Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia
- Author:
Hong YAQIANG
1
,
2
;
Zhang DAKE
;
Zhou XIANGTIAN
;
Chen AILI
;
Abliz AMIR
;
Bai JIAN
;
Wang LIANG
;
Hu QINGTAO
;
Gong KENAN
;
Guan XIAONAN
;
Liu MENGFEI
;
Zheng XINCHANG
;
Lai SHUJUAN
;
Qu HONGZHU
;
Zhao FUXIN
;
Hao SHUANG
;
Wu ZHEN
;
Cai HONG
;
Hu SHAOYAN
;
Ma YUE
;
Zhang JUNTING
;
Ke YANG
;
Wang QIAN-FEI
;
Chen WEI
;
Zeng CHANGQING
Author Information
1. 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
2. Tsinghua-Peking Center for Life Sciences,School of Life Sciences,Tsinghua University,Beijing 100084,China
- Keywords:
Postzygotic mutation;
Mutational signature;
Healthy individual;
Embryonic development;
Hypoxia
- From:
Genomics, Proteomics & Bioinformatics
2022;20(1):177-191
- CountryChina
- Language:Chinese
-
Abstract:
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.
