Contrastive sequence signatures between the both sides of a recombination spot reveal an adaptation at PPARD locus from standing variation for pleiotropy since out-of-Africa dispersal

Abstract

Background Drug metabolism and transporter genes are a specialized class of genes involved in absorption, distribution, metabolism and excretion. They easily present distinct genetic population differentiation and are vulnerable to natural selection. Results We initiated a study using a special panel of informative genetic markers in such genes and dissected the genetic structure in representative Chinese and worldwide populations. A distinctive sub-population stratification was discovered in extensive Eurasians and resulted from divergence at the PPARD locus. The contrastive sequence signatures between the both sides of a recombination spot prove a selective sweep on this locus for genetic hitchhiking effect. A genealogy-based framework demonstrates the positive selection acting from standing variation exerted a moderate pressure in Eurasians, and drove the adaptive allele up to a high frequency. The timing and tempo estimations for the genetic adaptation indicate its onset coincided with the early out-of-Africa migration of modern humans and it lasted over a prolonged evolutionary history. A phenome-wide association analysis reveals an extended cis-regulation on the local gene expression and the pleiotropy implicated in a variety of complex traits. The colocalization analyses between the genetic associations from cis-acting gene expression and complex traits signify the most likely selective pressure from physical capacity, energy metabolism, and immune-related involvement, and provide prioritization for the effective genes and casual variants. Conclusions This work has laid a foundation for following efforts to make full sense of the biological mechanisms underlying the genetic adaptation. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-025-11620-y. Keywords: Drug gene, Genetic stratification, Positive selection, Evolutionary history, Selective pressure, Causal prioritization