Shou Weihua, Zhang Chenhui, Wang Ying, Wang Haifeng, Guo Lei, Li Li, Zhang Tiesong, Huang Wei, Shi Jinxiu
Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Institute of Pediatrics, Kunming Children's Hospital, 288 Qianxing Road, Kunming, Yunnan, 650228, P.R. China.
Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies (SIBPT), 2140 Xietu Road, Shanghai, 200032, P.R. China.
BMC Genomics. 2025 Apr 30;26(1):427. doi: 10.1186/s12864-025-11620-y.
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.
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.
This work has laid a foundation for following efforts to make full sense of the biological mechanisms underlying the genetic adaptation.
药物代谢和转运体基因是一类参与吸收、分布、代谢和排泄的特殊基因。它们很容易呈现出明显的遗传群体分化，并且容易受到自然选择的影响。
我们使用这类基因中的一组特殊信息性遗传标记启动了一项研究，并剖析了代表性中国人群和全球人群的遗传结构。在广泛的欧亚人群中发现了一种独特的亚群分层，这是由PPARD基因座的分歧导致的。重组位点两侧的对比序列特征证明了该基因座上存在因遗传搭便车效应而产生的选择性清除。一个基于谱系的框架表明，从现有变异起作用的正选择在欧亚人群中施加了适度的压力，并将适应性等位基因频率提高到了较高水平。对遗传适应的时间和速度估计表明，其开始与现代人类早期走出非洲的迁徙相吻合，并且持续了漫长的进化历史。全表型关联分析揭示了对局部基因表达的扩展顺式调控以及涉及多种复杂性状的多效性。顺式作用基因表达与复杂性状之间的遗传关联共定位分析表明，最可能的选择压力来自身体能力、能量代谢和免疫相关参与，并为有效基因和因果变异提供了优先级。
这项工作为后续全面理解遗传适应背后的生物学机制奠定了基础。
