Abstract
Mutations are the raw material of evolution but have been difficult to study directly. We report the largest study of new mutations to date, comprising 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58, whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4–2.3 × 10−8 mutations per base pair per generation (90% credible interval) and that human-chimpanzee speciation occurred 3.7–6.6 million years ago.
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References
Roach, J.C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010).
1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Conrad, D.F. et al. Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43, 712–714 (2011).
Crow, J.F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).
Crow, J.F. Age and sex effects on human mutation rates: an old problem with new complexities. J. Radiat. Res. 47 Suppl B, B75–B82 (2006).
Nachman, M.W. & Crowell, S.L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000).
Arnheim, N. & Calabrese, P. Understanding what determines the frequency and pattern of human germline mutations. Nat. Rev. Genet. 10, 478–488 (2009).
Ellegren, H. Microsatellites: simple sequences with complex evolution. Nat. Rev. Genet. 5, 435–445 (2004).
Weber, J.L. & Wong, C. Mutation of human short tandem repeats. Hum. Mol. Genet. 2, 1123–1128 (1993).
Xu, X., Peng, M. & Fang, Z. The direction of microsatellite mutations is dependent upon allele length. Nat. Genet. 24, 396–399 (2000).
Whittaker, J.C. et al. Likelihood-based estimation of microsatellite mutation rates. Genetics 164, 781–787 (2003).
Huang, Q.Y. et al. Mutation patterns at dinucleotide microsatellite loci in humans. Am. J. Hum. Genet. 70, 625–634 (2002).
Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).
Makova, K.D. & Li, W.H. Strong male-driven evolution of DNA sequences in humans and apes. Nature 416, 624–626 (2002).
Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. USA 107, 961–968 (2010).
Slatkin, M. A measure of population subdivision based on microsatellite allele frequencies. Genetics 139, 457–462 (1995).
Goldstein, D.B., Ruiz Linares, A., Cavalli-Sforza, L.L. & Feldman, M.W. An evaluation of genetic distances for use with microsatellite loci. Genetics 139, 463–471 (1995).
Ballantyne, K.N. et al. Mutability of Y-chromosomal microsatellites: rates, characteristics, molecular bases, and forensic implications. Am. J. Hum. Genet. 87, 341–353 (2010).
Cummings, C.J. & Zoghbi, H.Y. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum. Mol. Genet. 9, 909–916 (2000).
Kruglyak, S., Durrett, R.T., Schug, M.D. & Aquadro, C.F. Equilibrium distributions of microsatellite repeat length resulting from a balance between slippage events and point mutations. Proc. Natl. Acad. Sci. USA 95, 10774–10778 (1998).
Zhivotovsky, L.A., Feldman, M.W. & Grishechkin, S.A. Biased mutations and microsatellite variation. Mol. Biol. Evol. 14, 926–933 (1997).
Feldman, M.W., Bergman, A., Pollock, D.D. & Goldstein, D.B. Microsatellite genetic distances with range constraints: analytic description and problems of estimation. Genetics 145, 207–216 (1997).
Sainudiin, R., Durrett, R.T., Aquadro, C.F. & Nielsen, R. Microsatellite mutation models: insights from a comparison of humans and chimpanzees. Genetics 168, 383–395 (2004).
Garza, J.C., Slatkin, M. & Freimer, N.B. Microsatellite allele frequencies in humans and chimpanzees, with implications for constraints on allele size. Mol. Biol. Evol. 12, 594–603 (1995).
Kondrashov, A.S. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12–27 (2003).
Patterson, N., Richter, D.J., Gnerre, S., Lander, E.S. & Reich, D. Genetic evidence for complex speciation of humans and chimpanzees. Nature 441, 1103–1108 (2006).
Steiper, M.E. & Young, N.M. Primate molecular divergence dates. Mol. Phylogenet. Evol. 41, 384–394 (2006).
Green, R.E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).
Burgess, R. & Yang, Z. Estimation of hominoid ancestral population sizes under bayesian coalescent models incorporating mutation rate variation and sequencing errors. Mol. Biol. Evol. 25, 1979–1994 (2008).
McVicker, G., Gordon, D., Davis, C. & Green, P. Widespread genomic signatures of natural selection in hominid evolution. PLoS Genet. 5, e1000471 (2009).
