estimates ballpark the heritability of autism at around 0.7, which is pretty high even if less than 1. One puzzle to ponder first is the heritability of known infectious diseases. The following are the monozygotic and dizygotic twin concordance rates for such diseases, taken from Vogel & Motulsky's Human Genetics (p.237): Measles - MZ = 97, DZ = 94 We can see that, aside from the presence of the pathogen known to cause the disease, there are also genetic factors involved (as shown by differences b/w MZ and DZ twins), as well as chance factors (as shown by MZ rate far less than 1 in most cases). Presumably, the role of genes is that of susceptibility to initial infection, weakness in attacking the infection, allowing an easier-to-navigate route to the site where the pathogen does its thing, and so on. Given the complexity of such a role, there are presumably many genes involved. So, the picture is quite like that of autism (and the MZ & DZ concordance rates of autism are just like those of leprosy). However, no one classifies measles, scarlet fever, pneumonia, tuberculosis, or leprosy as genetic. The reason is that classification of diseases follows a different modus operandi from other empirical inquiries. For example, philosophers view establishing "causation" as determining what the necessary and sufficient conditions are for X -- that is, a potentially multi-item checklist so that when all items are checked off (no more, no less), then X happens. Statistical scientists talk about which variables account for what portion of the total variance among outcomes, e.g., what variables (race, sex, IQ, etc.) account for individual differences in educational outcomes? That's not how it's done for diseases, though. In this case, a disease is classified as infectious if the infection by pathogen(s) is a necessary condition -- it doesn't have to be sufficient. It seems a strange departure from the stricter defintions of philosophy and statistics, but think of it from the germ's point-of-view: you're trying to infect some host in order to reproduce. All sorts of other things have to line up in order for you to succeed -- they have to inhale the right gust of air or have sex w/ the right person, while you have to turn left instead of right in their gut, dodge their immune system response, etc. Hell, you may even have to rely on the host having a particular genetic profile for the job to get done right. But all of these things are just one or another potential obstacle that threatens to thwart your best efforts to exploit the host's body for your reproductive purposes. There is another, pragmatic reason why the definition is relaxed when classifying a disease as infectious -- on a purely analytical level, there may be various factors involved that interact in complex ways, but in the real world, we want to isolate the factors that we can easily change in order to prevent disease. Complex suites of genes are notoriously more difficult and expensive to alter here-and-now on a population level compared to vaccination, antibiotics, sanitizing the water supply, spraying DDT, and so on. That's why a disease is classed as infectious if removing the pathogen prevents the disease (i.e., is just a necessary condition) -- it answers the pressing question: Is it possible to get rid of this stuff by the aforementioned cheap & easy methods? So that's about it for the wrap-up. I'm sure this is longer than the original post, but I try to strike a balance between being too wordy and too vague, since I neurotically obsess over how much of a blabbermouth I come off as! From now on, though, I'll err more on the side of wordiness & depth.
The front page of Science Blogs went through a redesign today and more than 20 weblogs were added. Worth checking out.
Thursday, June 08, 2006
Can you understand this? Let me teach you a lesson, yo / The pre-existence of the mathematical biochemical equations / the manifestations of God: earth, air, fire, and water which are in it's basic formation / solid, liquid, and gases that caused the land masses, and the space catalyst and all matter that exists and is dense... - RZA
I plan on writing about RNA interference (RNAi) a lot as there are new discoveries in this area all the time and I'm trying to keep up to date. In the interest of not having to re-introduce the basics everytime, I am creating this post so I can link to it from now on when I write about any of the details. I will focus entirely on regulation at the translation (protein synthesis) level, since I have only recently discovered the transcription-level literature and I haven't been able to digest it at all. I don't study RNAi directly in my research. That is to warn you that my knowledge of it is probably more incomplete than I may let on, and I may be misunderstanding certain aspects of it with no negative feedback sources around. In spite of this, I find the whole scene fascinating, and I think it is really an exciting time to understand molecular biology and watch this entirely new regulatory system with myriad potential applications as a research and therapeutic tool unfold. Small regulatory RNAs come in two major types: small interfering RNAs (siRNAs) and microRNAs (miRNAs). In their mature, effective state they range from 21 to 30 nucleotides long. The function of these small RNAs is to specifically inhibit translation of target messenger RNAs (mRNAs). Messenger RNAs are the normal RNA that you think about in the central dogma of genetics (DNA -> RNA -> protein). Translation is the process by which ribosomes and associated factors gather around an mRNA and translate from the triplet code of nucleotides to an amino acid chain (protein). Just a reminder in case you don't think about this everyday. I say that these small RNAs work specifically because they don't globally inhibit translation. A given small RNA will have a sequence that is the mirror image of the sequence of some particular mRNA. The small RNA will guide silencing machinery to its target mRNA through this sequence complementarity, so that no protein is made from this mRNA. This is RNA silencing or RNA interference. You can distinguish siRNAs from miRNAs by their biogenesis pathways. The siRNA pathway is rather short relative to the miRNA pathway. In the end, for both pathways, you have a small RNA template loaded into RNA silencing machinery. Then the function of small RNAs can diverge again based on their mechanism of silencing, which is determined by the structure created when the template binds to its target RNA. Biogenesis  Small interfering RNAs are derived from larger chunks of double-stranded RNA. The siRNA pathway seems to function as a viral defense or maybe a genome integrity defense mechanism. HIV-1 and HIV-2, for instance, are dsRNA viruses. Cells also encounter dsRNA in the form of transposons (jumping genes). Transposons are a lot like viruses that just happen to be hanging out in our own genome. Alu elements, which have been used in human ancestry studies are a form of transposon. Transposons get transcribed from one section of the genome and then seem to sort of randomly insert into other parts. This can cause problems if they were to drop into the middle of an important gene, so cells generally would like to keep transposon activity at a minimum. Another source of dsRNA is pesky experimenters, who synthesize it themselves and inject it into cells. One thing to note is that you don't need two RNA strands to get dsRNA. A single strand can form a "hairpin" or "stem-loop" structure in which it folds back and base-pairs with itself, leaving a little loop at one end and single-strand tails at the other end. Thus, sometimes researchers that will fold into short hairpin RNAs (shRNAs) that are good for RNA silencing.Long dsRNAs are converted to small RNAs by a protein called Dicer. Recent work has shown that Dicer acts as a molecular ruler, measuring out chunks of dsRNA in the proper ~25 nucleotide range and chopping them off. Dicer contains a conserved dsRNA-binding domain called PAZ that is actually found in proteins in later steps of the RNAi process too. The proposed mechanism relies on the ~65 angstrom (corresponding to the length of about 25 nucleotides) distance between a portion of the PAZ domain and the active site of RNA cleavage where two RNase III domains line up in the 3D structure and cut across the dsRNA. The main thing here is that Dicer is the protein that produces siRNAs from long dsRNA precursors.  