Recombination and mutation shape variations in the major histocompatibility complex

作     者：Yuying Sun Fang Yuan Ling Wang Dongfa Dai Zhijian Zhang Fei Liang Nan Liu Juan Long Xiao Zhao Yongzhi xi Yuying Sun;Fang Yuan;Ling Wang;Dongfa Dai;Zhijian Zhang;Fei Liang;Nan Liu;Juan Long;Xiao Zhao;Yongzhi Xi

作者机构：Department of Immunology and National Immunoassay LaboratoryFifth Medical Center of Chinese PLA General HospitalBeijing 100071China Institute of Beijing 307 HospitalAnhui Medical UniversityHefeiAnhui 230032China 

出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)

年 卷 期：2022年第49卷第12期

页      面：1151-1161页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071007[理学-遗传学] 

基　　金：supported by grants from the National Key Basic Research Development Program of China(grants No.2009CB522401 and 2003CB515509 and AWS14C014)。 

主　　题：Major histocompatibility complex(MHC) Recombination De novo mutation Positive selection Disease-associated genetic variants 

摘      要：The major histocompatibility complex(MHC)is closely associated with numerous diseases,but its high degree of polymorphism complicates the discovery of disease-associated variants.In principle,recombination and de novo mutations are two critical factors responsible for MHC polymorphisms.However,direct evidence for this hypothesis is lacking.Here,we report the generation of fine-scale MHC recombination and de novo mutation maps of~5 Mb by deep sequencing(100×)of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families(a total of 190 individuals).Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries.The average MHC de novo mutation rate is higher than the genome-wide de novo mutation rate,particularly in MHC recombinant individuals.Notably,mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC,respectively,and evolution of the MHC locus was mainly controlled by positive selection.These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.