Molecular adaption of alcohol metabolism to agriculture in East Asia

Human Alcohol metabolic gene families ADH and ALDH mainly comprise ten genes, expressing in different organs and tissues. Two of the variants, ADH1B*47His and ALDH2*504Lys reach very high frequency in East Asia, while are almost absent in the rest of the world, which is believed to be results of positive selection related to the development of agriculture in Neolithic time. In addition to the ADH alcohol metabolic pathway, a microsomal ethanol oxidizing system involving the gene CYP2E1 has also been identified. The study on the micro-evolution of alcohol metabolic genes will help us understand how human adapted to the artificial environment of agriculture.We collected 1211 samples from 44 worldwide populations including 19 representative populations in East Asia, combined with 2504 samples of 26 populations from 1000 Genome project. We scanned all the 23 missense mutations or pathogenic SNPs in ADH and CYP2E1 pathways. Then we examined the selection signature on the genetic polymorphism in East Asia and estimated the allele ages. Our analyses revealed that the long-term farming ethnic groups in East Asia, such as Han, differed from the nomadic populations in the pattern of alcohol-related genetic polymorphism. This divergence was mainly attributed to the 6 closely related functional SNPs rs1229984 (ADH1B), rs671 (ALDH2), rs8187929 (ALDH1A1), rs2228093 (ALDH1B1), rs3813867 (CYP2E1), and rs2031920 (CYP2E1). The derived core haplotypes of the new detected SNPs showed moderate to strong selection signals and the estimated allele ages coincided with the Neolithic time. The driving force tended to be the emergence and expansion of agriculture in East Asia.