Evolutionary History of the Risk of SNPs for Diffuse-Type Gastric Cancer in the Japanese Population

A genome wide association study reported that the T allele of rs2294008 in a cancer-related gene, PSCA, is a risk allele for diffuse-type gastric cancer. This allele has the highest frequency (0.63) in Japanese in Tokyo (JPT) among 26 populations in the 1000 Genomes Project database. F ≈ 0.26 at this single nucleotide polymorphism is one of the highest between JPT and the genetically close Han Chinese in Beijing (CHB). To understand the evolutionary history of the alleles in PSCA, we addressed: (i) whether the C non-risk allele at rs2294008 is under positive selection, and (ii) why the mainland Japanese population has a higher T allele frequency than other populations. We found that haplotypes harboring the C allele are composed of two subhaplotypes. We detected that positive selection on both subhaplotypes has occurred in the East Asian lineage. However, the selection on one of the subhaplotypes in JPT seems to have been relaxed or ceased after divergence from the continental population; this may have caused the elevation of T allele frequency. Based on simulations under the dual structure model (a specific demography for the Japanese) and phylogenetic analysis with ancient DNA, the T allele at rs2294008 might have had high frequency in the Jomon people (one of the ancestral populations of the modern Japanese); this may explain the high T allele frequency in the extant Japanese.