Spatial and temporal diversity of positive selection on shared haplotypes at thePSCAlocus among worldwide human populations

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 not unique to specific 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 mainly in Asian populations. Conversely, the C-A-G haplotype carrying the same C allele has become a selection target in African populations. However, Asian and African populations share both haplotypes, consistent with the haplotype divergence time (170 kya) prior to out-of-Africa. The frequency of C-C-A/C-A-G is 0.344/0.278 in Asia and 0.209/0.416 in Africa. 2D-SFS 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 TMRCA of selected haplotypes, the estimated 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 on standing genetic variation. 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 positive selection at PSCA . This switching may reflect potential of rapid adaptability to distinct environments.