David Goldstein and collegues report today the results of a genome-wide association study for a particular side effect (treatment-induced anemia) of treatment for hepatitis C. It turns out that variants in a single gene–ITPA–are overwhelmingly associated with the development of this side effect. This is a nice, probably clinically-important result, and there’s likely some interesting biology here as well.

One twist is that the authors identify two presumably causal variants in the gene–one a nonsynonymous SNP, and the other a SNP falling in a splice site. The authors make the following point:

Two related features of these observations are worth emphasizing. First, the ITPA variants constitute a clear example of a synthetic association in which the effects of rarer functional variants are observed as an association for a more common variant present on a whole-genome genotyping chip: indeed, the minor-allele frequency is higher for the top-associated SNP rs6051702 (19.4%) than for the causal variants rs1127354 (7.6%) and rs7270101 (12.3%) in European-Americans

Some readers will recall the paper recently published by this group on “synthetic associations“, where they posited a model for common diseases in which multiple rare (< 5% minor allele frequency) SNPs in a gene can lead to identification of as association with a common allele. Now, it appears, any gene with more than one functional variant, rare or not, fits their model!

That aside, I can see their point–the patterns of linkage disequilibrium around a locus with two causal variants leads in this case to a strong association signal at a SNP that happens to be correlated with both of them. But this isn’t a new phenomenon worthy of a special name; for example, multiple correlated SNPs in the MHC influence risk for celiac disease, and most people are happy to call it that–multiple causal variants at a locus. It seems a bit like the authors are trying to shoehorn the data to fit their theories a bit awkwardly.

There’s apparently a game in this sport at the Olympics tonight. Canada is the favorite. Which is awesome, because if the USA loses, no one in the USA will care. But if the USA wins, we’ll get to laugh at the Canadians. Don’t lie, you know Canada is the country that keeps on giving in terms of humor.
Update: Yeah, you guys are funny. LOL.

Lost of discussion about Basques below. Some interesting examples which are less speculative.
Hungary = Language changes, genes do not
The intrusion of ethnic Magyars, and later the settlement of Kipchak Turks fleeing the Mongols, within Hungary is historically attested. Additionally, down to the Reformation there were isolated settlements of Turks among the Magyars which maintained their own linguistic tradition. But digging through the literature it is very difficult to find much genetic impact. Anatolian Turks are a milder case; eastern genetic contributions can be found, but it is the minor component, and this may reflect the greater genetic distance of Turks from Europeans/Anatolians than the Ugric groups of the lower Volga.
Bulgaria = Neither language or genes change
Bulgaria is interesting because it resembled Hungary in many ways. An alien ethnic elite on top of a local substrate. In this case though the alien Bulgar elite was Slavicized, leaving only their ethnonym. Again, no genetic impact.
Japan = Language and genes change
This is a case where the preponderance of evidence seems to be that the Yayoi rice-culture bearers arrived from the continent and predominantly replaced the indigenous post-Jomon culture. The Ainu may be a residue of the Jomon natives, and a non-trivial, though minority, component of the Japanese ancestry can be traced back to the Jomon (a Uyghur treatment would clear up the case of Japan, because if admixture did occur in the manner posited above it would should up in the form of decayed linkage disequilibrium. Though the parent populations in this case are much closer than in that of the Uyghurs).
Basques & Brahui = Language does not change, genes do

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Original map at Strange Maps.
H/T M. Yglesias

An interesting exchange in Nature on ways to conceptualize the evolution of virulence. First, Adaptation and the evolution of parasite virulence in a connected world:

Adaptation is conventionally regarded as occurring at the level of the individual organism, where it functions to maximize the individual’s inclusive fitness…However, it has recently been argued that empirical studies on the evolution of parasite virulence in spatial populations show otherwise...In particular, it has been claimed that the evolution of lower virulence in response to limited parasite dispersal…provides proof of Wynne-Edwards’s…idea of adaptation at the group level. Although previous theoretical work has shown that limited dispersal can favour lower virulence, it has not clarified why, with five different suggestions having been given…Here we show that the effect of dispersal on parasite virulence can be understood entirely within the framework of inclusive fitness theory. Limited parasite dispersal favours lower parasite growth rates and, hence, reduced virulence because it (1) decreases the direct benefit of producing offspring (dispersers are worth more than non-dispersers, because they can go to patches with no or fewer parasites), and (2) increases the competition for hosts experienced by both the focal individual (‘self-shading’) and their relatives (‘kin shading’). This demonstrates that reduced virulence can be understood as an individual-level adaptation by the parasite to maximize its inclusive fitness, and clarifies the links with virulence theory more generally….

