genetic mutation research paper

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• Published: 23 June 2021

The origin of human mutation in light of genomic data

• Vladimir B. Seplyarskiy 1 , 2 &
• Shamil Sunyaev 1 , 2  

Nature Reviews Genetics volume  22 ,  pages 672–686 ( 2021 ) Cite this article

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• DNA damage and repair
• DNA replication
• Statistical methods

An Author Correction to this article was published on 10 August 2021

This article has been updated

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.

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The impact of rare germline variants on human somatic mutation processes

The mutational landscape of human somatic and germline cells

Germline de novo mutation rates on exons versus introns in humans

Data availability.

De novo mutations from trio sequencing studies were obtained from refs 110 , 112 , 135 . The authors used rare polymorphisms from gnomAD v2 ( https://gnomad.broadinstitute.org/downloads ).

Change history

10 august 2021.

A Correction to this paper has been published: https://doi.org/10.1038/s41576-021-00410-3

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Acknowledgements

The authors thank C. Gilissen, F. Supek and the other, anonymous, reviewers for valuable discussions. This work was supported by US National Institutes of Health grants R35GM127131, R01MH101244 and U01HG009088.

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Vladimir B. Seplyarskiy & Shamil Sunyaev

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Correspondence to Shamil Sunyaev .

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Nucleotide substitutions accumulated in the germ line that, thus, could be transmitted to the offspring.

Nucleotide substitutions accumulated during cell divisions of somatic cells in human tissues.

The direction of the replication fork creates a natural asymmetry between the two DNA strands, which provides a very informative statistic, similar to T-asymmetry.

Characterized by DNA helix distortion, DNA damage that is detectable for global genomic nucleotide excision repair. Usually, bulky lesions are a serious obstacle for replication forks and transcription.

Human DNA replication is a complex process involving hundreds of thousands of origins. Despite firing of individual replication origins being stochastic, genomic loci have a tendency to be replicated early or late in S phase.

The direction of transcription creates a natural asymmetry between the two DNA strands. Although it is not always possible to estimate the mutation rate separately on the transcribed and the non-transcribed strands, because fixed mutations affect both strands, it is easy to calculate the imbalance between reverse complementary mutations located on one of the strands. For example, if lesions leading to A>G mutations are depleted on the transcribed strand, then the A>G rate would be higher than the T>C rate on this strand. If the aetiology of the damaging agent and resulting types of mutations are known, one may estimate differences in the mutation rate between the two strands.

DNA–RNA hybrids that are usually formed co-transcriptionally on the transcribed strand. R-loops are important in the context of mutagenesis, because they stabilize non-transcribed strands in the single-stranded state.

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Seplyarskiy, V.B., Sunyaev, S. The origin of human mutation in light of genomic data. Nat Rev Genet 22 , 672–686 (2021). https://doi.org/10.1038/s41576-021-00376-2

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Accepted : 06 May 2021

Published : 23 June 2021

Issue Date : October 2021

DOI : https://doi.org/10.1038/s41576-021-00376-2

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