Wednesday, November 19, 2008

How predictive are known genetic factors for disease risk?   posted by p-ter @ 11/19/2008 08:16:00 PM

Two studies published today demonstrate what was immediately evident from genome-wide association studies of many common diseases: the genetic variants identified account for only a small fraction of risk.

In these cases, the authors try to predict whether an individual will get type II diabetes from a number of clinical variables, as well as recently identified genetic risk factors. The genetic factors only marginally improve the prediction of diabetes, likely to a clinically insignificant extent.

This was obvious, of course, from the initial studies themselves--you can't expect variants responsible for a meager fraction of overall disease risk to function as effective predictors of the disease. But somewhat notable nonetheless.

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Sunday, September 28, 2008

Feeling sleepy?   posted by p-ter @ 9/28/2008 05:06:00 PM

Nature Genetics this week has published a genome-wide association study of narcolepsy in the Japanese population. The finding in the paper is a variant that confers a modest risk of narcolepsy, but personally, I was blown away by Figure 1, reproduced above. The figure shows the strength of association of each of 500,000 SNPs with narcolespy, and the novel reproducible finding is on chromosome 22 (ie, it doesn't stand out all that impressively in this plot). The major signal, absolutely swamping everything else, is in fact in the MHC region (called HLA in humans).

This region, of course, contains risk factors for type I diabetes, crohn's disease, and most (all?) other autoimmune diseases. A quick google confirms that, indeed, thinking of narcolepsy as an autoimmune disease is not new, but it's definitely new to me, and it's pretty striking to see just how much more important the risk factors in HLA are compared to everything else.

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Wednesday, July 30, 2008

Copy number variation in schizophrenia   posted by p-ter @ 7/30/2008 08:00:00 PM

Nature has published a couple papers reporting (using partially overlapping samples) associations between rare recurrent microdeletions and schizophrenia. The paper from Deocde Genetics hits an evolutionary angle from the first sentences:
Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed.
Rare variants often have much larger phenotypic effects than more common ones; this case is no different:
All three deletions, at 1q21.1, 15q11.2 and 15q13.3, significantly associate with schizophrenia and psychosis in the combined sample with high odds ratio (OR) (p = 2.9x10e-5, OR = 14.83; p = 6.0x10e-4, OR = 2.73; and p = 5.3x10e-4, OR = 11.54, respectively)
Note that despite these massive odds ratios, these deletions explain a tiny fraction of all cases of schizophrenia due the their extremely low frequency. Still, these genomic regions seem like important areas for following up via functional studies or searching for more common polymorphisms.

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Saturday, July 12, 2008

CALHM1 and Alzheimer's   posted by p-ter @ 7/12/2008 02:31:00 PM

It's fun to read association studies published in Cell; the molecular biology community generally takes a massively different path to an association than the current "big science" approach of massive genome-wide studies. Case in point: a recent paper identifying a non-synonymous variant in a previously unannotated gene associated with late-onset Alzheimer's disease.

The approach the authors took was this: linkage studies had identified a region of chromosome 10 as potentially harboring a potential Alzheimer's variant, and the hippocampus is among the first tissues affected by the disease. Thus, genes located in the chromosome 10 region and highly expressed in the hippocampus are potential candidates. There are a whole host of reasons you can come up with to convince yourself that this has no chance of working, but in this case, it did.

The authors identified a transcript that fit their profile, but of course, there was absolutely nothing known about it. So they painstakingly characterized it as a calcium channel and identified a common non-synonymous polymorphism in it that's associated with Alzheimer's in several different cohorts. To top it off, they show evidence that the SNP changes the activity of the channel. Overall, quite an impressive piece of work.

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Monday, June 30, 2008

Increased rates of sexually transmitted diseases amongst the older   posted by Razib @ 6/30/2008 01:55:00 AM

Doubling Of Sexually Transmitted Infections Among Over-45s In Under A Decade. Dare we say an "epidemic???" If you want to push the envelope of course, She was 82. He was 95. They had dementia. They fell in love. And then they started having sex. In any case:
While the numbers of infections identified in younger age groups rose 97% during the period of the study, those identified in the over 45s rose 127%.
"Indeed, it may be argued that older people are more susceptible [to sexually transmitted infections] as they are less likely to use condoms than younger people," they say, adding that as successive waves of people with more liberal sexual attitudes and behaviours age, the problem is likely to worsen.

I guess the "safe sex" message just isn't getting through to the less young.

Related: Your generation was sluttier.

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Tuesday, March 18, 2008

Backwards in Time   posted by gcochran @ 3/18/2008 11:32:00 AM

It's hard to have a recessive lethal hang around for a long time without some kind of heterozygote advantage: selection reduces its frequency. If the population is even moderately large, more than a few thousand, changes in allele frequency over time are very predictable: deterministic.

That also means that one can calculate past frequencies, as long as as these assumptions hold (i.e. as long as there was no tight bottleneck & selection coefficients were the same).

Going forward in time , the frequency of a recessive lethal with no het advantage declines more and more slowly, since the ratio of homozygotes to heterozygotes declines as the allele frequency declines. But if you go backward in time, the frequency grows, and it grows more and more rapidly as you go further and further back in time. This doesn't continue indefinitely: the frequency can't go above 100%. Project the frequency of such a recessive lethal back in time and you hit a singularity.

Today, lethal cystic fibrosis alleles have a frequency of 2% in northern Europeans. Unless I'm wrong, it takes 50 generations for a recessive lethal to go from almost 100% to 2%, and another 50 to go from 2% to 1%, assuming no reproductive compensation. 'Reproductive compensation' means that parents have another kid when one dies young and thus end up with the same number of children raised to adulthood. This effect weakens, but does not eliminate, selection against lethal recessives. With full reproductive compensation, it takes 80 generations for a recessive lethal to go from 99.5% to 2%, and another 75 to go from 2% to 1%.

If the frequency of lethal CF alleles is 2% today, there must have either been a selective advantage in heterogygotes over most the of the past two thousand years, or the population of northern Europe must have crashed down to a few hundred or less sometime during that period.

There was no such crash, which would have been worse than a nuclear war. Indeed, there was no bottleneck of any kind in that time period: we know this from the historical record. Events like the Black Death do not a bottleneck make: you need to get the population down into the low thousands or less. The Black Death left tens of millions.

So lethal CF mutants had some kind of selective advantage, or were closely linked to some allele that did.

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Wednesday, February 13, 2008

Deletions and autism   posted by p-ter @ 2/13/2008 08:09:00 PM

A recent paper in NEJM is worth a read; it suggests a deletion on chromosome 16 predisposes to autism. The phenotype appears to be highly variable, though:
[I]n a study of the same population by investigators at deCODE Genetics, this deletion was observed at a markedly increased rate in subjects with a psychiatric or language disorder. This study showed that the deletion was present in 1 of 648 patients with schizophrenia, 1 of 420 patients with bipolar disorder, 1 of 203 patients with ADHD (the father of a child with autism, as noted above), and 1 of 3000 patients with panic disorder, anxiety, depression, or addiction. In addition, 1 of 748 patients with dyslexia carried the deletion. Overall, in the Icelandic samples, the carrier frequency among patients with autism was 1%; the frequency was approximately 0.1% among patients with a psychiatric or language disorder and 0.01% in the general population.
All these disease phenotypes can probably be thought of as extremes of some distribution of an underlying trait; I wonder how much variation in the "normal" range can be explained by de novo or rare copy number variants like this one.

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Friday, February 08, 2008

Retroviruses & Evolution   posted by Matt McIntosh @ 2/08/2008 09:15:00 AM

Our adaptive immune system (thought to have evolved around the time of the earliest jawed vertebrates) functions by recognizing things in our bodies that aren't us and attacking them, which is why transplants and grafts of tissues that are different from our own tend to get rejected by our bodies. But this poses an interesting problem for the evolution of placental mammals (first pointed out by Peter Medawar in 1953): The fetus is genetically different from the mother, so before she can start carrying her progeny around inside her for long stretches of time there would have to be some mechanism in place to prevent her immune system from going into attack mode on it.

