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SummaryMitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2 * 504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2 * 504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2 * 504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2 * 504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2 * 504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2 * 504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2 * 504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.

Progress in the mapping of population genetic substructure provides a core source of data for the reconstruction of the demographic history of our species and for the discovery of common signals relevant to disease research: These two aspects of enquiry overlap in their empirical data content and are especially informative at continental and subcontinental levels. In the present study of the variation of the Y chromosome pool of ethnic Russians, we show that the patrilineages within the pre-Ivan the Terrible historic borders of Russia have two main distinct sources. One of these antedates the linguistic split between West and East Slavonic-speaking people and is common for the two groups; the other is genetically highlighted by the pre-eminence of haplogroup (hg) N3 and is most parsimoniously explained by extensive assimilation of (or language change in) northeastern indigenous Finno-Ugric tribes. Although hg N3 is common for both East European and Siberian Y chromosomes, other typically Siberian or Mongolian hgs (Q and C) have negligible influence within the studied Russian Y chromosome pool. The distribution of all frequent Y chromosome haplogroups (which account for 95% of the Y chromosomal spectrum in Russians) follows a similar north-south clinal pattern among autosomal markers, apparent from synthetic maps. Multidimensional scaling (MDS) plots comparing intra ethnic and interethnic variation of Y chromosome in Europe show that although well detectable, intraethnic variation signals do not cross interethnic borders, except between Poles, Ukrainians, and central-southern Russians, thereby revealing their overwhelmingly shared patrilineal ancestry.

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The Slavic branch of the Balto-Slavic sub-family of Indo-European languages underwent rapid divergence as a result of the spatial expansion of its speakers from Central-East Europe, in early medieval times. This expansion–mainly to East Europe and the northern Balkans–resulted in the incorporation of genetic components from numerous autochthonous populations into the Slavic gene pools. Here, we characterize genetic variation in all extant ethnic groups speaking Balto-Slavic languages by analyzing mitochondrial DNA (n = 6,876), Y-chromosomes (n = 6,079) and genome-wide SNP profiles (n = 296), within the context of other European populations. We also reassess the phylogeny of Slavic languages within the Balto-Slavic branch of Indo-European. We find that genetic distances among Balto-Slavic populations, based on autosomal and Y-chromosomal loci, show a high correlation (0.9) both with each other and with geography, but a slightly lower correlation (0.7) with mitochondrial DNA and linguistic affiliation. The data suggest that genetic diversity of the present-day Slavs was predominantly shaped in situ, and we detect two different substrata: ‘central-east European’ for West and East Slavs, and ‘south-east European’ for South Slavs. A pattern of distribution of segments identical by descent between groups of East-West and South Slavs suggests shared ancestry or a modest gene flow between those two groups, which might derive from the historic spread of Slavic people.