The final step in microRNA production is the same. A pre-miRNA is cleaved into a properly sized mature miRNA by Dicer. However, the miRNAs are purposefully endogenously produced to play a regulatory role in several cellular processes. They are conserved across higher eukaryotes, and are estimated to regulate some 30% of human genes. The precursors to miRNAs are transcribed from our DNA by RNA polymerase II just like plain old mRNAs. The initial transcript is called a pri-miRNA. These can be thousands of bases long. Pri-miRNAs are processed by a pair of proteins, one of which is called Drosha. Part of the difficulty in reading RNAi work is that it is being done across several model systems, and people may name a newly-discovered protein one thing in flies and a different thing in human cells. For instance, Drosha's partner-in-crime is called Pasha in invertebrates and DGCR8 in vertebrates. The whole pri-miRNA processing complex is referred to as the Microprocessor.The Microprocessor recognizes stem-loop structures that arise in the transcribed pri-miRNA and cuts them out to produce ~65 nucleotide-long pre-miRNAs that consist of ~22 base-pairs, a loop at one end, and a little single-stranded overhang at the other end. This overhang is on the 3' end of the pre-miRNA sequence and is important for further miRNA processing. The 'R' in RNA is for Ribose, a sugar with 5 carbons. Because nucleotides polymerize by linking the third (3') carbon to the fifth (5') carbon, the nucleotides at either end of a string will have the 3' or 5' carbon unattached, and we designate that end accordingly. I think of the 5' end as the start of the strand and place it on the left in my head because that's how my molecular genetics prof drew it. Then you read left to right to get to the 3' end. The third and fourth nucleotides from the 3' end of a pre-miRNA base-pair with the first two nucleotides on the 5' end, leaving a two-nucleotide, 3' overhang. The reason I'm making a big deal about the 3' overhang is that the concept will pop up again later in the process, and also the 3' overhang is recognized by exportin 5, the protein responsible for transporting pre-miRNAs out of the nucleus to the cytoplasm. Exportin 5 also requires the pre-miRNA to have a dsRNA stem that is larger that 16 base-pairs. The loop part on the other end of the stem from the 3' overhang doesn't seem to be important. Once the pre-miRNA is out in the cytoplasm it can be recognized by Dicer and cut down to the small, double-stranded mature miRNA size. The final step in miRNA and siRNA maturation occurs as the little double-stranded chunks are being loaded into RNA-induced silencing complex (RISC). One of the strands in the duplex will have slightly less thermodynamic stability in base-pairing near its 5' end. This strand will serve as the template for RNA silencing while the other strand is degraded. Mechanisms The RNA-induced silencing complex (RISC) is the conglomeration of proteins that actually carries out the dirty work of RNA inteference. Dicer cuts the dsRNAs down to size, but then remains bound to them and ends up associating with RISC through an interaction with another protein called R2D2 (at least that's what it's called in flies). Dicer and R2D2 in complex are in part responsible for loading the siRNAs into RISC. There are associated proteins found in some purifications of RISC but not others: certain RNA-unwinding proteins and even the fly version of fragile X mental retardation protein (Fmr1). Argonaute is the protein at the catalytic center of RISC and has been found in every preparation of RISC so far. RISC is usually detected by is endonuclease activity. This is the simplest mechanism of RNA silencing. The target RNA is simply lined up with the template and then chopped into two pieces by a protein that until recently wasn't identified, but was referred to as Slicer. In recent years it has become apparent that Slicer is Argonaute. Argonaute activity relies on two important domains: a PAZ domain similar to the one that is present in Dicer and a PIWI domain. The PAZ domain plays the same role in Dicer and Argonaute. It binds to the 3' overhang of the template strand and positions it in relation to a RNA slicing domain. The actual slicing is performed by the PIWI domain. Slicing is very specific, cutting in between the two nucleotides on the target strand that lie across from the 10th and 11th nucleotides of the template. People in the field characterize the mechanism of cleavage by way of analogy to an enzyme called RNase H, but this may not help in this case. The RNA backbone is built by connecting sugars through phosphate groups. The PIWI domain acts on the target strand and separates the phosphate from the 3' carbon. This reaction is dependent on divalent metal ions. This may be more than you want to know, but that's the price you pay for reading this far. All that is to introduce you to RISC. siRNAs and miRNAs are incorporated into RISC to do their job. This is often referred to as 'programming' the RISC. In most cases, siRNAs guide this cleavage reaction of their target sequence. MicroRNAs, on the other hand, often don't lead to cleavage, but instead reduce the level of their target RNA in a slicer-independent manner. The major distinction determining whether RNA is reduced by slicer or not appears to be the degree of base-pairing complementarity between template and target. If there are bumps in the base-pairing (i.e. the sequences aren't exact mirror images) especially at the site where slicing would occur then the reaction cleavage reaction doesn't take place. It just happens that siRNAs tend to have perfect base-pairing and miRNAs tend not to, but the issue doesn't appear to be route of biogenesis. A miRNA that base-pairs perfectly will probably guide cleavage.  