The Origin of Human Mutation in Light of Genomic Data

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2021 Jun 24

PMID 34163020

Citations 27

Authors

Vladimir B Seplyarskiy

Shamil Sunyaev

Affiliations

Soon will be listed here.

Abstract

Despite years of active research into the role of DNA repair and replication in mutagenesis, surprisingly little is known about the origin of spontaneous human mutation in the germ line. With the advent of high-throughput sequencing, genome-scale data have revealed statistical properties of mutagenesis in humans. These properties include variation of the mutation rate and spectrum along the genome at different scales in relation to epigenomic features and dependency on parental age. Moreover, mutations originated in mothers are less frequent than mutations originated in fathers and have a distinct genomic distribution. Statistical analyses that interpret these patterns in the context of known biochemistry can provide mechanistic models of mutagenesis in humans.

Citing Articles

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References

Yang Z . PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol. 2007; 24(8):1586-91. DOI: 10.1093/molbev/msm088. View

Kosmicki J, Samocha K, Howrigan D, Sanders S, Slowikowski K, Lek M . Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017; 49(4):504-510. PMC: 5496244. DOI: 10.1038/ng.3789. View

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

Hoang M, Chen C, Sidorenko V, He J, Dickman K, Yun B . Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci Transl Med. 2013; 5(197):197ra102. PMC: 3973132. DOI: 10.1126/scitranslmed.3006200. View

Poon S, Pang S, McPherson J, Yu W, Huang K, Guan P . Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med. 2013; 5(197):197ra101. DOI: 10.1126/scitranslmed.3006086. View

Huang M, Yu W, Teoh W, Ardin M, Jusakul A, Ng A . Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors. Genome Res. 2017; 27(9):1475-1486. PMC: 5580708. DOI: 10.1101/gr.220038.116. View

Liu J, Konstantinopoulos P, Matulonis U . PARP inhibitors in ovarian cancer: current status and future promise. Gynecol Oncol. 2014; 133(2):362-9. DOI: 10.1016/j.ygyno.2014.02.039. View

Polak P, Kim J, Braunstein L, Karlic R, Haradhavala N, Tiao G . A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet. 2017; 49(10):1476-1486. PMC: 7376751. DOI: 10.1038/ng.3934. View

Kurat C, Yeeles J, Patel H, Early A, Diffley J . Chromatin Controls DNA Replication Origin Selection, Lagging-Strand Synthesis, and Replication Fork Rates. Mol Cell. 2016; 65(1):117-130. PMC: 5222724. DOI: 10.1016/j.molcel.2016.11.016. View

10.

Devbhandari S, Jiang J, Kumar C, Whitehouse I, Remus D . Chromatin Constrains the Initiation and Elongation of DNA Replication. Mol Cell. 2016; 65(1):131-141. PMC: 5256687. DOI: 10.1016/j.molcel.2016.10.035. View

11.

Adar S, Hu J, Lieb J, Sancar A . Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis. Proc Natl Acad Sci U S A. 2016; 113(15):E2124-33. PMC: 4839430. DOI: 10.1073/pnas.1603388113. View

12.

Mao P, Brown A, Esaki S, Lockwood S, Poon G, Smerdon M . ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma. Nat Commun. 2018; 9(1):2626. PMC: 6035183. DOI: 10.1038/s41467-018-05064-0. View

13.

Petljak M, Alexandrov L, Brammeld J, Price S, Wedge D, Grossmann S . Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis. Cell. 2019; 176(6):1282-1294.e20. PMC: 6424819. DOI: 10.1016/j.cell.2019.02.012. View

14.

Zou X, Owusu M, Harris R, Jackson S, Loizou J, Nik-Zainal S . Validating the concept of mutational signatures with isogenic cell models. Nat Commun. 2018; 9(1):1744. PMC: 5931590. DOI: 10.1038/s41467-018-04052-8. View

15.

Volkova N, Meier B, Gonzalez-Huici V, Bertolini S, Gonzalez S, Vohringer H . Mutational signatures are jointly shaped by DNA damage and repair. Nat Commun. 2020; 11(1):2169. PMC: 7195458. DOI: 10.1038/s41467-020-15912-7. View

16.

Kucab J, Zou X, Morganella S, Joel M, Nanda A, Nagy E . A Compendium of Mutational Signatures of Environmental Agents. Cell. 2019; 177(4):821-836.e16. PMC: 6506336. DOI: 10.1016/j.cell.2019.03.001. View

17.

Segovia R, Shen Y, Lujan S, Jones S, Stirling P . Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast. Proc Natl Acad Sci U S A. 2017; 114(10):2663-2668. PMC: 5347559. DOI: 10.1073/pnas.1618555114. View

18.

Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S . Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015; 348(6237):880-6. PMC: 4471149. DOI: 10.1126/science.aaa6806. View

19.

Yokoyama A, Kakiuchi N, Yoshizato T, Nannya Y, Suzuki H, Takeuchi Y . Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature. 2019; 565(7739):312-317. DOI: 10.1038/s41586-018-0811-x. View

20.

Moore L, Leongamornlert D, Coorens T, Sanders M, Ellis P, Dentro S . The mutational landscape of normal human endometrial epithelium. Nature. 2020; 580(7805):640-646. DOI: 10.1038/s41586-020-2214-z. View