a. State Key Laboratory of Genetics and Development of Complex Phenotypes, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai 200438, China;
b. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;
c. Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200433, China
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This study was supported by the National Natural Science Foundation of China (NSFC) grants (32030020), the National Key Research and Development Program of China (No. 2023YFC2605400), the National Natural Science Foundation of China (NSFC) grants (32288101, 32470649, 323B2013, 32300499, 32270665), the Shanghai Science and Technology Commission Program (25JS2810100, 23JS1410100, QNKJ2024023), and the Office of Global Partnerships (Key Projects Development Fund). The CFFF Computing Platform of Fudan University supported the computational work in this study. The funders had no role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
Recent advancements in genome sequencing have enabled the estimation of genetic load through deleterious mutation profiling. However, Chinese populations remain underexplored in this context. We analyze whole-exome sequencing data from 5002 individuals, encompassing major Han subgroups—North Han (N-Han), South Han (S-Han), and Guangxi Han (G-Han)—as well as 13 ethnic minorities. Notably, G-Han exhibits significant genetic affinity with the Zhuang population. Systematic curation of 2110 ClinVar pathogenic or likely pathogenic variants reveals 93.4% are ultra-rare. Exceptions include GJB2 rs72474224-A (hearing loss), which shows higher frequencies in Zhuang and G-Han, and β-thalassemia-associated HBB variants (rs33986703-A and rs33950507-T), which are elevated in G-Han compared to other Han subgroups. Among 96 autosomal dominant mutation carriers, LDLR variants are predominant (∼25%), with comparable frequencies across Han subgroups. Adaptive signatures highlight gene-environment interactions: MTHFR rs1801133-A (UV adaptation) declines southward, while ALDH2 rs671-A (alcohol metabolism) displayed the opposite trend. ABCC11 rs17822931-A, associated with tropical adaptation, is particularly prevalent in G-Han. Gene-based rare-variant collapsing analyses identify an elevated risk of retinitis pigmentosa in S-Han (PRPF4, TUB). Our findings demonstrate that genetic load in Chinese populations is influenced by demographic history, population structure, and regional adaptation, emphasizing the importance of population-specific frameworks in precision medicine.
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