There are a few different ways this could plausibly be accomplished, but the one that evolution actually seems to have hit on is pretty neat, I think. One way we know it doesn't happen is by the mother somehow recognizing that the fetus carries half her genes, because otherwise IVF blastocysts implanted into surrogate mothers would spontaneously abort. So whatever is going on here is a "kin-blind" adaptation.

A significant chunk of our DNA had its origins as retroviral DNA. Most of these are now inactive, but a tiny portion actually appear to still code proteins. It's been found in mice, sheep and humans (and presumably generalizes to all placental mammals) that a particular kind of endogenous retrovirus is highly expressed in the outermost layer of the blastocyst (see e.g. Venables et al. 1995 for the human example). Furthermore, when you inhibit the expression of these genes the result is uniform spontaneous abortion immediately following implantation (Dunlap et al. 2006).

Most retroviruses are immunosuppressive, the most infamous example being HIV. Connecting the dots, it's quite plausible that these particular ancient retroviruses have been recruited into the mammalian genome and serve as local immunosuppressors in the uterus during development. In fact, we already know that syncytin, a protein crucial in placenta formation, is the product of a retroviral gene (Knerr et al. 2004), so there's nothing at all far-fetched about this. (In fact talking about these genes as if they were viruses just clouds the issue: The fact that they're now propagated in exactly the same way as the rest of your nuclear genome means that they're just as much your genes as any other bit of your DNA.)

The idea that viruses played a crucial role in the evolution of placental mammals is pretty nifty, but this is just the best-investigated case and there's circumstantial evidence suggesting that retroviruses have been involved in other major evolutionary innovations too. For instance, it turns out that eukaryotic DNA polymerases bear a closer structural resemblance to viral DNA polymerases than they do to those of eubacteria, suggesting that perhaps the genes of DNA viruses were recruited in the evolution of eukaryotic cellular machinery (Villarreal & Filippis 2000).

But around here we're more interested in human evolution, and there's some suggestive data on that score: Turns out human endogenous retroviruses are expressed in a wide range of tissues during development (Andersson et al. 2002; Muir, Lever & Moffett 2004); that retroviral promoters, enhancers & silencers inserted near genes can alter gene expression (Thornburg, Gotea & Makalowski 2006; Dunn, Medstrand & Mager 2003; Ting et al. 1992); and that sequence & phylogenetic analysis suggests they may be responsible for a significant portion of large-scale deletions and insertions on the genome (Huges & Coffin 2001). We're used to thinking of predators and parasites as indirect drivers of evolutionary change in organisms, but when the parasites can obtain direct access to their host's DNA this gets taken to a whole deeper level that's only recently been appreciated.

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Wednesday, January 23, 2008

Lactase peristence & Cystic Fibrosis   posted by Razib @ 1/23/2008 12:59:00 PM

Yann points to a new paper, new paper, Cystic Fibrosis: Cystic fibrosis and lactase persistence: a possible correlation (Open Access):
The simplest and most economical explanation is that a dairy-milk diet became established in a single area and remained restricted to that area for a period of time sufficient to allow the T and the F508del alleles to attain high values. Then, in a second phase, the population of that area exported to the rest of Europe its dairy-milk diet culture together with the two adaptive genes, that is, the adaptogen and the two genetic adaptations to it. These two alleles would have then been amplified in the recipient populations because of their adaptive value owing to the co-imported dairy milk diet.

The two models to explain the high frequency of the deleterious CF allele in Europeans are that it has a high mutational bias and heterozygote advantage for those with one copy. Most people would say that the latter is much more likely. The authors here propose that the derived CF allele was a really kludgey adaptive response to a new cultural regime predicated on raw milk consumption. Paul has some Ireland related thoughts (as usual!). I've never seen the term "adaptopgen" before. In any case, I need to think on this case more...but I do think that if human evolution has been on hyperdrive the last 10,000 years we should be many kludgey genetic responses laying around the adaptive landscape.....

Related: Lactase persistence posts. Another from Yann, Is there a fitness advantage to being a CFTR carrier?

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Sunday, January 06, 2008

Reproductive benefits of dying horribly   posted by sweep @ 1/06/2008 04:51:00 PM

A review in the latest Medical Hypotheses discusses the evolutionary basis of Huntington's disease, a rare dominant genetic disorder affecting around 3-7 per 100,000 people of European origin. Individuals carrying a single mutant copy of the huntingtin gene (HD+) typically suffer serious neurological and physical problems beginning between age 35 and 50, and killing them within 10 to 15 years.

From an evolutionary POV, the existence of Huntington's disease alleles seems straightforward: the disease typically hits people after their reproductive years, and due to the nature of the mutation (an expansion of a polyglutamine repeat) the incidence of new sporadic mutations is pretty high - around 5% of cases are due to new mutations.

However, it appears that another factor is in play. The review lists five studies indicating greater reproductive fitness in HD+ individuals, who apparently produce between 1.14 and 1.34 children for every child borne by unaffected sibling controls. Apparently the popular theory is that this increased fertility is due to heightened promiscuity in HD+ individuals, presumably due to some early-onset sub-clinical psychological manifestation of the disease.

The authors of this review pooh-pooh the promiscuity hypothesis, pointing out the lack of evidence that most HD+ individuals suffer any neurological alterations during their reproductive years, and also arguing that promiscuity doesn't necessarily increase reproductive fitness. Instead, they point to a single study indicating substantially decreased cancer risks in HD+ subjects. Their hypothesis is not that this reduced cancer risk itself increases reproductive output, but rather that this reflects increased immune surveillance and vigour that would be expected to increase overall health and attractiveness in young HD+ individuals.

There is lengthy speculation about a link between the huntingtin protein and p53, a well-known tumour-suppressor. In support of their argument for a general immune boost in HD+ carriers they cite increased rates of type 2 diabetes and Alzheimer's, which both have a substantial auto-immune component.

Like most adaptive Just So stories the immune-boosting hypothesis is almost certainly wrong, and both it and the promiscuity story have essentially nothing in the way of direct evidence. Still, the increased fertility rates in HD+ individuals - which seem fairly well-supported - scream out for an explanation. With luck, someone will eventually carry out some actual experiments to figure out what that explanation is.

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Monday, December 24, 2007

Autism & yawning   posted by Razib @ 12/24/2007 10:12:00 PM

Absence of contagious yawning in children with autism spectrum disorder:
This study is the first to report the disturbance of contagious yawning in individuals with autism spectrum disorder (ASD). Twenty-four children with ASD as well as 25 age-matched typically developing (TD) children observed video clips of either yawning or control mouth movements. Yawning video clips elicited more yawns in TD children than in children with ASD, but the frequency of yawns did not differ between groups when they observed control video clips. Moreover, TD children yawned more during or after the yawn video clips than the control video clips, but the type of video clips did not affect the amount of yawning in children with ASD. Current results suggest that contagious yawning is impaired in ASD, which may relate to their impairment in empathy. It supports the claim that contagious yawning is based on the capacity for empathy.

Someone should do behavioral economics studies on groups of autistic individuals. Would surely validate the mid-20th century microeconomic consensus.

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Monday, October 22, 2007

Pedophiles are short   posted by Razib @ 10/22/2007 10:20:00 PM

Are Some Men Predisposed To Pedophilia?:
A difference in average height is a trait found in other illnesses with biological links. The average difference in height was two centimeters, which is similar to the shorter height associated with schizophrenia or Alzheimer's disease.

Further research is necessary, but this finding re-enforces evidence that pedophilia has a biological cause, possibly related to brain development before birth.