If RNAs aren't being chopped up by RISC, what is happening to them? This is where all the recent buzz about P-bodies comes in. P-bodies (processing bodies) are cytosolic sites of mRNA degradation, a conglomeration of proteins that carry out the orderly sequential steps of deadenylation, decapping, and exonucleolytic degradation. These exo- and endo- nuclease terms may be unfamiliar. All they indicate is whether the RNA is being chopped up from the ends of the strand or from within the stand, respectively. Some of the proteins involved in decapping are Dcp1, Dcp2, and Xrn1 (more here). They are all found in these little foci in the cytoplasm called P-bodies, and it turns out that Argonaute proteins co-localize with P-bodies in a small RNA-dependent fashion. So even if Argonaute can't directly catalyze target RNA destruction it can drag it to the processing center where it will be degraded via another pathway. Finally, miRNAs don't even have to cause RNA degradation to regulate translation. The target RNA can remain intact but inaccessible to the translation initiation machinery. This process again may involve P-bodies, as ribosomes and initiation factors are excluded from P-bodies. I think this avenue could lead to the most sensitive regulation since you wouldn't need to transcribe a whole new mRNA if you wanted to turn translation of that particular protein back on. You could just release it from translational repression. An issue that remains to be resolved is whether translational repression leads to P-body targeting and degradation or vice versa.Summary siRNAs and miRNAs are distinguished by their route of biogenesis. miRNAs are endogenous regulatory molecules and must be processed through a series of steps culminating Dicer action whereas siRNAs usually start out as foreign dsRNAs and are processed directly by Dicer. Dicer chauffeurs the diced product into RISC which is the effector of RNA interference/silencing. RISC can silence RNAs through three mechanisms: 1) If the template and target have perfect complementarity, the target is cleaved directly by Argonaute, 2) If there are mismatches in the base-pairing the target RNA can be localized to P-bodies for degradation, or 3) sequestered away from translation machinery also in P-bodies. Recommended Reading If you're feeling ambitious after reading this, Nature Genetics has a "MicroRNA Revolution" supplement this month offered for free. Zamore PD. Haley B. 2005. Ribo-gnome: The big world of small RNAs. Science. 309:1519-1524. Sontheimer EJ. 2005. Assembly and function of RNA silencing complexes. Nat. Rev. Microbio. 6:127-138. Valencia-Sanchez MA. Liu J. Hannon GJ. Parker R. 2006. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes & Dev. 20:515-524. MacRae IJ. Zhou K. Li F. Repic A. Brooks AN. Cande WZ. Adams PD. Doudna JA. 2006. Structural Basis for Double-Stranded RNA Processing by Dicer. Science. 311:195-198. Zeng Y. Cullen BR. 2004. Structural requirements for pre-microRNA binding and nuclear export by Exportin 5. Nuc. Acids. Res. 32:4776-4785. Seitz H. Zamore PD. 2006. Rethinking the microprocessor. Cell. 125:827-829.
Here's a ScienceDaily report from the latest annual meeting of the American Society for Microbiology, where one team of researchers presented evidence of which genes in gum disease pathogen P. gingivalis empower it to invade the arteries, where it likely contributes to atherosclerosis. I couldn't find the poster / abstract at the ASM website, but here is a pretty recent journal article from the same research department on the topic. So, rather than representing just another correlational study that provides more evidence for Cochran & Ewald's new germ theory (popularized by Ewald in Plague Time), this research illuminates the mechanism behind the process. God knows what other garbage is living in your mouth, so remember the mouthwash -- or perhaps soon, a mini light sabre for attacking oral cavity microbes.
Tuesday, June 06, 2006
I'm not ignorant of David Stove, though antipodean intellectuals seem always to be big fish in a small pond. His criticisms of "Darwinism" I'd assumed to be rather ignorant and uninformed from what samples I'd seen, but regular and longtime reader Robert Spiers keeps alluding to Stove as if he had something important to say. I assume that longtime readers of this weblog have some discernment, so I figured why not, I picked up David Stove's Darwinian Fairytales and so far I've read 50 pages on my spare time today. From the preface:
I think this is a good taste of the type of person David Stove is, at least judging by the subsequent 50 pages. First, not only does he deny the science, but it seems that on a fundamental level the science bores him. It seems anything beyond the sight of his armchair bores him. So far, the first 50 pages pages of Darwinian Fairytales has convinced me of the cogent analytic clarity and empirical solidity of Michael Behe's Darwin's Black Box. Being who I am, I will no doubt finish this book, but, I am about as likely to say anything more (or listen to anything more from someone who takes this pile of shit seriously) on this as I am to review Ken Ham's The Lie: Evolution. At least Ken has sincerity on his side. Shorter Stove: My common sense says x, therefore x is true, Q.E.D. Addendum: I am sparing you Stove's points against Darwinism because some of them are as sophisticated as the toddler's-philosophy-of-the-universe. For Stove admirers, do you know what spontaneous abortion is? PS: John Derbyshire's review of Stove 5 years ago is where I first encountered him. This bit is important, "Often Stove falls into the philosopher's disdain for mere facts." This is perhaps excusable in a grand system builder who is looking for the big picture, but that is not what Stove seems to be. A negative skeptical stance is easy, easy enough that you don't usually need to ignore facts.
A few weeks ago I mentioned differences in response to cold as a function of population. Well, I found this article, Pleistocene migration routes into the Americas: Human biological adaptations and environmental constraints, which hits most of the major points. First, there are non-heritable development aspects to cold tolerance. Individuals can acclimatize in a few weeks to different temperatures, more or less. There also seems to be a developmental window of acclimatization, so that families who live in Peru in Cuzco vs. Lima and only recently separated show varied rates and magnitudes of cold tolerance as adults, implying that a development window had closed (e.g., uncle & aunt move to Lima and have children there, those children are less cold tolerant than their cousins in Cuzco). Finally, there is the heritable element, where northern peoples to be more cold tolerant than southern peoples. In any case, snips of interest:
The Great Khan's double entry bookkeeping! ("for entertainment purposes only")
posted by
Razib @ 6/06/2006 12:22:00 AM
It was bound to happen, the first European (American) has been discovered who is part of the lineage which is strongly suggestive of Genghis Khan. The man is an accountant. I assumed they checked and double checked the results, because they got only 1 hit out of 25,000 in the search for the Great White Khan. That there was only 1 hit out of 25,000, even if it isn't a mistake, is important, because remember that nearly 1 out of 10 "Central Asians" and perhaps 1 out of 200 men the world over are part of this Y chromosomal lineage (that is, father to son, father to son, father to son, and so on). The fact that so few Europeans are part of this lineage tells us that Genghiside paternal ancestry isn't magical, that the numerosity of the first few generations might not account for its subsequent distribution. Rather, my reading of the history suggests that a paternal line of descent from Genghis Khan carried great prestige in the Muslim world (ironic since he was a confirmed infidel), to the point where "Khan" became equivalent to "Caesar" (ie., "Czar," "Kaiser," etc.) in the Western world. This would have given this Y lineage success in because of social conditions (a drop of Genghiside ancestry conferring legitimacy to any upstart), but where those conditions did not hold (ie., the Khan name carried no aura of authority) it did not penetrate and spread.
