摘要
了解人类进化过程中经历的正选择,可以洞察塑造我们物种的事件,以及今天继续困扰我们的疾病.作为人口最多的民族,汉族在其特定的历史、地理和文化环境中一直在经历基因选择.本文通过对3946个中国汉族人高深度全基因组测序数据进行分析,鉴定了24个近期选择的基因组区域,包括免疫相关基因区(MHC cluster、IGH cluster、STING1、PSG)、酒精代谢相关基因区(ADH1B、ALDH2、ALDH3B2)和嗅觉感知基因OR4C16.其中MHC cluster、ADH1B和ALDH2也被TOPMed和西湖生物库WBBC鉴定.在这些信号中,IGH cluster值得关注,其中变异14105737776CT(rs117518546,IgG1-G396R)的优势等位基因可促进免疫反应,但也增加了自身免疫性疾病系统性红斑狼疮(SLE)的风险.另外,本研究新发现的ALDH3B2的进化方向对酒精代谢的影响与ALDH2的相反.除了单基因性状,本文发现多个复杂性状经历了多基因适应;特别是,多种方法一致表明,在自然选择中,较低的血压更受青睐.最后建立了一个名为RePoS的数据库(http://bigdata.ibp.ac.cn/RePoS/)以集成和显示多种群选择信号.综上,本研究扩展了我们对汉族和其他人群的自然进化和表型适应的理解.
Characterizing natural selection signatures and relationships with phenotype spectra is important for understanding human evolution and both biological and pathological mechanisms.Here,we identified 24 genetic loci under recent selection by analyzing rare singletons in 3946 high-depth whole-genome sequencing data of Han Chinese.The loci include immune-related gene regions(MHC cluster,IGH cluster,STING1,and PSG),alcohol metabolism-related gene regions(ADH1B,ALDH2,and ALDH3B2),and the olfactory perception gene OR4C16,in which the MHC cluster,ADH1B,and ALDH2 were also identified by TOPMed and WestLake Biobank.Among the signals,the IGH cluster is particularly interesting,in which the favored allele of variant 14_105737776_C_T(rs117518546,IgG1-G396R)promotes immune response,but also increases the risk of an autoimmune disease systemic lupus erythematosus(SLE).It is also surprising that our newly discovered ALDH3B2 evolved in the opposite direction to ALDH2 for alcohol metabolism.Besides monogenic traits,we found that multiple complex traits experienced polygenic adaptation.Particularly,multi-methods consistently revealed that lower blood pressure was favored in natural selection.Finally,we built a database named RePoS(recent positive selection,http://bigdata.ibp.ac.cn/RePoS/)to integrate and display multi-population selection signals.Our study extended our understanding of natural evolution and phenotype adaptation in Han Chinese as well as other populations.
作者
罗华夏
张鹏
张皖豫
郑宇
郝頔
史忆戎
牛仪伟
宋廷瑞
李燕燕
赵石磊
陈华
徐涛
何顺民
Huaxia Luo;Peng Zhang;Wanyu Zhang;Yu Zheng;Di Hao;Yirong Shi;Yiwei Niu;Tingrui Song;Yanyan Li;Shilei Zhao;Hua Chen;Tao Xu;Shunmin He(Key Laboratory of Epigenetic Regulation and Intervention,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;College of Life Sciences,University of Chinese Academy of Sciences,Beijing 100049,China;University of Chinese Academy of Sciences,Beijing 100049,China;CAS Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China;China National Center for Bioinformation,Beijing 100101,China;National Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;Shandong First Medical University&Shandong Academy of Medical Sciences,Taian 271016,China)
基金
supported by National Key R&D Program of China(2021YFF0704500,2021YFF0703701,and 2022YFC3400405)
the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38040300)
the 14th Five-year Informatization Plan of Chinese Academy of Sciences(CASWX2021SF-0203)
the National Natural Science Foundation of China(91940306,31871294,31970647,81902519,and 32200478)
the Special Investigation on Science and Technology Basic Resources of the MOST,China(2019FY100102)
the China Postdoctoral Science Foundation(2022M713311)
the National Genomics Data Center,China。