I'm really not that interested in the biological origins of pedophilia, instead my attention was drawn to the fact that such a height difference is known for a range of disorders. In The Mating Mind Geoffrey Miller hypothesized that variance in mutational load across individuals tracked beauty. This is basically a "good genes" model for why organisms exhibit sexual preferences. Miller was assuming a polygynous social system, but this makes me wonder as to the importance of "good health" due to provisioning in a monogamous species.

Though height is about 80% heritable in modern environments that still leaves an unaccounted for 20%; where does that come from? Possibly infection or developmental instability early on for whatever exogenous reason. In pre-modern contexts one assumes that heritability would be a bit lower because of the random stresses during pregnancy and during early childhood growth. In any case, adult height in males would surely be a good proxy for how healthy he is, and how productive a provider he might be. Additionally, good genes is still operative in a scenario where ability to resist and fight off infection is a proxy for fitness.

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Monday, July 23, 2007

The genetics of HIV infection   posted by p-ter @ 7/23/2007 08:16:00 PM

AIDS is obviously not a genetic disease-- if one were to make a list of risk factors predisposing to HIV infection, genetics would be a pretty low-ranking member (though still present on the list, of course). Yet genetics is still a useful tool for understanding the disease, as evidenced by this paper:
Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701, while a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated a third locus encoding a RNA polymerase subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.
People trained to think about disease from a "public health" (read: short-term) standpoint might be a little appalled by the amount of money spent on a study like this-- those hundreds of thousands of dollars could very well have been spent on far more effective ways to reduce AIDS prevalence.

However, the goal here is more long-term-- understanding the variation in how humans interact with pathogens will lead to more effective drug targeting and greater understanding of immunity down the road. Genome-wide association studies also, given the fact that they are largely hypothesis-free, also provide a way to generate novel hypotheses (or confirm old ones) about disease aetiology. In this study, for example, one of the major signals lies in an endogenous retrovirus-- that is, a virus that has incorporated itself into the genome. This raises the intriguing possibility that some of our immune response is mediated by viruses that previously spliced themselves into the genome (the authors mention that antisense transcripts would be a very plausible mechanism by which that could work).

The genetics of any phenotype you can think of will eventually be mapped, and this information will be useful not necessarily for its predictive value (though in some cases that will be the case), but also for the basic understanding of the phenotype that it carries with it. This site sometimes sees speculation as to the causes of variation in sexual orientation, for example-- genetic studies (assuming they're carried out) will severely restrict the plausible "hypothesis space" on that question.

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Thursday, July 12, 2007

Baron-Cohen on Autism   posted by DavidB @ 7/12/2007 05:01:00 AM

The UK Times today has an interview with Professor Simon Baron-Cohen on autism. Baron-Cohen is cautious about the supposed increase in the incidence of autism, and believes it could be largely due to 'diagnostic practice'.

Judging by the absurdly vague and loose criteria listed at the bottom of the article, I'm surprised anyone (except the jolliest of extroverts) escapes being diagnosed (and stigmatised) with some variety of autism. Thank Dawkins there was none of this nonsense when I was a kid. The whole thing looks to me like a monstrous boondoggle for the benefit of doctors and therapists.


Saturday, July 07, 2007

Williams syndrome in The New York Times Magazine   posted by Razib @ 7/07/2007 06:50:00 PM

David Dobbs has an interesting article in The New York Times Magazine about Williams syndrome; a disorder characterized by verbosity and hypersociality in concert with abstraction capacities so attenuated that most suffers are mentally retarded. The piece juggles many phenomena, from general to domain specific intelligences and the interaction between environment and genetic biases which shape the mind's developmental arc.

Inverted: Hidden Smarts: Abstract thought trumps IQ scores in autism:
There's more to the intelligence of autistic people than meets the IQ. Unlike most individuals, children and adults diagnosed as autistic often score much higher on a challenging, nonverbal test of abstract reasoning than they do on a standard IQ test, say psychologist Laurent Mottron of Hopital Riviere-des-Prairies in Montreal and his colleagues.

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Thursday, June 28, 2007

Coeliac disease - gluten intolerance   posted by Razib @ 6/28/2007 03:04:00 PM

A comment below about gluten intolerance (which is associated with problems digesting products with wheat) made me curious. In much of Eurasia this would be a serious problem since wheat is the staff of life. Hard numbers are difficult to come by. This is as good as anything else I've seen:
Celiac disease affects as many as 1 in 300 people in Italy and southwestern Ireland, but is extremely rare in Africa, Japan, and China...According to a multicenter study in 2003, there is a 1 in 133 chance that people with no risk factors or family history in the U.S. have celiac disease. Additionally, a person's risk increases to a 1 in 22 chance if they have a first-degree relative with celiac disease and a 1 in 39 chance if they have a second-degree relative...Around 60,000 Americans are diagnosed with celiac disease annually and a total of over 2 million have the disease, making it perhaps the most common genetic disorder in the United States...Celiac disease can occur at any age, and females are more commonly affected than males. Of females presenting during their fertile years, the male to female ratio is almost 3 to 1....

From Wiki:
The vast majority of coeliac patients have one of two types of HLA DQ, a gene that is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. There are 7 HLA DQ variants (DQ2 and D4 through 9). Two of these variants-DQ2 and DQ8-are associated with coeliac disease. Every person inherits two copies, one from each parent. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage this locus has been labeled CELIAC1.

Coeliac disease shows incomplete penetrance, as the gene alleles associated with the disease appear in most patients, but are neither present in all cases nor sufficient by themselves cause the disease. Over 95% of coeliac patients have an isoform of DQ2 (DQA1*0501:DQB1*0201 haplotype or more simply DQ2.5) and DQ8 (DQA1*0301:DQB1*0302), which is inherited in families.

Incomplete penetrance might be due to the fact that there are other genetic actors which haven't been elucidated that are necessary for the emergence of this syndrome. Or, there might be environmental or pathogenic triggers which only affect a minority with the necessary genetic predisposition. But in any case, my first thought was gluten intolerance might be the result of an incomplete selection sweep as populations shifted from hunter-gatherer lifestyles to agricultural ones. I'm skeptical of this since populations in Africa and Australia which don't have a history of wheat agriculture don't exhibit this syndrome. Additionally, though wheat agriculture is practiced in north China this was originally a region of millet production. Finally, all the reports suggest massive underestimates of the extent of this condition within the population. Like lactose intolerance this isn't a disease with a clean set of symptoms which are easy to assay quantitatively (is there a way a metric for stool firmness?). The implication of MHC loci as necessary preconditions makes me wonder if gluten intolerance is simply a low frequency condition which is a byproduct of a disease adaptation on the genes in question which was operant in western Eurasia.

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Tuesday, February 27, 2007

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

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

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

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

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

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Thursday, February 15, 2007

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

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

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

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

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

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

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

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


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

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Wednesday, January 31, 2007

Thrifty genotype hypothesis   posted by amnestic @ 1/31/2007 07:46:00 PM

For the population geneticist, diabetes mellitus has long presented an enigma. Here is a relatively frequent disease, often interfering with reproduction by virtue of an onset during the reproductive or even pre-reproductive years, with a well-defined genetic basis, perhaps as simple in many families as a single recessive or incompletely recessive gene. If the considerable frequency of the disease is of relatively long duration in the history of our species, how can this be accounted for in the face of obvious and strong genetic selection against the condition? If, on the other hand, this frequency is a relatively recent pheonomenon, what changes in the environment are responsible for the increase?

-James V. Neel, "Diabetes Mellitus: A 'Thrify' Genotype Rendered Detrimental by 'Progress'?" (1962) [pdf]
The above quote is from the abstract of the highly influential paper by James Neel outlining the so-called "thrifty genotype hypothesis" for the prevalence of diabetes in modern populations. As this hypothesis is still widely cited (on this website, it has both praised and criticized), I present here my interpretation of the original paper, with comments as to how the hypothesis could be falsified or bosltered by the generation of unprecedented levels of population genetic data that we see today. I must note that this paper was written in 1962, and knowledge has certainly progressed since then. Some of the literature discussed by Neel or the paradigms he takes for granted are rather puzzling to me, and I may have missed some of the sublety of his arguments; readers are invited to peruse the .pdf linked above at their convenience and call me out on any mistakes.