Monday, June 05, 2006
From the abstract:
OBJECTIVE: The goal was to determine the relationship between the parental use of sunscreen products and the skin color of children in first grade. It's funny because it's true.
Science Matters is run by Jennifer S. Griffin, a grad student in mol bio at Princeton who is looking to pursue a career in science writing and the weblog is a first run. She "addresses aspects of pathogenesis and evolution of microbes, with a focus on viruses." Anyway, I assume this is one weblog that won't go dead, and since germs are of interest to many here I suspect we'll be seeing some bookmarking soon.
Sunday, June 04, 2006
No fear of Patrick Henry College - the Borg shall assimilate
posted by
Razib @ 6/04/2006 12:35:00 PM
Many GNXP readers will at this point probably be aware of Patrick Henry College, the fundamentalist Christian college oriented toward homeschoolers and founded with a mission to influence and reshape mainstream culture. The New Yorker has done the profile thing, and many people forwarded me the piece in The New York Times Magazine. I also recommend this interview on NPR, it is somewhat amsuing in that Michael Farris excoriates the Post Modernism of the modern academy in contrast with his belief in an objective reality, all the while Larry Arnhart chronicles PHC's unsurprising discomfort with the objective realities of biological science (this is the inversion of some on the Left who accept biology in the animal domain, but perceive humans to be a biology-transcending species).
Patrick Henry College has ambitious goals. Michael Farris seems to want to take over the mainstream culture, and he has spoken of the possibility of PHC alums becoming studio heads in Hollywood as well as President of the United States of America. A quick survey of the web shows concern and curiosity from liberals, and some positive vibes from conservatives (though intellectual elite conservatives rarely espouse fundamentalist Protestant Christianity). Myself, I think PHC is going to be an irrelevant flash in the pan. Here is why.... In the 18th century a college was founded to train Calvinist ministers who espoused an "orthodox" theological orientation because Harvard had become notoriously unfriendly to old-style Puritan religion (eventually Harvard's theological seminary became operationally Unitarian). That college? Princeton. Today the Princeton Theological Seminary is not much more conservative than the Harvard Theological Seminary. Today, the "Harvard of evangelical America" is Wheaton College. How fundamentalist is Wheaton? Well, evolutionary theory has been taught in anthropology, and the department chair teaches a course titled "populations and evolution." This is not to say that Wheaton does not have a Protestant evangelical orientation, it does, but it is not "fundamentalist" in a narrow fashion (an issue with some). The American Scientific Affiliation bills itself as "a fellowship of men and women in science and disciplines that relate to science who share a common fidelity to the Word of God and a commitment to integrity in the practice of science." My understanding is that this organization of scientists began with a strong Creationist slant, but today in regards to evolution theistic evolutionists are a majority. My point overall is that the historical record shows a strong tendency for Christian conservative groups which attempt to "mainstream" and take over the discourse at the center of the culture to be coopted and transformed. In regards to Christian colleges there is a notorious tendency for them to become more ecumenical, liberal and vanilla as time passes. The idea that PHC can change the mainstream culture proactively is naive and ahistorical, the more success it has the more likely it is to be transformed, and the more it resists transformation, the less success it will have. Part of the problem is probably that fundamentalist Christianity tends to be a populist movement. Once a movement attempts to force its way into the elite it becomes vulnerable to the excessive reflection and compromise that are the hallmark of elite religious movements. When you don't have social status at stake a "hell fire" theology which is intolerant of others does not imply much cost, but when you do do have social status than such intolerance tends to be problematic in your interaction with others outside your own group. I do not believe any movement without an elite leadership can really succeed in transforming society, and I do not believe that fundamentalist Christianity can succeed as the dominant belief system of any elite because of its transparent superficiality and attendant sociological costs.
The title says it all. If you haven't, you should check out A Frigid and Pitiless Dogma, John Derbyshire's review of A Party of Death in The New English Review. Excepts do not suffice, just be aware that Derb has the rusty knife out and dogmas and cults are out of luck (there is a reason that National Review is not going to publicize this work of commentary). Pity the brown man, for Derb has taken up the white man's skeptical burden.
My favorite bookstore in Denver is the Tattered Cover. This can be wholly attributed to the fact that they have Nature on the shelf in the science periodicals section. This enabled me to sit down and peruse the actual journal today while killing time before watching the Mavs take the western conference championship (I'm a Nowitzness). Something different happens when I'm looking at the actual magazine for some reason. I hadn't noticed this article (Grimm et al. 2006, pdf) before, but I think it's a nice example given recent negativity about the usefulness of animal research. Plus we get to talk about RNA interference (RNAi), and RNAi is cool.