Lebatard, A.E. et al. Cosmogenic nuclide dating of Sahelanthropus tchadensis and Australopithecus bahrelghazali: Mio-Pliocene hominids from Chad. Proc. Natl. Acad. Sci. USA 105, 3226–3231 (2008).
Brunet, M. et al. A new hominid from the Upper Miocene of Chad, Central Africa. Nature 418, 145–151 (2002).
Lieberman, D.E. The Evolution of the Human Head (Belknap Press of Harvard University Press, Cambridge, Massachusetts, 2011).
Wood, B. & Harrison, T. The evolutionary context of the first hominins. Nature 470, 347–352 (2011).
Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
Hinch, A.G. et al. The landscape of recombination in African Americans. Nature 476, 170–175 (2011).
Weber, J.L. & Broman, K.W. Genotyping for human whole-genome scans: past, present, and future. Adv. Genet. 42, 77–96 (2001).
Johansson, A.M. & Sall, T. The effect of pedigree structure on detection of deletions and other null alleles. Eur. J. Hum. Genet. 16, 1225–1234 (2008).
Callen, D.F. et al. Incidence and origin of “null” alleles in the (AC)n microsatellite markers. Am. J. Hum. Genet. 52, 922–927 (1993).
Gudbjartsson, D.F., Thorvaldsson, T., Kong, A., Gunnarsson, G. & Ingolfsdottir, A. Allegro version 2. Nat. Genet. 37, 1015–1016 (2005).
Fenner, J.N. Cross-cultural estimation of the human generation interval for use in genetics-based population divergence studies. Am. J. Phys. Anthropol. 128, 415–423 (2005).
Helgason, A., Hrafnkelsson, B., Gulcher, J.R., Ward, R. & Stefansson, K. A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes. Am. J. Hum. Genet. 72, 1370–1388 (2003).
Marjoram, P., Molitor, J., Plagnol, V. & Tavare, S. Markov chain Monte Carlo without likelihoods. Proc. Natl. Acad. Sci. USA 100, 15324–15328 (2003).
Efron, B. & Gong, G. A leisurely look at the bootstrap, the jackknife, and cross-validation. Am. Stat. 37, 36–48 (1983).
Acknowledgements
We thank D.F. Gudbjartsson for advice on running Allegro 2.0; J. Fenner, J. Hawks, K. Langergraber, D. Pilbeam and L. Vigilant for discussions that informed the Bayesian prior distributions on evolutionary parameters; and Y. Erlich, M. Gymrek, D. Lieberman, B. Payseur, D. Pilbeam, A. Siepel, S. Sunyaev and the anonymous reviewers for critiques. This work was supported by a Bioinformatics and Integrative Genomics PhD training grant (J.X.S.), a Burroughs Wellcome Travel Grant (J.X.S.), a Burroughs Wellcome Career Development Award in the Biomedical Sciences (D.R.), a HUSEC seed grant from Harvard University (D.R.), a SPARC award from the Broad Institute of Harvard and MIT (D.R.), a National Science Foundation HOMINID grant 1032255 (D.R.) and US National Institutes of Health grant R01HG006399 (D.R.).
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J.X.S., A.H., G.M. and D.R. conceived and performed the research. A.H., G.M., A.K., D.R. and K.S. jointly supervised the study, with A.H. acting as the coordinator at deCODE Genetics and D.R. at Harvard Medical School. A.H. and G.M. prepared the raw microsatellite data. J.X.S., A.H. and S.S.E. designed and analyzed the regenotyping, resequencing and electropherogram re-examination experiments; and A.H. analyzed next-generation sequencing data to independently validate mutations. J.X.S., A.H., N.P., A.K. and D.R. designed and analyzed the microsatellite modeling and the statistics. S.M., H.L. and J.X.S. processed and extracted sequence data for the 23 HapMap individuals. S.M., S.G. and D.R. performed the analyses of human-chimpanzee genetic divergence and developed the Bayesian prior distributions relevant to human-chimpanzee speciation. The manuscript was written primarily by J.X.S., A.H. and D.R. The supplementary information was prepared by J.X.S. and D.R.
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The authors at deCODE Genetics (A.H., G.M., S.S.E., A.K. and K.S.) work for a for-profit company carrying out genetic research and thus declare competing financial interests.
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Sun, J., Helgason, A., Masson, G. et al. A direct characterization of human mutation based on microsatellites. Nat Genet 44, 1161–1165 (2012). https://doi.org/10.1038/ng.2398
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DOI: https://doi.org/10.1038/ng.2398
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