I. The understanding of diabetes circa 1962

In 1962, "diabetes" was still considered more or less a single disease-- it wasn't until later that the current split between type I and type II diabetes was formalized. The adult-onset diabetes relevant to Neel is type II, so from now on, when I say "diabetes", I will be referring to type II. Further, the notion of a "complex" disease was also absent-- as is apparent from the quote above, Neel considered diabetes to be possibly caused by a single recessive allele, a situation subsequent research essentially ruled out.

In terms of the disease phenotype itself, Neel puts together a number of observations that suggest a certain advantage to the diabetic genotype. First, the children of diabetic mothers have increased birthwights as compared to the children of non-diabetic mothers. The children of non-diabetic mothers with diabetic fathers have higher than average birthweights, as well. Further, children who later develop diabtes tend to reach puberty slightly earlier, and thus could perhaps bear more children, than children who do not eventually develop diabetes. These observations, Neel suggests, indicate that the early diabetic phenotype is "thrifty", in the sense that the children are particularly efficient in their use of the resources available to them.

Of course, the eventual diabetic phenotype consists of insensitivity to insulin and the inablility to properly process carbohydrates. Neel reconciles the apparent early "thriftiness" with this eventual insensitivity with a discussion of the physiology of diabetes. In this discussion, there are two major hormonal players who, while normally in equilibrium, are thrown out of balance in diabetes. The first hormone is insulin, which moves glucose from the blood to storage, and the second Neel refers to as "anti-insulins", a class I can only assume refers to hormones like glucagon which release glucose into the blookstream.

In diabetics, then, Neel argues, there is an initial over-production of insulin, which accounts for the "thrifty" aspects of the genotype early on (the increased body weight and early menarche), which is then compensated by the stimulation of the "anti-insulins". An inbalance results, and in adulthood this is manifested by insulin insensitivity[1]. The major question becomes, why has diabetes become so prevalent now?

II. The "thrifty genotype hypothesis"

Neel's major insight in forming an answer to the above question is to note that "during the first 99 per cent or more of man's life on earth, while he has existed as a hunter and gatherer, it was often feast or famine". That is, there has been a marked change in environment in "modern" societies. He mentions three possible changes relevant to the control of the insulin/anti-insulin balance:

1. "Primitive" groups have less opportunities to overeat, have lower caloric intake, and greater physical activity than "modern" groups. This results in less stimulation of insulin, which in turn results in no over-stimulation of the anti-insulins.

2. The stress response in modern societies is less often followed by physical exertion than in primitive societies, which may disturb a "physiologic balance" established during human evolution.

3. The release of adrenaline in modern societies is also less often followed by physical exertion than in primitive societies. As adrenaline results in increased insulin production, this is an opportunity for the over-compensation of anti-insulins.

These last two are both similar in that they are involved with the stress response; indeed, Neel tentatively calls diabetes a "stress disease" along with peptic ulcers and hypertension!

In sum, the thrifty genotype hypothesis poses 1. that diabates results from a relative over-production of insulin, but more importantly 2. that "what we must now regard as an 'over-production' with unfortunate consequences was, at an earlier stage in man's evolution, an asset in that is was an important energy conserving mechanism when food intake was irregular and obesity rare."

III. The value of this hypothesis today

Now, I've noted the myriad assumptions made by Neel which are simply wrong-- the assumption of a single gene being one of them[2]. I imagine the modern view on the physiology of diabetes is quite different than his as well. So what remains of this hypothesis?

I would argue that his key insight still remains valid-- that, in population genetics, environment matters. Selection coefficients are not constant, and the way we alter our environment plays a large role in the selective forces exerted on us. More concretely, though, in terms of the genetic basis for diabetes, I can think of a couple predictions. First, any risk allele found for the disease will be ancestral-- that is, a protective allele will have arisen recently. Second, the derived protective allele will have been under recent positive selection.

The prevalence of diabetes in different populations, assuming all have more or less the same diet, should also be negatively correlated with the time since switching from a hunter-gatherer lifestyle. This is the statement that is perhaps the most contentious-- newcomers to the "modern", high-carb diet certainly have high incidences of diabetes, but it's impossible to tell whether this is due to the new availability of food or rather due to the content of the food itself. This may end up being a prediction that's impossible to test, so my instinct is to stick with the genetic evidence. Of course, I'm a geneticist, so I would say that.

[1] I am not at all familiar with modern reseatch into diabetes, and Neel's views on all of this are likely a vast simplification or even entirely wrong. I don't think, however, that this takes away from his later insights.

[2] An aside on Neel's discussion of the genetics of diabetes. I found the following passage, under the heading "Some Eugenic Considerations", to be interesing:
If the dietary and cultural conditions which elicit the relatively high frequency of diabetes in the Western World are destined to spread and persist over the entire globe, then, to the extent that modern medicine makes it possible for diabetics to propogate, it interferes with genetic evolution. But if, on the other hand, the mounting pressure of population numbers means an eventual decline in the standard of living with, in many parts of the world, a persistence or return to seasonal fluctuations in the availability of food, then efforts to preserve the diabetic genotype through this transient period of plenty are in the interest of mankind. Here is a striking illustration of the need for caution in approaching what at first glance seem to be "obvious" eugenic considerations!


Wednesday, November 29, 2006

Schizophrenia and IQ   posted by p-ter @ 11/29/2006 02:17:00 PM

Low IQ is a risk factor for developing schizophrenia, though the mechanism behind this association is somewhat unclear. A new study sheds a little light on this subject, and suggests the link might be genetic. The gene in questions is neuregulin 1, about which little is known. They find, first, that a regulatory SNP is associated with the development of psychotic symptoms in a particularly at-risk population (see part a above-- each bar is the percentage of subjects developing symptoms for a given genotype). They also find lower levels of activity in certain part of the brain in the patients with the TT genotype (see parts b and c above).

Further, here are the means and standard deviations of the IQ distributions of the different genotypes:

CC: 101.9 (8.4)
CT: 100.4 (9.4)
TT: 94.3 (6.9)

So this regulatory polymorphism could explain some of the natural variation in IQ.

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Sunday, October 22, 2006

Regulatory change in autism   posted by JP @ 10/22/2006 09:05:00 AM

The twin concordance rate in autism is something like 90% for monozygotic twins and 5% for dizygotic twins. This suggests a signigicant role for genetics in the development of autism. A new study identifies one of the possible genetic contributors, a regulatory change in the MET gene. MET signaling is important in a number of tissues, which the authors suggest is support for this being a valid finding. I'm pretty convinced--there's a replication study, and the authors don't do any funny things with statistics to make associations appear where they shouldn't.

Further, the variant they identify is in the promoter of the gene, and they show that, in vitro, it leads to reduced transcription factor binding and reduced transcription. This, of course, is the most presuasive evidence.

Given the hypotheses that posit epigenetic modifications in autism, it would be interesting to see what the methylation patterns are like in the region. In fact, the SNP is a C-->G change, which creates a CpG dinucleotide, a possible target for methylation.


Monday, October 16, 2006

Autism & genetics   posted by Razib @ 10/16/2006 09:01:00 PM

Mutated gene raises autism risk, US study finds:
People with two copies of the mutated gene [MET] have 2 to 2.5 times the normal risk of autism and people with one mutated copy have 1.7 times the risk, he said.
Levitt said the mutation does not change the function of the gene, but changes gene expression -- how active the gene is.

The study is going to be published in PNAS.


