Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia
| Autor: | Changqing Zeng, Amir Abliz, Yaqiang Hong, Xinchang Zheng, Zhen Wu, Xiaonan Guan, Qianfei Wang, Mengfei Liu, Qingtao Hu, Aili Chen, Fuxin Zhao, Jian Bai, Shaoyan Hu, Hong Cai, Wei Chen, Junting Zhang, Xiangtian Zhou, Dake Zhang, Yang Ke, Kenan Gong, Yue Ma, Hongzhu Qu, Liang Wang, Shujuan Lai, Shuang Hao |
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| Rok vydání: | 2022 |
| Předmět: |
Adult
Male Genetics Mutation Postzygotic mutation Biology medicine.disease_cause Biochemistry Embryonic stem cell Epigenesis Genetic Computational Mathematics Semen medicine Humans Hypoxia-Inducible Factor 1 Epigenetics Allele Hypoxia Molecular Biology Gene Exome sequencing Human embryonic stem cell line |
| Zdroj: | Genomics, Proteomics & Bioinformatics. 20:177-191 |
| ISSN: | 1672-0229 |
| Popis: | 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 proportion of signature B in mutation profiles. Notably, signature C, characterized by CT 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 CT transitions at GpCpN sites; and individuals' genetic background may also influence their postzygotic mutation profiles. |
| Databáze: | OpenAIRE |
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