I've argued that a large part of the promise of whole genome research won't be fulfilled until we can use that information medically. We need to be able to pick which genes and variants we want more or less of in which cell-types and turn them up or down in adult humans (i.e. gene therapy). Gene therapy hasn't really got its act together just yet, and we've had some really tragic consequences. The problem thus far in most cases has been that, while the gene therapy did what it was supposed to do, it also did some other things... like causing leukemia or overblown immune response and death. We've made quite a bit of progress in determining how to get gene therapy vectors into the right cells without disrupting other important segments of DNA if we wanted to turn up a gene. In parallel, the discovery and characterization of RNA interference has provided a good way to knockdown a gene that is causing a ruckus. I'm planning on explaining the details of the RNA interference pathway in a later post, but essentially RNAi allows scientists to co-opt endogenous regulatory pathways and virus fighting machinery to specifically silence any gene you'd like. If the cell comes across double-stranded RNA (dsRNA, many viruses look like this) it chops it up and uses one half of the RNA as a template, hunting around for any other matching RNA to silence. So if we want to knockdown a gene, you just shoot a vector in there that codes for a dsRNA with complementarity to the gene of interest. The system works best if there is a little loop connecting the two strands which makes the whole construct look like a little hairpin, so they're called short hairpin RNAs (shRNAs). The authors discovered a huge negative side-effect of a therapy in development in mice that we might not have expected and pinned down its cause, so they can now work on figuring out a ways to circumvent it. I'm not sure what started this line of research. Probably they were trying to test out the efficiency of their adeno-associated viral vector (AAV8) and noticed that their mice kept dropping dead, and it turned into a Nature paper. The first couple of experiments they report are something to this effect. They had mice expressing either luciferase in their liver (a fluorescing molecule) or a human gene called hAAT (it's not really important what it is). They then targeted these genes with specific liver-directed shRNAs. Injecting high doses of almost all of their different AAV8-shRNA constructs knocked down the gene for a little bit, but within about a month the mice keeled over from liver toxicity. In fact, the shRNA didn't even have to have a target to cause toxicity. shRNA vectors aimed at nothing in particular caused the same sorts of problems. Others have shown that trying to induce RNA interference with certain constructs can lead to negative side-effects due to inflammation. You get a reaction from sort-of the wrong virus-detecting widget in the cell, and all these inflammatory proteins get made and the whole system goes haywire and cells die. Grimm et al. couldn't find any evidence that this was happening in their mice. Nor was there any evidence that the delivered constructs were disrupting the cell-cycle. The first clue to the actual cause of toxicity was the fact that the constructs that were causing major toxicity tended to make a major amount of shRNA. Following this up, the authors found that toxicity was also associated with a decrease in overall microRNA levels. MicroRNAs are short regulatory RNAs that happen to use a lot of the same machinery as the shRNA system does. Here's the punchline: shRNAs that are too highly expressed clog up the works, so essential miRNAs don't get made. Grimm et al. performed a couple of different experiments showing competition for resources between their shRNAs and endogenous miRNAs. Both shRNAs and miRNAs are transcribed in the nucleus just like your average everyday messenger RNAs, but they have their own special exit from the nucleus called exportin-5. This is one of many nodes where the competition could be occuring, but it turns out to be an important one. When Grimm et al. overexpressed exportin-5 so there was enough to go around, the competition effects dropped off. Since this step in the pathway pretty much runs exactly the same in mice and humans it serves as a good warning for folks who are developing shRNA-based therapies. More expression in this case is not better. The aim will be to produce only as much shRNA as can get the job done. Grimm seems particularly interested in using this technique against hepatitis. While they haven't figured out exactly what elements differentiate a non-toxic, effective construct from a toxic one, they did report one that works to stably knockdown one of the hepatitis B virus particles specifically in the liver for over 5 months after transfection. The main feature of the effective construct as far as I can tell is that it is shorter than all the rest. I guess maybe its shortness leads to weaker expression for some reason so it doesn't crowd the door out of the nucleus. It's great they were able to catch this effect so early. Since the recent "elephant man trial" (discussed in the Slate article linked above), animal rights fanatics are trying to argue that discoveries in animal research don't translate to humans, so we should stop being so mean to the poor mousies. Here's an example of a promising new approach to treating a debilitating human disease that is being developed with the help of mice. This potentially lethal side-effect was caught before the final therapeutic construct has even been designed. Not to mention that screening for side-effects probably accounts for the smallest portion of animal experiments. You have to get the basic biology down and find treatments that work against animal disease models before you start worrying about this off-target side-effect business. How hard is it to decide it was worth a few mouse lives to avoid lethal liver toxicity in hepatitis patients?
Saturday, June 03, 2006
The use of information in race and ethnicity in biomedical studies is of course controversial, but this controversy is often minimized with an appeal to the utility of the information. I recently made this case here. But how useful of a concept is race, really?
I assume most geneticists would agree that, given enough genetic markers from a person and the worldwide distribution of those makers, one could give a good guess as to that person's ancestry. And from that, one could predict the label that person would apply to themselves in any given culture. A paper from Neil Risch's group showed essentially the United States version of this, finding that clusters of individuals created blindly using genetic information corresponded extraordinarily well to how people self-identified by race. However, the utility of the concept of race does not come from how well it can be predicted using genetic information, but the inverse. That is, the utility of the concept of race comes from how well genetic information can be predicted from it. And that is much more complicated a question to address. A quick bit of context, so people know how this problem is set up in my head: imagine you're a researcher and you've got this idea that a couple mutations play a role in a disease you study. So you want to do a case-control study-- genotype the mutations in some people with the disease, some people without, and see if there's a difference between the two groups. Of course, if you're going to type a large number of people, you know you need to control for possible confounding due to population structure (don't know what I'm talking about? Read part I of my old post). There are a number of ways to due this, but they all involve genotyping a bunch of extra markers, and you don't want to pony up the cash for that-- you want to type your two candidate mutations and be done with it. You've heard that controlling for race reduces error due to population stratification, so you limit your study to African-Americans. You do it, analyze the data, and sure enough there's a significant association. What's the interpretation? Clearly, saying that this association is real depends on race acting as a proxy for the rest of the genome you don't genotype. There's strong evidence that this is not a generally good assumption: A couple studies have essentially repeated the Tang et al. study I linked to before with fewer markers, and their results are conflicting. One found that, with only 15 markers, the genetic clusters corresponded well to self-indentified racial clusters. But another, using the same marker set found significant population structure within each cluster. That is, genetic information--at least at some markers--is not consistently predicted by self-identified race. The interesting thing about comparing these two studies is that they take place in different cities (San Francisco and Detroit), so the conflicting results could be due to differences in the populations involved. This would seem to square with other reports from the Risch group that the level of admixture in African-American populations varies geographically. This is not particularly surprising-- deCODE Genetics made news a couple years back when they documented the level of population structure present in Iceland, considered a fairly genetically homogenous place. The authors of one of the papers above write that "when the true underlying genetic structure and the self-defined racial/ethnic groups were roughly in agreement with each other, the self-defined race/ethnicity information was useful in the control of population structure". Well, yes. But that's the whole point-- it's impossible to know if the two are in agreement until you test it. So it seems there's no getting around paying the extra money to type more markers to test for population structure in a study-- controlling for race will get rid of the obvious structure, but not less-obvious, but still important, differences within the population being studied.