Tuesday, August 15, 2006

Schizo genes   posted by Razib @ 8/15/2006 08:29:00 PM

Study finds gene related to brain development and function plays causal role in schizophrenia:

The study showed that genetic variation in OLIG2 was strongly associated with schizophrenia. In addition, OLIG2 also showed a genetic association with schizophrenia when examined together with two other genes previously associated with schizophrenia--CNP and ERBB4--which are also active in the development of myelin. The expression of these three genes was also coordinated. Taken together the data support an etiological role for oligodendrocyte abnormalities in the development of schizophrenia.

The paper is in PNAS. Interestingly the authors seriously consider the possibility of epistatic (gene to gene interaction) as being part of the risk for schizophrenia.


Tuesday, July 18, 2006

Common disease, common variant   posted by JP @ 7/18/2006 01:53:00 PM

In the years after whole-genome association scanning was proposed as a more powerful alternative to linkage studies for locating the alleles involved in "complex" (i.e. involving multiple genetic and environmental factors) phenotypes, there was much debate about the true prospects of this approach. One of the major points of contention in this debate centered around what is now called the CDCV (common disease, common variant) hypothesis, which proposed that common polymorphisms would confer susceptibility to common diseases like heart disease, diabetes, etc.

Why was this an important question? If common polymorphisms were underlying these traits, it would explain the inability of linkage studies to find them, as linkage studies have low power in this situation. In this case, association studies might succeed in places where linkage studies could never come up with any consistent results (see linkage versus association). However, if complex diseases were caused by multiple rare loci, the association approach would still be powerless and, well, human geneticists would be out of luck. For population genetic models supporting either side (multiple rare variants versus common variants) see the links in this post.

Five to ten years on, what's the emerging consensus? Well, as is often the case in these kinds of scientific debates, both sides are kind of right. In some cases, rare variants play a role, and in others, common variants. But it's clear that those who argued against the whole-genome association approach and the development of the HapMap on the grounds that the CDCV hypothesis was unfounded are currently in the process of ending up looking a little Luddite.

A new paper in Nature Genetics gives another example of a common disease being influenced by a common polymorphism. In this case, the risk of a heart attack in a Japanese population was shown to be slightly increased by the presence of a mutation, present on 35% of chromosomes, in a gene that regulates inflammation. The increase in risk is slight-- on the order of a 20% increase in the probability of having a heart attack, but significant nonetheless.

This suggests where population genetic models in the past have gone wrong: common disease phenotypes are products of underlying variation in quantitative traits, and assigning a "fitness" to a certain level of a trait is extremely difficult, as different genetic backgrounds and environmental variation can absolutlely swamp small effects. So assuming a polymorphism that causes a disease must be detrimental, as opposed to neutral, nearly neutral or even beneficial, creates a model that may not track reality. As I've argued before, new paragims for describing alleles that influence disease are arising; "associated with disease = negative fitness" is out.


Monday, July 10, 2006

ASPM and schizophrenia-- nada   posted by JP @ 7/10/2006 01:09:00 PM

Regular readers know that ASPM is a microencephaly gene under selection in humans, though the particular pressure driving the selection is unknown. A group of Spanish researchers decided to test whether there is an association between variants of the gene and schizophrenia. The result: nothing.

Of course, with only 233 cases and 161 controls, the actual power to detect an effect was probably around zero (not that that ever stopped anyone from publishing before). There are certainly many genetic factors that play a role in the disease, so any well-designed study should be big enough to detect multiple weak effects. And the authors note this is a preliminary study; presumably there will be larger sample sizes in the future.

Related: GNXP on ASPM


Tuesday, June 20, 2006

Autism and the imprinted brain   posted by JP @ 6/20/2006 10:26:00 AM

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.


Sunday, May 21, 2006

Fitness and disease II   posted by JP @ 5/21/2006 09:03:00 AM

The second point made by Eyre-Walker et al. in their paper "The distribution of fitness effects of new deleterious amino acid mutations in humans" is that "it will be very difficult to locate most of the genes involved in complex disease" (see my discussion of their first point here).

They come to this conclusion because, using their model, the variations that contribute the most to the variance of a disease-associated trait are rare (see Jonathan Pritchard's 2001 paper for a different way to come to a similar conclusion), and thus difficult to map, except in two cases: when the disease has no effect on fitness or the alleles invloved have been under positive selection. They clearly don't think those two cases are likely, though they do acknowledge they may number "a few".

I disagree. We've all heard the story about the guy at night, searching for a lost coin under a streetlight because "that's where the light is". That's essentially what's happening here. They've derived the distribution of fitness effects of new deleterious amino acid mutations, so obviously disease alleles must be new. And deleterious. And amino acid mutations. Right?

Ok, ok, it's true they mention a couple possible violations of those assumptions, but they still feel confident enough to say that "most of the genes involved in complex disease" can be described with their model. But here are a couple different theoretical paradigms to consider: the "thrify genotype" and "cryptic genetic variation".

1. The "thrify genotype" hypothesis. We've mentioned this hypothesis before, as a part of the ancestral susceptibility model for common disease. It was first formulated about type II diabetes and obesity, and goes something like this: imagine a normal distribution of a quantitative trait like the efficiency with which excess calories are converted to fat. Some people quickly convert all of their excess to fat, some less efficiently, and some not efficiently at all. In an environment of scare food resources, the first group has the clear advantage: in times of famine, they can live off the fat they stored from before. So those variants that predispose one to be on the right half of the curve (if we define the x-axis as efficiency) are favored.

Now enter agriculture, which allows food from good times to be stored and eaten in rough times. The selective pressure for fat storage efficiency is somewhat relaxed, so new mutations that predispose one to be more on the left half of the curve can gain traction in the population. Finally, enter a "modern" diet of, most importantly, lots of sugar. In this environment, the people on the right half of the curve, with their "thrifty" ancestral genotype, well, get fat, while people with the new derived genotype don't as much.

To extend the "thrify genotype" hypothesis to other traits, one needs a trait that was adaptive in an ancient environment but is neutral or even selected against now. One example is susceptibility to hypertension: in the expansion to colder climates, selection against ancestral alleles adapted to hotter climates have given rise to the current differential susceptibility to hypertension between populations of African and European origin.

2. Uncovering crytpic genetic variation (for a review, see here[pdf]). The premise here is that common disease is a result of the uncovering, through either genetic or environmental perturbation, of variation that wouldn't normally contribute to human health. That is, alleles influencing common disease are only conditionally deleterious or beneficial. Following the obesity example from above, operating in this paradigm would lead to the hypothesis that alleles that don't affect fat storage efficiency in normal circumstances do play a role when the environment is perturbed (i.e. in the presence of a high-sugar diet). One possible example: a mutation in the regulatory region of the gene coding for the dopamine transporter DAT1 (which has a frequency of ~70%, suggesting it may be ancestral) is associated with cocaine dependance. This variant slightly affects expression of the DAT1 gene under normal conditions (caveat: I mean normal tissue culture conditions), but in the presence of cocaine, that difference is amplified. Thus, the varation in expression is only made obvious in an altered condition.

If this paradigm holds, it would mean that many of the alleles (either derived or ancetral) contributing to common disease are neutral except in certain circumstances. So if the environment that exposes this variation is our modern environment (long lifespans, high food availability, etc.), the alleles have been neutral for most of history.

In general, Eyre-Walker et al. are operating in a world where an amino acid-changing mutation arises with a certain selection coefficient, and where this selection coefficient is constant until the mutation is removed from the population. If common diseases are caused by these new, deleterious amino acid changes, their conclusion that it will be very difficult to locate disease alleles is fair. But, as I've tried to show, other models for the allelic architecture of common disease are certainly plausible, and perhaps even more likely.


Wednesday, May 17, 2006

Type I diabetes and viral infection   posted by JP @ 5/17/2006 09:53:00 AM

In the comments of a recent post, I and a couple other people mentioned Type II, or insulin independent, diabetes. You might assume that the existence of a type II means there must be a type I and, well, you'd be right.

