The human haplotype map (HapMap) shows that human populations differ genetically and have been subject to strong, recent positive selection: selection ‘for’ particular genetic variants. Surprisingly, patterns of inferred selection vary markedly between the three human groups analyzed thus far, one Caucasian, one African, and one Asian (Voight et al. 2006). Ethnicity, and natural selection, may thus play stronger roles in diverse human traits, including genetic susceptibility to disease, than previously believed.

One ethnic group, famous for reasons including its high incidence of otherwise-rare diseases, is the Ashkenazi. The concentration of recessive diseases in this group has usually been attributed to founder events, but this interpretation has been challenged by Cochran, Hardy and Harpending (2006), who describe evidence that some ‘disease’ alleles in the Ashkenazi have actually been selected for via benefits to heterozygotes. The benefits? Controversially, they suggest higher intelligence, strongly selected for in the context of a cultural and genetic milieu that strongly translated such intelligence into reproductive success, and led over many generations to the higher IQs considered uniquely-characteristic of this group.

So, we have a human population, largely-isolated genetically, undergoing founder events, and subject to strong selection for ‘intelligence’ over many generations – sound familiar? This is the precise scenario postulated for the origin of modern humans, on a much larger scale – just replace Abraham with Adam and Eve, and Eden may indeed coincide with Ur.

How can we critically evaluate these ideas? First, we can use the published HapMap data to assess whether Ashkenazi disease genes have indeed been subject to positive selection. Go to the Haplotter web site and in Query by Gene (for phase II) enter each gene “APC”, “BRCA1”, “GBA” and “HEXA” and click “submit”, – for each, scroll down to the yellow highlights – see the P-values under 0.05? Positive selection has also been inferred for BLM, BRCA1, FANCC, GBA and HEXA in other data sets (Pavlicek et al. 2004; Bustamante et al. 2005; Voight et al. 2006; Tang et al. 2007; Wang and Moyzis 2007). None of these analyses involve the Ashkenazi, or their specific disease alleles, but they all provide inferential evidence that these particular genes may have undergone adaptive evolutionary change in humans.

Second, we need a HapMap specific to the Ashkenazi, to rigorously evaluate the roles of selection and drift on disease-gene evolution in this population. As of February, we have it (Olshen et al. 2008). The authors report on genomic differences between the European HapMap population and the Ashkenazi that “likely… reflect the impact of both selection as well as genetic drift”. Further analyses of such data should provide crucial insights into the nature and sources of Ashkenazi (and other) genetic diseases, and the evolution of modern humans.


* Bustamante CD, et al. (2005) Natural selection on protein-coding genes in the human genome. Nature 437:1153-7.

* Cochran G, Hardy J, Harpending H. (2006) Natural history of Ashkenazi intelligence. Journal of Biosocial Science 38:659-93.

* Olshen AB, et al. (2008) Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping. BMC Genetics 9:14.

* Pavlicek A, Noskov VN, Kouprina N, Barrett JC, Jurka J, Larionov V. (2004) Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. Human Molecular Genetics 2004 13:2737-51.

* Tang K, Thornton KR, Stoneking M. (2007) A New Approach for Using Genome Scans to Detect Recent Positive Selection in the Human Genome. PLoS Biology 5:e171.

* Voight BF, Kudaravalli S, Wen X, Pritchard JK. (2006) A map of recent positive selection in the human genome. PLoS Biology 4:e72.

* Wang ET, Moyzis RK. (2007) Genetic evidence for ongoing balanced selection at human DNA repair genes ERCC8, FANCC, and RAD51C. Mutation Research 616:165-74.