Spatial and temporal diversity of positive selection on shared haplotypes at the PSCA locus among worldwide human populations

Abstract

Selection on standing genetic variation is important for rapid local genetic adaptation when the environment changes. We report that, for the prostate stem cell antigen (PSCA) gene, different populations have different target haplotypes, even though haplotypes are shared among populations. The C-C-A haplotype, whereby the first C is located at rs2294008 of PSCA and is a low risk allele for gastric cancer, has become a target of positive selection in Asia. Conversely, the C-A-G haplotype carrying the same C allele has become a selection target mainly in Africa. However, Asian and African share both haplotypes, consistent with the haplotype divergence time (170 kya) prior to the out-of-Africa dispersal. The frequency of C-C-A/C-A-G is 0.344/0.278 in Asia and 0.209/0.416 in Africa. Two-dimensional site frequency spectrum analysis revealed that the extent of intra-allelic variability of the target haplotype is extremely small in each local population, suggesting that C-C-A or C-A-G is under ongoing hard sweeps in local populations. From the time to the most recent common ancestor (TMRCA) of selected haplotypes, the onset times of positive selection were recent (3-55 kya), concurrently with population subdivision from a common ancestor. Additionally, estimated selection coefficients from ABC analysis were up to ~3%, similar to those at other loci under recent positive selection. Phylogeny of local populations and TMRCA of selected haplotypes revealed that spatial and temporal switching of positive selection targets is a unique and novel feature of ongoing selection at PSCA. This switching may reflect the potential of rapid adaptability to distinct environments.