The difference between type I and type II is fairly straightforward: type II diabetes is characterized by a loss of sensitivity to the hormone insulin, while people with Type I diabetes don't make any insulin to begin with. The reason for this lack of insulin (in people with Type I) is, broadly speaking, that the cells that make it have been destroyed by their own immune system.

The genetic basis of type I diabetes is murky, but it's known that there are risk factors in genes involved in immunity and the production of insulin, as one might expect. But there's also evidence of a strong environmental role (these points are essentially copied from the abstract of this paper):
1. a pairwise concordance of type 1 diabetes of <40% among monozygotic twins
2. a several-fold increase in the incidence over the last 50 years
3. migration studies indicating that the disease incidence has increased in population groups who have moved from a low-incidence to a high-incidence region.

In this context, it's interesting that a new study looking for genetic susceptibility factors in type I diabetes fingered IFIH1, a gene coding for a protein the authors descibe as "a sensor or pathogen recognition receptor for viral infection"

The implication is thought-provoking: the environmental factor (or one of the environmental factors) that "pulls the trigger" on the autoimmune destruction of insulin-producing cells may be a virus, but genetic factors in the host determine whether the response is catastrophic or not.

See also: Agnostic on No Two Alike and developmental noise.


Monday, April 03, 2006

Dog bites man: Germs cause prostate cancer, mental disease   posted by agnostic @ 4/03/2006 10:45:00 AM

Carl Zimmer describes a new paper from PLoS Pathogens which demonstrates a causal link between a virus and prostate cancer (full article here). Nothing will surprise readers of Paul Ewald's Plague Time, the popularized version of a journal article he co-authored with Gregory Cochran (google "infectious_causation_of_disease.pdf"). The basic logic is simple: diseases which have been around for awhile, are common, and impose fitness costs should be weeded out by natural selection if they were genetic in origin; so, such diseases are likely to be infectious. This simple point is left out of a lot of the articles on newly discovered infectious origins of common diseases (the prostate cancer article, for example), which is a shame since this theoretical guide would lead to better allocation of resources for curing diseases -- namely away from genetic studies and toward microbial studies. Indeed, a putative genetic link for prostate cancer failed to be replicated, and the PLoS article shows why: if a variant of a gene is only involved in susceptibility to infection, then a link between the defective variant and the cancer will show up only if that individual has already been infected. This point generalizes.

Also in the current issue of PLoS Pathogens is this article showing that infection of neurons with the Borna virus impairs neuronal function -- not the most basic functions, but for example long term potentiation, which is a fancy neuroscience term for the long-term strengthening of connections between neurons based on external stimuli, which is thought to underlie higher functions such as learning and memory. I'll confess that the molecular information is over my head, but for those who understand it, the authors show what molecular mechanisms are involved in the neuronal impairment caused by the Borna virus. Plague Time mentioned a link between the Borna virus and schizophrenia, mood disorders, and chronic fatigue syndrome, and only six years later we have a decent understanding of how it can cause mental disease. In fact, the PLoS authors suggest that the effects of a Borna-infected brain are similar to those observed in Alzheimer's and autism. Now, whether or not the Borna virus turns out to be the culprit for these diseases is an open question, but the implication is that this is where time and energy should be devoted if we want to cure common mental diseases.


Monday, March 06, 2006

Obesity germ - pass it on!   posted by agnostic @ 3/06/2006 12:14:00 AM

Make that germs: abstract here, other review here, older review of previous work here (1st link via Jerry Pournelle). Even when food intake & activity was controlled, chickens became obese when infected with a human adenovirus (Ad-37, though other adenoviruses were already known to be implicated). Presumably they play a role in human obesity as well, and so yet another case where germs play a role in chronic illness, as predicted by Gregory Cochran & Paul Ewald's New Germ Theory (click 1st item), which Ewald popularized in Plague Time. Of course, germs aren't the only cause of obesity, since there are plenty of ways to screw up a system. Aside from usual suspects like poor diet & exercise, I thought up another obesity germ scenario here (item 3i). Exploring this study further:

1) These viruses are respiratory & spread by droplets, so this may be a case like polio where a germ occasionally meanders from its natural habitat (for polio, the gut) and does inadvertent damage elsewhere (for polio, the nervous system). So, implication of germs in an illness at site X doesn't imply that the germs are adapted to exploit site X, and thus we don't need to spin an evolutionary story about how the germs screwing up X helps them spread. Polio only infects the nervous system about 1 per 100 cases, the rest of the time hanging out in the gut.

2) Also like polio & other known infectious diseases, obesity could turn out to be simple to cure once a vaccine were engineered. You don't cure dysentery with surgery or GE -- you just clean up the damn water. With all of the health care costs due to obesity & its concomitant health problems gone, it would be a hell of a financial relief for all.

3) Speaking of Behavior Genetics below, studies like these highlight the role that microbes play in individual differences, namely the mysterious "non-shared environment" which accounts for ~50% of the variation in intelligence & personality. That is, one monozygotic twin gets infected, the other doesn't; both get infected, but the germ deviates from its niche to some unintended site in one but not the other; both get infected, the germ deviates from its niche in both, but one twin houses some other germ that blocks the path of the deviant one before it can get into the nervous system.

Emulating obesity researchers, we need a hard-nosed approach to figure out the "ideal" range for Big Five personality traits, as nutritionists have for BMI. That is, not "ideal" for living an enjoyable, fulfilling life, but "ideal" in the biologist's sense of optimal for making babies. Suppose investigators find out that some population's mean for, say, Introversion is a standard deviation or so below the ideal score -- as if the mean for BMI were far above ideal. Now, if some individuals were below the ideal, no big deal, but if the population mean were noticeably below the ideal, it would suggest either environmental toxins or pathogens -- or selected genetic response to such pathogens, like sickle-cell.

After all, if germs are implicated in obvious mental illnesses such as schizophrenia (considering its frequency, fitness cost, and having been around for at least several hundred years), these illnesses may represent only the extreme cases of a more general pattern of microbes negatively affecting cognition (vis-a-vis reproductive fitness), much as pneumonia represents an extreme complication arising from typically mild influenza.


Saturday, February 25, 2006

Genius germs?   posted by agnostic @ 2/25/2006 10:00:00 PM

I began this series at my other blog before I became a poster here. You could read this on its own, but the first four parts -- I here, II here, III here, IV here -- provide the necessary background (esp. part I, first 3 paragraphs of part II, and part III, all of which are short). Briefly, the idea was to investigate whether microbes could affect human cognition in ways more subtle than rabies. Now comes the empirical support I've uncovered: a strong winter-spring birth seasonality effect on "genius," which I take to reflect early infection. (Somewhat long read.)

We present evidence that early infection likely contributes to "genius" status -- recall from part II our definition of "genius" as anyone who had an Index Score (IS) of at least 50 (from 0-100) in the inventories of Charles Murray's Human Accomplishment. The prediction is that at the highest level -- the "giants," who score in any category's 10th "decile" (i.e., IS at least 90) -- the births will be the most lopsided toward winter-spring (WS = Dec-Feb and Mar-May), when infant infection is most likely; that the top 5 deciles will show less lopsidedeness though still toward WS; and that the bottom 5 deciles will not necessarily show the pattern. More, we predict that the more abstract the field (and thus the more it requires superhuman creativity), the more pronounced the bias. We first examine the giants, then the geniuses of the most abstract fields -- Philosophy in the humanities, Music in the arts, and Math in the sciences -- and finally the geniuses of the remaining fields. In our research, we found birth month data only for Westerners, which constrains the scope of the argument w.r.t. the arts, though no non-Westerner is among the geniuses of any science category. All lists of births available by email (see my bl*gspot profile).

First, in HA 18 Westerners scored 90 or above in any field, though only 16 figures had known birth months (unknown: Aristotle & Hippocrates). Of these 16 giants, 14 are WS: Galileo, Kepler, Darwin, Newton, Einstein, Euler, Pasteur, Koch, Edison, Watt, Beethoven, Mozart, Michelangelo, Shakespeare. Among these, 10 are winter, 4 spring. Only 2 of 16 are summer-fall (SF): Lavoisier and Lyell. The prediction checks out: 87.5% are WS, and the actual value of winter births is 2.5 times the expected value of 4.

