Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes

Vagheesh M. Narasimhan; Raheleh Rahbari; Aylwyn Scally; Arthur Wuster; Dan Mason; Yali Xue; John Wright; Richard C. Trembath; Eamonn R. Maher; David A. Van Heel; Adam Auton; Matthew E. Hurles; Chris Tyler-Smith; Richard Durbin

doi:10.1038/s41467-017-00323-y

Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes

Vagheesh M. Narasimhan^*, Raheleh Rahbari, Aylwyn Scally, Arthur Wuster, Dan Mason, Yali Xue, John Wright, Richard C. Trembath, Eamonn R. Maher, David A. Van Heel, Adam Auton, Matthew E. Hurles, Chris Tyler-Smith, Richard Durbin

^*Corresponding author for this work

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

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Abstract

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10^-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10^-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5′ CCG 3′ to 5′ CTG 3′ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

Original language	English
Article number	303
Journal	Nature Communications
Volume	8
Issue number	1
Early online date	21 Aug 2017
DOIs	https://doi.org/10.1038/s41467-017-00323-y
Publication status	Published - 21 Aug 2017

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Estimating the human mutation_NARASIMHAN_Acc20June2017_Publishedonline21August2017_GOLD VoR (CC BY)Final published version, 652 KBLicence: CC BY

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Narasimhan, V. M., Rahbari, R., Scally, A., Wuster, A., Mason, D., Xue, Y., Wright, J., Trembath, R. C., Maher, E. R., Van Heel, D. A., Auton, A., Hurles, M. E., Tyler-Smith, C., & Durbin, R. (2017). Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes. Nature Communications, 8(1), Article 303. https://doi.org/10.1038/s41467-017-00323-y

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abstract = "Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5′ CCG 3′ to 5′ CTG 3′ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.",

author = "Narasimhan, {Vagheesh M.} and Raheleh Rahbari and Aylwyn Scally and Arthur Wuster and Dan Mason and Yali Xue and John Wright and Trembath, {Richard C.} and Maher, {Eamonn R.} and {Van Heel}, {David A.} and Adam Auton and Hurles, {Matthew E.} and Chris Tyler-Smith and Richard Durbin",

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Narasimhan, VM, Rahbari, R, Scally, A, Wuster, A, Mason, D, Xue, Y, Wright, J, Trembath, RC, Maher, ER, Van Heel, DA, Auton, A, Hurles, ME, Tyler-Smith, C & Durbin, R 2017, 'Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes', Nature Communications, vol. 8, no. 1, 303. https://doi.org/10.1038/s41467-017-00323-y

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AU - Wuster, Arthur

AU - Mason, Dan

AU - Xue, Yali

AU - Wright, John

AU - Trembath, Richard C.

AU - Maher, Eamonn R.

AU - Van Heel, David A.

AU - Auton, Adam

AU - Hurles, Matthew E.

AU - Tyler-Smith, Chris

AU - Durbin, Richard

PY - 2017/8/21

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N2 - Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5′ CCG 3′ to 5′ CTG 3′ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

AB - Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5′ CCG 3′ to 5′ CTG 3′ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

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Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes

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