New data on Ashkenazi population history26 Aug 2010
Bray and colleagues
There’s a lot in the paper. One of the key findings in the paper is that the Ashkenazi population doesn’t look bottlenecked – in fact, it looks outbred compared to Europeans generally. The paper also documents a high amount of admixture with non-Ashkenazi Europeans, ranging from 35% to 55%. Figuring out the actual history of the population – when and where its ancestors lived and how they interacted with other people – is beyond the scope of this kind of analysis. But I expect that somebody can put together a really compelling historical account using these data.
I turned quickly to the issue of selection. They are able to substantiate evidence of positive selection on several disease-causing alleles in the Ashkenazi population, including the Tay-Sachs allele. The lack of evidence for bottlenecks or founder effects pretty much takes away the alternative explanation. Yet they were unable to show statistical evidence of selection on some other disease-causing alleles in Ashkenazi populations:
To explore whether regions of selection in the AJ population included any loci of known Ashkenazi diseases, we examined 21 disease- and cancer-susceptibility loci with known mutations found at higher frequency in the Ashkenazi population. Only 6 of the 21 genes fell in or near (within 500 kb) the top 5% of the AJ iHS windows (Table 2). Among these is the Tay-Sachs disease gene, HEXA, whose selection has been widely debated (4, 5, 1416) and was found ~400 kb downstream of a window on chromosome 15 identified in the top 1% of the AJ iHS hits. Although none of the SNPs interrogated immediately adjacent to the HEXA locus showed elevated iHS signals, it is possible that the nearby region may contain regulatory elements under selection that affect HEXA expression. Cochran et al. (14) speculated that selection of many of the AJ- prevalent disease loci, especially the lysosomal diseases, conferred an increase in intelligence that was necessary historically for the AJ economic survival. Our data shows evidence of strong selection at or near only six disease loci, including only one out of the four AJ- prevalent lysosomal storage diseases, thus arguing that most AJ disease loci are not under strong positive selection, but rather rose to their current frequency through genetic drift after a bottleneck. However, we cannot exclude the possibility that selection of some AJ disease loci are outside the limits of detection by the extended haplotype tests, which are known to have less power to detect se- lection of lower frequency alleles (38, 41).
It seems to me that this passage probably wasn’t written by the same author who showed the lack of evidence for founder effects a few pages before. In this case, the confusion probably comes from the fact that the “detection of positive selection” is actually a refutation of the hypothesis of genetic drift. With a larger sample it will be possible to test the hypothesis with greater power.
Ddisease-causing alleles are at low frequencies currently, making them unlikely to rise to the top percentages of the statistics. It would be interesting to control for current frequency, but I haven’t seen a test that uses frequency information in this way.
It’s quite remarkable to reflect on the idea that positive selection has now been demonstrated on six disease-causing alleles in the Ashkenazi population. Every one of these is a case of overdominance – where the heterozygote carrying an allele has some selective advantage, while the homozygote carrying two copies has a disorder. I was having a conversation with a very prominent geneticist a few months ago, who claimed that no case of overdominance in humans had ever been demonstrated except sickle cell. Now, that was obviously false even at the time – as I pointed out, the many hemoglobinopathies are fairly clear examples. But we’ve come an awfully long way.
From data like these, we’re going to learn a huge amount about low-frequency selected alleles. The Tay-Sachs-causing allele is one of the most common recessive lethal genes in any human population, but like all genes subject to strong selection in homozygotes, it remains rare. Finding selection on these kinds of alleles is very hard unless sample sizes increase to several hundred individuals. Here we are seeing evidence of selection in historic populations – within the last 2000 years. More will be coming.