Friday, June 02, 2006
Gene Expression is 4 years old today, and Razib flexed his blog overlord muscles and made me write a retrospective. I don't think I have quite the encyclopedic memory he thinks, but he's right that I've followed the blog before there was a blog, as it were, back in April of 2002, when Razib and Godless Capitalist both had their own separate websites. So I'll add some perspective for the 2002-2003 period.
GNXP B.C. The "blogosphere" was really starting to consolidate in 2001-2002. Bloggers like Glenn Reynolds, Andrew Sullivan, and Atrios were all growing in influence as grass-roots commentators, and were helping to build up a real, new Internet community of exchange, linking, and debate by highlighting and encouraging talent in smaller blogs. By that time I had already read most of the canon of popular science books, and taken my position in the Sociobiology Wars (as first brought to my attention in 1999) firmly on the side of the genetics camp. I may have been riding the wave in, because it was, by that time, obvious and increasingly obvious, that the anti-sociobiologists had been lying and mud-slinging, like their Creationist brethren, for decades (the Bell Curve backlash of the mid 1990s perhaps - hopefully - serving as their last popular opinion "victory". The Larry Summers backlash of 05 was pretty much an embarrassment for the Blank Slaters). Since sociobiology has so many implications for politics and society, and yet many liberals are hostile, indifferent or baffled by sociobiology, and many conservatives are embarrassed, hostile or baffled by biology, there was a peculiar and important intellectual vacuum waiting to be filled. One of the few pundits independent enough to fill that lonely void at the time was Steve Sailer, a conservative who is/was easy to find through any sociobiology related web searches, and yet fit none of the stereotypes of what those evil people who dare think seriously about genetics and human behavior should look like. Sailer was not afraid of race and his writings confounded both antiracists by accepting racial differences, and racists by not generally implying differences meant people/races were "inferior" or "superior" and by rejecting racial nationalism. That this niche was so empty is an indictment of the intellectual landscape of the time: the "realists" were the racists and they were not moderate, and the "moderates" were the antiracists, and they were not realist. It's not surprising then that many realist whites and nonwhites would find Sailer's oasis of moderate realism attractive. It is fairly amazing how much Razib and Godless Capitalist had in common, even though they started both of their blogs in the first quarter of 2002 unaware of each other. Both were from first generation South Asian-American families (Razib a Muslim family from Bangladesh, GC a Hindu family from India) but both grew up in America as atheists. Both were in their mid 20s, had degrees in bioscience (Razib biochemistry, Godless genetics/bioinformatics), were race-realist sociobiologists, and could be described politically as neoconservative-libertarians (as was a majority of the blogosphere at the time, e.g. Sullivan and Reynolds), tempered with the unique bioconservative perspective developed earlier by intellectuals such as Steve Sailer, James Q. Wilson, Richard Herrnstein, and Charles Murray. 'Race' is the one word that best describes the underlying theme and focus of early Gene Expression and proto-GNXP. I say "early" because it has evolved into something somewhat different today, as a less political and more general science blog, but it started in a very real way as a blog about race and all surrounding issues - affirmative action, population genetics, IQ and crime differences, Rushton, Jensen, and Lynn, genetic differences, hapmap, race as a biological reality, identity politics, immigration, reparations, ethnology, racism, white nationalism, interracial dating, and multiracial hotties, were all the centermost topics. Razib's blog (which if I remember correctly was called Razib's Rants, Raves. & Reflections) is no longer with us, not even in Wayback. It wasn't really even a blog, per se, but a personal website where Razib toyed around with his web-development. Sailer started his blog in December 2001 and Razib had been lending his population genetic expertise to Sailer's commentary. Sailer linked to Razib's pseudo-blog in April 2002, calling it "a new human biodiversity-oriented blog", and Razib was trapped by the label! Sailer soon received and advertised an email from Godless noting that he was, coincidentally, a different brown-American who had started a similar Hb-d themed blog the previous month. Godless Capitalist's blogspot archives are still available. Razib and GC soon had numerous exchanges on different race issues, including H-1B (skilled) immigration, race and homosexuality, Asian education, and Asian vs. White hotties Godless also had debates with other bloggers and "debating the blogosphere" would carry over to Gene Expression as kind of a longstanding tradition that continues today. The key to these debates is that they were/are often on controversial race-related topics where the GNXP side always has the facts, so you quickly either see slow conversion/revision on the other side or a sorry flameout out on their part, where a GNXPer usually gets banned or threatened with a lawsuit - either way good times all around. Godless extensively debated race and IQ with early science bloggers Charles Murtaugh and Paul Orwin, and these debates carried over to Gene Expression. GNXP A.D. Godless and Razib combined forces to create GNXP in June of 2002, together with three other bloggers that had the same interests in/opinions on Capitalism and sociobiology, but had much less to say on race. First there was Mary C. who had her own early science blog. Second there was Joel Grus, who designed the logo! Third was Elizabeth Spiers, maybe GNXP's most famous alumna, she went on to found the popular celebrity gossip site Gawker, and now the popular wallstreet gossip site Dealbreaker, which is apparently pulling in something like 30,000 hits a day. She also has a book coming out. Razib and Godless initially pushed race (and especially race and IQ) very hard, amounting to virtually all their posts. Godless continued his exchanges with Murtaugh and Orwin and began a similar one with his early nemesis Philip Shropshire. Glenn Reynolds blogrolled Gene Expression early on (and even participated in some of the comment box discussions), and so these topics were forced into the mainstream of the blogospehere to the chagrin of many bloggers. Prominent early bloggers like Atrios and Anil Dash soon flocked into the comment box for debate but were quickly outgunned and sent into retreat by Godless and Razib, who