Postzygotic mutations are acquired in normal tissues throughout an individual's lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals.In blood,sperm,and muscle cells,we resolved three common types of mutational signatures.Signatures A and B represent clock-like mutational processes,and the polymorphisms of epigenetic regulation genes influence the pro-portion of signature B in mutation profiles.Notably,signature C,characterized by C＞T transitions at GpCpN sites,tends to be a feature of diverse normal tissues.Mutations of this type are likely to occur early during embryonic development,supported by their relatively high allelic frequencies,presence in multiple tissues,and decrease in occurrence with age.Almost none of the public datasets for tumors feature this signature,except for 19.6％of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1(HIF-1)signaling pathway.Moreover,the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α.Thus,embryonic hypoxia may explain this novel signature across multiple normal tissues.Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C＞T transitions at GpCpN sites;and indi-viduals'genetic background may also influence their postzygotic mutation profiles.

Yaqiang Hong;Dake Zhang;Xiangtian Zhou;Aili Chen;Amir Abliz;Jian Bai;Liang Wang;Qingtao Hu;Kenan Gong;Xiaonan Guan;Mengfei Liu;Xinchang Zheng;Shujuan Lai;Hongzhu Qu;Fuxin Zhao;Shuang Hao;Zhen Wu;Hong Cai;Shaoyan Hu;Yue Ma;Junting Zhang;Yang Ke;Qian-Fei Wang;Wei Chen;Changqing Zeng

CAS Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences and China National Center for Bioinformation,Beijing 100101,China;Tsinghua-Peking Center for Life Sciences,School of Life Sciences,Tsinghua University,Beijing 100084,China;Beijing Advanced Innovation Centre for Biomedical Engineering,Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education,School of Biological Science and Medical Engineering,Beihang University,Beijing 100191,China;School of Optometry and Ophthalmology and Eye Hospital,Wenzhou Medical University,Wenzhou 325035,China;The State Key Laboratory of Optometry,Ophthalmology and Vision Science,Wenzhou 325035,China;Key Laboratory of Carcinogenesis and Translational Research(MOE),Laboratory of Genetics,Peking University Cancer Hospital&Institute,Beijing 100142,China;Skull Base and Brainstem Tumor Division,Department of Neurosurgery,Beijing Tian Tan Hospital,Capital Medical University,Beijing 100050,China;China National Clinical Research Center for Neurological Diseases,Beijing 100050,China;University of Chinese Academy of Sciences,Beijing 100049,China;CAS Key Laboratory of Genome Sciences and Information,Beijing Institute of Genomics,Chinese Academy of Sciences and China National Center for Bioinformation,Beijing 100101,China;o Department of Hematology and Oncology,Children s Hospital of Soochow University,Suzhou 215025,China;Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;Collaborative Innovation Center for Genetics and Development,Shanghai 200438,China

基因组蛋白质组与生物信息学报（英文版）

[1]Yaqiang Hong;Dake Zhang;Xiangtian Zhou;Aili Chen;Amir Abliz;Jian Bai;Liang Wang;Qingtao Hu;Kenan Gong;Xiaonan Guan;Mengfei Liu;Xinchang Zheng;Shujuan Lai;Hongzhu Qu;Fuxin Zhao;Shuang Hao;Zhen Wu;Hong Cai;Shaoyan Hu;Yue Ma;Junting Zhang;Yang Ke;Qian-Fei Wang;Wei Chen;Changqing Zeng-.Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia)[J].基因组蛋白质组与生物信息学报（英文版）,2022(01):177-191

Postzygotic,GpCpN

Common,Mutational,Signatures,Healthy,Adult,Tissues,Related,Embryonic,Hypoxia,mutations,are,acquired,normal,tissues,throughout,lifetime,hold,clues,identifying,mutagenic,factors,Here,investigated,postzygotic,spectra,healthy,individuals,using,optimized,ultra,deep,exome,sequencing,series,samples,from,same,volunteer,well,different,In,blood,sperm,muscle,cells,resolved,three,common,types,mutational,signatures,represent,clock,processes,polymorphisms,epigenetic,regulation,genes,influence,portion,profiles,Notably,characterized,by,transitions,sites,tends,be,feature,diverse,Mutations,this,likely,early,during,embryonic,development,supported,their,relatively,high,allelic,frequencies,presence,multiple,decrease,occurrence,Almost,none,public,datasets,tumors,except,clear,renal,carcinoma,increased,activation,hypoxia,inducible,HIF,signaling,pathway,Moreover,accumulation,was,accelerated,human,stem,line,drug,induced,Thus,may,explain,novel,across,Our,study,suggests,that,hypoxic,condition,stage,crucial,inducing,background,also

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