Next, the most abstract art: Music. Homo sapiens' natural mode of expression is linguistic, and we can grope our way through visual modalities such as gesture, mime, etc. But we are utterly at a loss when it comes to non-linguistic sound. Moreover, Western music emphasizes both complex melodies, which are serial, as well as complex harmonies, where notes are stacked on top of one another. Juggling these elements for various instruments in one's head, all while attempting expression in the most foreign of artistic languages, is the greatest test of artistic genius. The Western Music inventory is particularly instructive since birth months are known for all figures save a neglible number down in the 2nd decile (2D: we use XD as short-hand for the Xth decile). There are 5 geniuses (people in 6D-10D), all 5 of whom are WS: Beethoven, Mozart, Bach, Wagner, Haydn. All graphs visible here.

Turning to the most abstract science, Math, there is little role for "inevitable discovery," and the objects it studies are farther removed from the real world than in other sciences. Moreover, we have less innate / intuitive scaffolding to hoist ourselves up by when it comes to math as compared to physics or biology. There are 8 geniuses, 1 of whose birth months is unknown (Euclid in 9D). Again, the hypothesis checks out, though not as strongly as in Music -- of the known 7, 5 are WS: Euler in 10D, Newton & Gauss in 9D, Descartes & Cantor in 6D. The 2 exceptions constitute 8D: Fermat & Leibniz.

As for Philosophy, it is the only humanities field Murray included, presumably because it is (at least for now) the only one demanding genius thought, fields like history being closer to (extremly important) clerical work. Again, we only found data for Westerners. There are 4 geniuses, 1 of whose birth months is unknown -- unfortunately, the top-ranked and only figure in 10D: Aristotle. We admit this weakness. Still, the hypothesis checks out -- of the known 3, all 3 are WS: Plato in 9D, Kant in 8D, Descartes in 6D.

To sum up so far: there are 17 geniuses in the three most abstract fields, and 15 of their birth months are known. 13 of these 15 (~87%) are WS, and the 2 exceptions show up in 8D in Math. So, the percentage of WS is almost identical to that among giants, though the gross overrepresenation of winter births is gone: of these 15, only 3 (or 4 -- Plato was born in either Dec or May) are winter, which, depending on Plato's birth, is either 0.25 above or 0.75 below the expectation of 3.75.

The link to the graphs begins w/ raw number and percentage of summer-fall births in the three most abstract fields; SF are shown in order to highlight data points that falsify the hypothesis. A dashed line indicates no data points in that decile; a red numeral indicates the number of points in the decile for which data were not found. Depending on the inventory, some of the lower deciles were not examined since 1) they did not bear on the hypothesis, 2) they had larger numbers that would have required more hard labor to collect, and 3) these are the people most likely to fluctuate in and out of the inventory depending on which encyclopedias are consulted (unlike, e.g., Mozart or Newton).

Next is a graph of the other arts, Western Art and Western Literature. In Art, there are 5 geniuses, 1 of whose birth months is unknown (Titian in 6D). Of the known 4, 3 are WS: Michelangelo in 10D, Raphael in 7D, Leonardo in 6D. The 1 exception, in 7D, is one of the few people widely considered by reviewers of HA to be an epochcentric anomaly (see, e.g., this review by Denis Dutton): Picasso, who scores two deciles above Dürer, Rembrandt, Giotto, Bernini, Cezanne, & Rubens (5D). The least abstract art, Lit, we predict to be least lopsided toward WS since Murray explains that creators of Lit encyclopedias strongly consider the role the writer played in social movements, since writing is used not only for expression but for communication and persuasion. (The Art and Music inventories do not show such an effect.) E.g., for his political impact, Rousseau (in 5D) ranks two deciles above inter alia Aeschylus, Ovid, Whitman, & Proust. There are 5 geniuses, 1 of whose birth months is unknown (Homer in 6D). Of the known 4, only 1 is WS: Shakespeare, the lone figure in 10D. As the graph shows, Lit is the most SF-friendly art, as predicted.

We continue w/ a graph of the Combined Sciences. Murray only listed the top 20 figures, though his point was only to illustrate the "big fish in a small pond" effect for figures such as Lyell who dominate their small pond but don't show up in the larger pond. There are 6 geniuses, 1 of whose birth months is unknown (Aristotle in 8D). Of the 5 known, 4 are WS: Newton in 10D, Galileo in 9D, Kepler & Descartes in 6D. The 1 exception is Lavoisier in 6D. So considering the sciences as a whole, the prediction is met.

Considering each scientific pond, we turn next to the three most established sciences after Math: Physics, Chemistry, and Astronomy. In Physics, there are 9 geniuses, of whom only 4 are WS, though these include the two in 10D -- Newton & Einstein -- along w/ Galileo in 9D and Thomson in 6D. The exceptions are Rutherford & Faraday in 9D and Cavendish, Bohr, & Maxwell in 6D. In Chemistry, there are just 3 geniuses, 1 of whom is WS: Scheele in 6D. The 2 exceptions are Lavoisier in 10D and Berzelius in 7D. In Astronomy, there are 9 geniuses, 1 of whose birth months is unknown (Ptolemy in 8D). Of the 8 known, 5 are WS: Galileo & Kepler in 10D, Laplace & Copernicus in 8D, and Brahe in 6D. The 3 exceptions are Herschel in 9D, and Halley & Cassini in 6D. So, by zooming in closer on each pond, the actual value of WS is 0.5 below expectation (10 of 21 in these three fields), which weakens the hypothesis. Alternatively, sub-giant-level insight in these sciences may not require as much "outside the box" creativity as does giant-level insight in these sciences, or as does sub-giant insight in the arts.

Now we consider the two least abstract sciences (as of 1950, when Murray's survey ended): Earth Sciences and Biology. In Earth Sciences, there are 4 geniuses, 2 of whom are WS: William Smith & Agricola (Georg Bauer) in 6D. The 2 exceptions are Lyell in 10D and Hutton in 8D. This matches the prediction that the least abstract field will not show lopsidedness toward WS (as w/ Lit). Biology is another case in point, since by 1950 it was barely established as a field and not very abstract at that. There are 7 geniuses, 2 of whose birth months are unknown (Aristotle in 10D and Harvey in 6D). Of the known 5, just 2 are WS: Darwin in 10D and Linnaeus in 6D. The 3 exceptions are Lamarck in 10D, Cuvier in 9D, and Morgan in 8D.

None of the geniuses who developed biology into a mature science during the 20th Century even made it to 4D, again because Murray's encyclopedias focused on periods before 1950. For example, Darwin the Second -- Bill Hamilton -- is not included at all, while R.A. Fisher barely shows up in 1D. Though it is too early to provide a ranking of who encyclopedias 200 years from now will consider the equivalents of Newton and Rutherford, we can at least come up w/ an unordered list of newcomers and their birth seasons: Hamilton (sum), Haldane (fall), Fisher (win), Wright (win), Smith (win), Trivers (win). This is not definitive, but on the right track.

Haldane is clearly an exception, and though Hamilton's data point may appear to falsify the hypothesis of higher likelihood of infant infection among geniuses, the fuller story is revealing. Unlike every other European genius, he was born in Cairo, Egypt's most crowded, slum-ridden urban area, in Aug 1936 -- less than 4 months after Egypt had even established a Ministry of Health! More, his mother was a medical doctor, who would've been exposed to god knows what in those days and potentially have brought it home. In this sole case, we consider geographical location to be more informative than WS birth in assessing likelihood of infant infection. The geniuses in other categories show a general bias toward urban birth, but the effect is not as strong as birth month, and it is susceptible to alternative interpretations. We return to this point later.