were rearing to fight in those days. Razib's I thought liberals wanted a bridge to the 21st century-not a bridge to the past! and Godless' Modern Day Epicyclists are emblematic of the early character and focus of GNXP. Turnover was quick, and all the initital bloggers but Razib, including Godless, dropped out by December, though Jason Soon and Suman Palit had become regulars in the meantime. Godless would return and drop out several more times over the years, though his participation in the comment box has been more continuous (newbies look for box regular "GC"). Razib recruited comment box participants to preserve the founding character as a group blog, and almost all the people commenting in the box from those first months have either been subsequently absorbed as GNXP bloggers or are still commenting in the box today. I was among the first batch of 2002 recruits along with the ponderous Duende, and David Nierengarten. During this time Razib started moving away from the early polemics and growing into more serious, thoughtful pieces such as The Germanization of the liberal idea and Volkswanderung exploring cultural and population genetic themes. Ironically this was also the time that GNXP's reputation started to catch up with it. A peculiar lefty troll known as Mac Diva started leaving hysterical comments in many comment boxes about "the most racist of blogs". Conservative Richard Bennett was just as outraged. It was one of our earliest and most amusing dustups, here was an old white conservative shouting down a blog with mostly South Asian, Jewish, East Asian and even black (Nierengarten is 1/4 black) posters as "Nazis". Bennett didn't know too much about the subjects he was bloviating about, but we all had fun anyway. It was certainly the most racially diverse Internet defense of race differences up to that date. Duende and David Nierengarten didn't continue much longer as posters either. Razib and I began recruiting heavy-hitters; Razib added David Burbridge, a British chap in the tradition of Haldane and Fisher, who has been one of GNXP's best posters over the years - providing much intelligent and learned commentary on the sociobiological subjects we've always fixated on. I added Alex Beaujean, a professional psychometrician, to provide more serious commentary on the staple IQ issues. The belated antiracist backlash from early GNXP gradually slowed down, and in fact, 2003 began to see a push from the other side as well, as angry White Nationalists began to rebel against the consolidation of a race-realist world-view that did not accept their politics. Vituperation against Razib, Godless, and GNXP was common and very strong from both the Left, the far Left, the Right and the far Right during this time. Nevertheless GNXP was also very popular relative to the blogosphere during the 2002-2003 period; according to the Truth Laid Bear traffic ranking, we were one of the top 50 blogs. While the blog has grown from about 300 hits a day to 3000 hits a day today, the blogosphere has grown at a faster rate, and today we're shy of 300. Before Pandas Thumb and PZ Myers, GNXP was the first popular science blog, the only one, for a surprisingly long while, really with a focus on evolution and genetics. Since that time GNXP has also continued to develop and mature as a blog, covering a vast number of biology and psychology topics from population genetics to cognitive science, without losing any of the original human biodiversity perspective. Also, though sadly without Godless' contributions, we have a more diversely science educated and/or well-read cast today than ever before: Razib, Rikurzhen. Agnostic, Coffeemug, David Boxenhorn, David Burbridge, JP, Tangoman, Fly, Theresa, Alex, Darth Quixote, Matt McIntosh, Dobeln, Tangoman, and even the occasional post from Gregory Cochran. And, of course, as controversial as the blog may have been in its salad days, it has been rewarding to watch the intellectual landscape meet up with our point of view, as we can guess that it will continue to do over the next decade. There is no longer a hole in the intellectual landscape, extremists no longer have a monopoly on a certain realm of truth, and good people no longer need to rely on pseudoscientific "antiracist" arguments about world genetic sameness to maintain their liberal worldview. But please don't make my ramblings the final word! Hopefully GNXP guests and contributors have their own thoughts and memories to add for the comment box or front page. I know Godless Capitalist has to be itching to come out of his comment box hiding spot for an anniversary boast!
More evidence that Finns have no lives (below the fold)
 Karelians go home!
Possible ancestral structure in human populations:
5% isn't jack, but, that's enough to introduce lots of novel alleles which might reshape the larger population into which admixture results in introgression. Remember, probability of fixation of a novel allele in a population is 2 X the selection coefficient. Admixture can be thought of as operationally a hypermutational event as a spike in strange mutants enters the gene pool. Via Dienekes.
Thursday, June 01, 2006
Steve pointed me to Larry Arnhart's blog, Darwinian Conservatism. I haven't checked out Arnhart's recent manifesto, Darwinian Conservatism, because I am generally not too interested in such explicit derivations of political philosophy from nature. Nevertheless, the blog has made me reconsider my decision. Arnhart has some very interesting arguments and entertaining rhetoric to offer. The American Right has made an alliance with Christian evangelicals over the past generation (Frank Meyer's "fusionism" being the early precursor), and to a great extent they have remade conservatism in their own image, at least its public face. But, I have always found the aversion to evolution rather peculiar in a movement which in its intellectual circles appeals to society as "organic" and "evolved." In any case, as I said, more later on this topic, but I agree with John Derbyshire, there is nothing fundamentally "conservative" about a group of individuals who take succor from the radical Reformation.
The Fukazawa et al. paper I described before had a good deal of evidence suggesting that actin polymerizes in response to tetanic stimulation and underlies synaptic potentiation. They had the advantage interpretation-wise of working in live animals where the actin is remodelling in its natural environment. However, this comes with the disadvantage of not being able to observe the process directly. The hippocampus is buried deep in the rat brain and has to be dissected out and fixed in paraformaldehyde before it can be labeled with fluoresecent phalloidin (the polymerized actin indicator). The earliest timepoint after LTP induction we see in Fukazawa et al. is 20 minutes.
