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

Risa L Iwasaki,Hideaki Kanzawa-Kiriyama,Jun Gojobori,Koji Ishiya,Yoko Satta,Yosuke Kawai

doi:10.3390/genes11070775

Abstract

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. FST ≈ 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.

Highlights

Gastric cancer (GC) has a high incidence rate in East Asia and is the third leading cause of cancer death in the world [1]
We explore the evolutionary forces that may be responsible for this high frequency in Japanese in Tokyo (JPT) through: (i) the examination of the signature of natural selection operating on either the T or C alleles at the rs2294008 single nucleotide polymorphism (SNP), (ii) exploring the evolutionary trajectory of the risk allele through computer simulations, and (iii) a phylogenic analysis of ancient genome sequence data from one of the ancestral populations of the extant Japanese population, the Jomon people
(Figure 3) that was comprised of 125 SNPs in JPT

Summary

Introduction

Gastric cancer (GC) has a high incidence rate in East Asia and is the third leading cause of cancer death in the world [1]. GC is classified into two types, the diffuse type and the intestinal type [2]. The diffuse type of GC (DGC) is reported as geographically uniformly distributed [3] and the incident rate of DGC has been increasing compared with the intestinal type of GC [4,5]. The study analyzed 925 DGC cases with 1396 controls and reported a strong association with the T allele at rs2294008 in PSCA.

Methods

Results

Conclusion