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The origin of human mutation in light of genomic data

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

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

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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.

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Fig. 1: Sources of point mutations.
Fig. 2: Replication converts DNA damage into mutations.
Fig. 3: Determinants of mutation rate variation on different scales.
Fig. 4: Statistical footprints of mutational processes.
Fig. 5: Some CpG>TpG mutations are of replicative origin.
Fig. 6: Sex-specific mutational patterns.

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Data availability

De novo mutations from trio sequencing studies were obtained from refs110,112,135. The authors used rare polymorphisms from gnomAD v2 (https://gnomad.broadinstitute.org/downloads).

Change history

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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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  1. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Vladimir B. Seplyarskiy & Shamil Sunyaev

  2. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    Vladimir B. Seplyarskiy & Shamil Sunyaev

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  1. Vladimir B. Seplyarskiy
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Correspondence to Shamil Sunyaev.

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Glossary

Germline mutation

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

Somatic mutations

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

R-asymmetry

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.

Bulky lesions

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.

Replication timing

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.

T-asymmetry

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.

R-loops

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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