Okamoto et al. (pdf) developed a novel approach using fluorescence resonance energy transfer (FRET) to view actin's response to stimulation in cultured hippocampal tissue. This buys them the ability to be very certain about when and where (down to which compartment of the dendritic spine) these events occur. A drawback is that they have to use a model system that is now several steps away from the primary phenomenon of interest (memory): LTP instead of behavioral training and tissue that has developed in a dish lacking any external stimulation or feedback from other brain regions. Everybody does it, but before you see how pretty their FRET pictures are, you have to be reminded that they come at a price. FRET is less complicated than it sounds. It's the fluorescence equivalent of billiard balls bumping or dominoes knocking each other over. In the past handful of years, molecular biologists have branched out and modified the green fluorescent protein (GFP) that we all know and love. Now there are blue, yellow, red, and cyan fluorescent proteins and they each have characteristic excitation and emission wavelengths. The excitation wavelength is the specific color you can hit the molecule with to put it in an excited state. As the fluorophore relaxes back to its ground state it releases energy at its emission wavelength. In FRET a donor fluorescent protein emits energy that can excite an acceptor protein. So you shoot light in to excite the donor and, if the donor and acceptor are close, you will get signal back out at the emission wavelength of the acceptor. Okamoto et al. tagged actin monomers with CFP and YFP, excited CFP, and looked for YFP emissions as an indication that actin had polymerized. This is illustrated below:  The authors first show that the FRET signal really is reflecting actin dynamics as an actin depolymerizing drug (latrunculin A) reduces FRET and an actin filament stabilizing drug (jasplakinolide) increases FRET. They go on to investigate the effects of various plasticity-inducing signals. The first pass was bath application of NMDA (the specific synthetic agonist that NMDA receptors are named after). They found a relatively rapid (within 3 minutes) increase in polymerization. This is a little troublesome because other papers that the authors cited have shown an decrease in F-actin (the polymerized form) following NMDA bath application. This decrease was attributed to excitotoxicity, where excess calcium influx can actually lead to cell death. This is thought to be a mechanism by which extensive brain damage occurs in the face of traumatic brain injury and oxygen deprivation. It could be that the previous studies and this one use different model systems or that the other studies didn't have the temporal resolution to observe this initial increase. Since you asked, I don't think people should bother bath applying neurotransmitter agonists in plasticity studies. Constant receptor occupancy is so far from the physiological norm it seems impossible to interpret this information correctly. Fortunately, the authors went on and used common electrophysiological stimuli for the rest of the paper. It is still hard to say whether the activity induced by these protocols is like that in the brain, but at least neurons are deciding how much neurotransmitter is in the synapse instead of researchers dumping it on for 10 minutes at a time. One of the most remarkable findings is how fast the actin state changes in response to tetanic stimulation. In a particular spine-head, FRET levels increased within 20 seconds of stimulation. The increase is synapse-specific, meaning that spines that are on the same dendrite but distant from the stimulation electrode don't show a change. This shows that the signaling events necessary to induce actin polymerization must happen right there next to the spine rather than being a dendrite or cell-wide event. I've written a lot about LTP, but its sinister partner never gets as much play. You can increase synaptic strength using high-frequency stimulation, but you can also decrease it with low-frequency stimulation. The lasting decrease is termed long-term depression (LTD). Okamoto et al. followed actin dynamics after a dose of high or low frequency stimulation. In accordance with the Fukazawa et al. findings, LTP increased actin polymerization. However, the increase was observed within 3 minutes. F-actin decreased after low-frequency stimulation, but it's harder to say how long it took because the stimulation took 15 minutes. There was a huge reduction in FRET signal from before the stimulation (0 min) to right after (15 min). This might be a good time to show you some FRET pictures. The big green thing is a dendritic branch. The little knobby-do's sticking off are dendritic spines. The top image is LTD stimulation, and the bottom is LTP. Actin polymerization is sort of orange. The numbers indicate minutes in relation to the start of stimulation.  What is the functional outcome of actin polymerization for a spine? For one, the spine head widens in correlation with the increased FRET signal. I've read enough to know that there is a pretty consistent relationship between spine head width and the number of AMPA receptors in a synapse, which makes sense. Another interesting consequence of actin polymerization that the authors noted was an increase in the beta subunit of calcium/calmodulin-dependent kinase II (CaMKII) in the post-synaptic density. I know that last bit is jargon-y. I say it "Cam kinase two beta". CaMKII has alpha and beta subunits that form together into a 12-unit holoenzyme that plays a structural and signaling role on the receiving side of the synapse, attaching to some receptors and phosphorylating others. I've gone into more detail about this particular molecule here. The obvious step after this is to see if this plays out in an actual learning situation. Joe LeDoux has started in on this route, but I don't think he's measured polymerization directly. My friend Joe (not LeDoux) posted a little something on that a while back. Also, we know now that polymerization can lead to CaMKII movement, but is it a reciprocal relationship? Also, which comes first, CaMKII signaling, spine head widening, or AMPAR insertion? Or does it all happen in one big "whoosh"? Perhaps all of the events are initiated in parallel by an unspecified (probably calcium-activated) signaling event. Addendum: I forgot I wanted to mention that a second high-frequency stimulation could induce even more polymerization after the first burst. The authors contrast this with the electrophysiology which seems to potentiate in an all-or-none fashion. While it is true that LTP generally goes up to the same peak during induction, more stimulation can lead to longer-lasting LTP. So it strikes me that the amount of actin that accumulates in filaments in a spine head during initiation must determine duration rather than magnitude. If that's true then it must go for the other correlates of actin polymerization: spine head width, CaMKII accumulation, the presumed AMPAR insertion. But more AMPARs ought to create greater synaptic strength, so that ought to affect magnitude. I don't have the answer at the moment. One of these correlations needs to be disconnected.
Brown Gaucho seems to have set up a petition under the heading "Conservatives against Intelligent Design." I am the first signer. Come now John, why not make it official?
Update: John not only signed, but he linked from The Corner. There have been some questions regarding whether I am a "conservative." I don't know, I am actually at this point a very milquetoast libertarian. But, I am not big on labels and I will accept what people term me, and many say I am right-wing or conservative. As a "person of color" my attitudes toward racial and cultural issues (against affirmative action, against identity politics, pro-Western civilization) put me firmly on the Right. Years ago the "black conservative" Shelby Steele would object when people termed him as such because he considered himself a liberal, who for the record was opposed to school prayer and was pro-choice. But several years ago he just gave up, because as a black man in America it became clear to him that there was only one set of issues that determined his politics in the eyes of the rest of the country. As for evolution and the Right, I pointed out in my post titled The Anglican origins of Neo-Darwinianism? that the leading light of the Modern Evolutionary Synthesis, R.A. Fisher, was himself a Tory and an Anglican. The connection between right-wing politics, evangelical Christianity and anti-evolutionism might seem fundamental and obvious to modern Americans, but there is nothing self-evident about these correlations. Rather, they are the product of particular historical circumstances and confluences of contingent events. More on this topic later.... |
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