Finally, we consider the two applied sciences: Technology and Medicine. While Technology is by definition creative and inventive, we are agnostic on whether it requires the genius of Beethoven or Newton; and Medicine is largely discovery, not creative model-building. Nevertheless, next is a graph for these two. In Technology, there are 6 geniuses, 1 of whose birth months is unknown (Archimedes in 6D). All 5 of the known are WS: Edison, Watt Leonardo, Huygens, Marconi. In Medicine, there are 8 geniuses, 3 of whose birth months are unknown (Hippocrates in 9D, Galen in 8D, and Paracelsus in 7D). Of the 5 known, all 5 are WS: Pasteur in 10D, Koch in 9D, and Ehrlich, Laennec, & McCollum in 6D. We interpret these data as not falsifying the hypothesis, though hardly a ringing endorsement of it, given the conceptual nature of the fields, their relative immaturity up to 1950, and the lacunae among the data for Medicine.

So, overall the hypothesis passes the tests for finding lopsided seasonality among genius births in abstract, creative fields, as we believe the Combined Sciences ranking better highlights scientific genius than the rankings in the separate fields which compose it. This was especially so for the mostly-winter "giants." But how do we interpret this finding? First, imagine we examined another trait w/ 0.5 probability of occuring in the general population -- say, male vs female sex. If we observed a similarly lopsided male to female ratio, we would need to account for it somehow: sex discrimination, different distributions in cognitive ability, a mix, etc. We find it implausible that social factors contribute to the seasonality of genius births: there is no evidence that WS children are encouraged more, that SF suffer Zodiac "stereotype threat," that either of these would make such a difference in magnitude anyway, and so on. In epidemiological studies, seasonality of births is typically taken to reflect the role of infection, as it cannot be easily confounded w/ other variables, unlike the effect of urban birth -- the latter could reflect selection bias for higher IQ, class structure, better access to mentors, and so forth. But the only powerful, non-magical explanation for seasonality is infection.

In principle, WS seasonality could also reflect, e.g., lack of sun exposure and thus lack of vitamin D. But unlike vitamins, microbes are alive & evolving, meaning their presence (or absence) can have either positive or negative effects, depending on whether they are mutualist or parasitic. We cannot easily conceive of how lack of vitamin D would help smart people become singular geniuses, so we find subtle microbial influence much more plausible. Indeed, a recent study done to assess seasonality of schizophrenic births also found higher cognitive development among normal WS children, as measured by various psychometric tests, though the data do not report adult IQ, which would be more noteworthy.

Now, are we saying that early infection is all there is to genius? No, because we already know from Behavior Genetics that in adulthood, the broad-sense heritability of g is ~0.7, so genes certainly play a crucial role as well, not to mention access to mentors, etc. Recall that in the lower 5 deciles of the inventories, there was no apparent seasonality, so this infection likely plays a role in a tiny minority of cases indeed -- though these are the most impressive of cases -- and again we assume the affected individuals already had a high IQ due to additive genetic effects. But since we do not know exactly what the germs are, we cannot tell what effect they would have on an average or below-average intellect; in principle, it could go either way. Therefore if the germs were identified, administering them in the hopes of turning one's child into the next Mozart would almost certainly fail, since presumably many more individuals were infected in addition to Mozart, Newton, et al. Now, if the parents had good reason to believe their child's IQ would already be quite high, the prospect would be more promising.

Where, then, does this leave us as far as exploring the cells in the "brain germ" matrix outlined in part III? We are utterly clueless as to the route, aside from knowing that it must begin early after birth, and we are also unsure of its impact of reproductive fitness. We could not easily locate data for average family size in the times and places that produced the "giants," but here are the numbers of children sired by each of the 14 WS giants: 0 (Newton, Beethoven, Michelangelo), 1 (Koch), 3 (Galileo, Kepler, Einstein, Shakespeare), 5 (Pasteur), 6 (Edison, Watt, Mozart), 10 (Darwin), and 13 for the man whose genetic output was second only to his mathematical (Euler). How these actual values compare to the expected values given the time & place in which they flourished, we leave open for now.

So if early infection is one piece of the puzzle behind Galilean excellence, might better hygiene play a role in the decline of the per capita *rate* of accomplishment that Murray wrestles w/ in HA (Ch. 21), which accelerated downward after 1800? Part of his argument is that the secularization of Europe left each generation after ~1800 w/ less motivation to pursue their calling in life. As in our discussion in Part IV of Judith Rich Harris' personality model, we don't discount social influences such as the ones Murray mentions. However, in Murray's own list of "Significant Events" (Ch. 9) for Medicine, he has boldfaced the entry of 1796 to underscore its importance: "Edward Jenner systematizes vaccination for smallpox, founding immunology" (p.194; original emphasis).

During the 19th Century, the scientists Paul Ewald calls "the microbe hunters" in his book Plague Time began searching out infectious causes for diseases and proposing cures or preventative measures, including Semmelweis' efforts to introduce rigorous hygiene among doctors who were delivering newborns in order to cut down neonatal mortality rates, not to mention Pasteur's establishment of the germ theory of disease and Koch's formulation of Koch's Postulates to determine infectious origin. Conversely, we interpret the increasing rate of accomplishment up to and shortly after the Renaissance to reflect in part the increasingly frequent exposure to microbes as a result of urbanization. Similar reasoning suggests a partial reason for why advanced civilizations produce more geniuses than hunter-gatherers.

The early immunological efforts and their present-day descendents have surely improved the quality of life for the average person born in Western nations. Yet they might also have contributed to the decline in the rate of genius-level accomplishment. As elsewhere, science can only illuminate a trade-off -- if our interpreation is correct, in this case between level of public health and rate of genius-level excellence -- and the value judgment of where to resolve the trade-off is ultimately up to the individual or the society, not scientists. More big thinkers are better than fewer, ceteris paribus, but few will accept a larger percentage of geniuses if it requires diminishing the effect of public health on quality of life for the average person. Still, we feel a certain optimism is in order: after all, the Industrial and Information Revolutions took off when the rate of accomplishment was declining, suggesting that what matters on a day-to-day level -- e.g., having electricity so you can listen to a Chopin CD -- is more a function of the raw number of big thinkers rather than their proportion of the general population.

Epilogue: Psychology. I can hardly drone on about genius cognition w/o mentioning the geniuses of Psychology. Now, the field is far too immature to show up in Murray's survey, but I came up w/ the tiny handful of psychologists I estimate will compose the top 5 deciles in the 200th anniversary edition of HA. There are two main groups in psychology: those that deal w/ universals and those that deal w/ individual differences. From the former, I'd wager that Francis Galton (win) will make it. From the latter, I'd wager that William James (win) will make it, and perhaps the founders of the two fields of cognitive psychology that are best understood: language pioneer Noam Chomsky (win) and vision pioneer David Marr (win). Just as I assume Cuvier will fall from the top 5 deciles in Biology once Hamilton & Fisher work their way into the encyclopedias, I assume the following will drop from their (even now decreasing) Deity status: Freud (win), Skinner (spr), & Piaget (sum).


Tuesday, October 18, 2005

Diffusion of HIV resistance   posted by Razib @ 10/18/2005 07:41:00 PM

The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele. A picture is worth a lot of words, so....

Note the appeal to the "wave of advance" model of R.A. Fisher, you've seen it before in reference to the possibility of advantageous alleles spreading throughout populations via selection without concomitant wholesale demographic dislocations and migrations. The authors of the above article, which is freely available to all via PLOS, suggest that one possible reason that the Δ32 mutation isn't more common is that selection hasn't had enough time to operate. For comparison, consider lactose tolerance, though in Eurasia the allele that confers the ability to adults to easily digest milk products as adults probably has its origins in Northern Europe, in places like Northern India the phenotype has reached ~70% levels of prevalence. Contrary to some Aryan fantasists this does not imply that an ancient influx of Swedes transformed the South Asian demographic landscape, rather, selection knows a good thing.