Variation in the mutation rate across mammalian genomes

Key Points

  • The germline mutation rate varies across the mammalian genome at several scales: between adjacent nucleotides; over hundreds of nucleotides; over hundreds of thousands to millions of nucleotides; and between whole chromosomes.

  • The strongest patterns are observed at the smallest scales.

  • Variation between adjacent nucleotides can either be dependent or independent of context.

  • Large-scale variation in the mutation rate is underestimated by between-species comparisons.

  • Variation between chromosomes is most conspicuous for the sex chromosomes.

  • There is variation in the somatic mutation rate across the genome. The variation has similarities and differences to that observed in the germline.

Abstract

It has been known for many years that the mutation rate varies across the genome. However, only with the advent of large genomic data sets is the full extent of this variation becoming apparent. The mutation rate varies over many different scales, from adjacent sites to whole chromosomes, with the strongest variation seen at the smallest scales. Some of these patterns have clear mechanistic bases, but much of the rate variation remains unexplained, and some of it is deeply perplexing. Variation in the mutation rate has important implications in evolutionary biology and underexplored implications for our understanding of hereditary disease and cancer.

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Figure 1: Variation between adjacent sites.
Figure 2: The effect of transcription.
Figure 3: The effect of indels on the rate of point mutations.
Figure 4: Variation in the mutation rate at the 1 Mb scale.
Figure 5: Variation between chromosomes.

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Acknowledgements

The authors are grateful to Y. Chen for help in compiling the data in figure 4 and to L. Hurst, C. Pink, N. Stoletzki and the four anonymous referees for comments on the manuscript.

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Glossary

Pseudogenes

Copies of a gene that are no longer functional, usually because of deactivating mutations, such as premature stop codons.

Transition

A mutation that converts a pyrimidine into another pyrimidine (that is, C↔T) or a purine into another purine (that is, A↔G).

Transversions

Mutations that convert a pyrimidine into a purine or vice versa (for example, C→G or C→A).

Coincident SNPs

(cSNPs). Orthologous sites that contain a SNP in two species.

Coincident single nucleotide substitutions

(cSNSs). Orthologous sites that have substitutions in two independent pairs of species.

Site frequency spectra

The distributions of allele frequencies within a sample of sequences.

DNase I hypersensitive sites

Sites that are digested by the endonuclease DNase I, which preferentially attacks exposed DNA, such as in open chromatin.

Synonymous sites

Sites at which some or all of the mutations do not change the amino acid. The rate of substitution at synonymous sites refers only to the rate of synonymous substitution at such sites.

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Hodgkinson, A., Eyre-Walker, A. Variation in the mutation rate across mammalian genomes. Nat Rev Genet 12, 756–766 (2011). https://doi.org/10.1038/nrg3098

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