Structural evolution of trypsinogen gene redundancy confers risk for pancreas diseases

doi:10.1101/2022.08.08.22278454

	Structural evolution of trypsinogen gene redundancy confers risk for pancreas diseases
	Lou, H.1; Wang, Y.2; Xie, B.2; Bai, X.3 ; Gao, Y.4,5; Zhang, R.2; Xu, S.1,2,3,4,5,6,7,8
	2022-08-09
状态	已发表
摘要	Trypsin is an important enzyme secreted by the pancreas for digesting proteins. The precursors of major human trypsin are encoded by trypsinogen genes PRSS1 and PRSS2. Here, we leveraged multi-omic data to study their evolutionary and functional impact. We estimated that the primate trypsinogen gene was duplicated from a single copy to multiple-copy 24-34 million years ago (Mya). Compared to six protein-coding genes in non-human great apes, the human ancestral state was a 5-copy with three being pseudogenized. Interestingly, a derived 3-copy form emerged in Africans ~260 Kya and dominated in non-Africans as one of the two major haplotypes. Although no longer encoding proteins, the pseudogene enhancers still function on pancreatic PRSS2 expression, leading to ~15% up-regulation for the 5-copy than the 3-copy haplotype. Notably, the 3-copy structure was under positive selection in East Asians, where lower trypsin might be adaptive during high-starch diet shift for protecting the pancreas from autodigestion, as also supported by the identified causality of the haplotype structure to pancreatitis risk. Our efforts in elucidating the structural evolution of trypsinogen genes advance our understanding of the genetic basis and molecular mechanism of human pancreas diseases.
关键词	Trypsinogen gene gene duplication structural variation pseudogene PRSS1-PRSS2
语种	英语
DOI	10.1101/2022.08.08.22278454
相关网址	查看原文
出处	medRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:11992847
WOS类目	Genetics & Heredity
资助项目	National Natural Science Foundation of China (NSFC)["2017SHZDZX01","NAF\\R1\\191094","XDPB17","32030020"] ; Strategic Priority Research Program["31871256","XDB38000000"] ; Chinese Academy of Sciences (CAS)[31961130380]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/348466
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_徐书华组生命科学与技术学院_硕士生
通讯作者	Lou, H.; Xu, S.
作者单位	1.Fudan Univ, Ctr Evolutionary Biol, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci,State Key Lab Genet Engn, Shanghai 200438, Peoples R China 2.Univ Chinese Acad Sci, Chinese Acad Sci, Key Lab Computat Biol, Shanghai Inst Nutr & Hlth, Shanghai 200031, Peoples R China 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Fudan Univ, Human Phenome Inst, Zhangjiang Fudan Int Innovat Ctr, Shanghai 201203, Peoples R China 5.Fudan Univ, Minist Educ Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China 6.Fudan Univ, Zhongshan Hosp, Dept Liver Surg, Shanghai 200032, Peoples R China 7.Fudan Univ, Zhongshan Hosp, Transplantat Liver Canc Inst, Shanghai 200032, Peoples R China 8.Chinese Acad Sci, Ctr Excellence Anim Evolut & Genet, Kunming 650223, Peoples R China
推荐引用方式 GB/T 7714	Lou, H.,Wang, Y.,Xie, B.,et al. Structural evolution of trypsinogen gene redundancy confers risk for pancreas diseases. 2022.