Ebola is very virulent. Swine flu is less virulent than ebola. The common cold is less virulent than swine flu. You get the picture. If a pathogen is very virulent it needs to be very transmissible to be evolutionarily successful (replicate itself); otherwise, it will kill its host before it is transmitted and so kill the golden goose. By contrast, if a pathogen is not very virulent, it can be relatively chilled out in terms of transmission since the host isn’t going to die anytime soon. Models of virulence aren’t of purely academic interest, since they are critical components of an evolutionary understanding of epidemics, and their potential future trajectories.
In any case, the “multi-level” point here is obviously that one can easily imagine conceptually that a fast replicator strain within a host can kill the golden goose. So even though that strain is successful within the host, it will decrease group level fitness. By contrast, those hosts which do not produce fast replicator strains within their population of pathogens will persist and the pathogens will have a better chance of being transmitted. The group level logic here is rather evident, but the authors of the above paper think that one can eliminate the need for this sort of thinking within a traditional individual level inclusive fitness framework.
In any case, I’ll skip the formal analysis and jump to their conclusion:

…Thus, irrespective of the relative strengths of within-group versus between-group selection, individuals are predicted to maximize their inclusive fitness. In contrast, groups are only predicted to evolve traits that function to maximize their fitness in extreme situations where there is no conflict of interest between the members of the group…Put another way, the presence of group selection does not invalidate the idea that the individual is an adaptive unit, and it does not validate the idea that the group is an adaptive unit

This is a standard individual selectionist dismissal of the multi-level selection viewpoint: group selection happens, but it is a rare dynamic which only crops up in marginal cases.
Recently this letter prompted a rely. Multilevel and kin selection in a connected world. In this response the authors basically argue that the equation at the heart of the first paper is just a restatement of the Price Equation. They say:

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From The Boston Globe, Ambition fueled a smoldering rage:

A friendship of sorts was kindled, based largely on a mutual interest in science. Over coffee and lunch, they would discuss Bishop’s research and McCann’s work in biotechnology.
Bishop never spoke of her husband or growing family.
During one meeting, Bishop listened patiently to McCann for a time before suggesting they switch topics.
“She said, ‘That’s very nice, Isabel, but can we talk about oxidation?‘ ” she recalled, with a chuckle. “That one moment in time encapsulated who Amy was. She just couldn’t connect with people.”

I would elaborate on the emphasized part above, but I’ll leave it to readers as to why this sort of behavior is informative….

Ruchira Paul points me to a blogger who’s been digging through Bishop’s recent published works, and there’s a lot of fishy stuff in there. You have to read it to believe it. Here’s the conclusion:

There is no question that Dr. Bishop is smart. But it also seems very evident that she suffers delusions of genuis. Far from establishing a record of accomplishment warranting the grant of tenure, since joining UAH Dr. Bishop took a long nap on her one true laurel — her affiliation with Harvard .
Evidence strongly suggests that Dr. Bishop used her husband, her family and by all appearances the sham ‘Cherokee Labsystems’ to fabricate a record of recent accomplishments. Her use of essentially an online vanity publisher further diminishes her professional stature.
It should have been no surprise to Dr. Bishop that the University easily saw through the smoke and mirrors and that she would not receive tenure. But an oversized ego can be blinding.
It seems clear that Dr. Bishop re-wrote the rules for herself. Rather than face the reality that she needed to conduct real research and publish substantial, scholarly work in peer reviewed journals, Dr. Bishop tried to cheat her way to tenure. And, when that failed, it appears Dr. Bishop premeditated a new plan: if you don’t accept what I publish, you will perish.

Some readers mentioned putting her kids on a paper as a co-author. But it might not have been an isolated incident.

Covers all the major angles. Nice that there’s a newspaper which can support this sort of reporting (on the other hand). Not surprising that Amy Bishop seems to have some history of delusions of grandeur, she’s claiming that both she and her husband have an I.Q. of 180. That’s 5.3 standard deviations above the mean. Assuming a normal distribution that’s a 1 in 20 million probability. Of course the tails of the distribution are fatter beyond 2 standard deviations than expectation for I.Q., but at these really high levels (above 160) I’m skeptical that most tests are measuring anything real.

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