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A direct characterization of human mutation based on microsatellites

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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Figure 1: Examples of mutations in a trio and in a family.
Figure 2: Characteristics of the microsatellite mutation process.
Figure 3: Empirical validation of our model with sequence-based estimates of TMRCA.
Figure 4: Human-chimpanzee speciation date inferred without calibration with the fossil record.

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References

  1. Roach, J.C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  3. Conrad, D.F. et al. Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43, 712–714 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Crow, J.F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Nachman, M.W. & Crowell, S.L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Arnheim, N. & Calabrese, P. Understanding what determines the frequency and pattern of human germline mutations. Nat. Rev. Genet. 10, 478–488 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ellegren, H. Microsatellites: simple sequences with complex evolution. Nat. Rev. Genet. 5, 435–445 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Weber, J.L. & Wong, C. Mutation of human short tandem repeats. Hum. Mol. Genet. 2, 1123–1128 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Xu, X., Peng, M. & Fang, Z. The direction of microsatellite mutations is dependent upon allele length. Nat. Genet. 24, 396–399 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Whittaker, J.C. et al. Likelihood-based estimation of microsatellite mutation rates. Genetics 164, 781–787 (2003).

    PubMed  PubMed Central  Google Scholar 

  12. Huang, Q.Y. et al. Mutation patterns at dinucleotide microsatellite loci in humans. Am. J. Hum. Genet. 70, 625–634 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Makova, K.D. & Li, W.H. Strong male-driven evolution of DNA sequences in humans and apes. Nature 416, 624–626 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. USA 107, 961–968 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Slatkin, M. A measure of population subdivision based on microsatellite allele frequencies. Genetics 139, 457–462 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cummings, C.J. & Zoghbi, H.Y. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum. Mol. Genet. 9, 909–916 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhivotovsky, L.A., Feldman, M.W. & Grishechkin, S.A. Biased mutations and microsatellite variation. Mol. Biol. Evol. 14, 926–933 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    CAS  PubMed  Google Scholar 

  25. Kondrashov, A.S. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Google Scholar 

  27. Steiper, M.E. & Young, N.M. Primate molecular divergence dates. Mol. Phylogenet. Evol. 41, 384–394 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Green, R.E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. McVicker, G., Gordon, D., Davis, C. & Green, P. Widespread genomic signatures of natural selection in hominid evolution. PLoS Genet. 5, e1000471 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brunet, M. et al. A new hominid from the Upper Miocene of Chad, Central Africa. Nature 418, 145–151 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Lieberman, D.E. The Evolution of the Human Head (Belknap Press of Harvard University Press, Cambridge, Massachusetts, 2011).

    Google Scholar 

  34. Wood, B. & Harrison, T. The evolutionary context of the first hominins. Nature 470, 347–352 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hinch, A.G. et al. The landscape of recombination in African Americans. Nature 476, 170–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Weber, J.L. & Broman, K.W. Genotyping for human whole-genome scans: past, present, and future. Adv. Genet. 42, 77–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gudbjartsson, D.F., Thorvaldsson, T., Kong, A., Gunnarsson, G. & Ingolfsdottir, A. Allegro version 2. Nat. Genet. 37, 1015–1016 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Marjoram, P., Molitor, J., Plagnol, V. & Tavare, S. Markov chain Monte Carlo without likelihoods. Proc. Natl. Acad. Sci. USA 100, 15324–15328 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Efron, B. & Gong, G. A leisurely look at the bootstrap, the jackknife, and cross-validation. Am. Stat. 37, 36–48 (1983).

    Google Scholar 

Download references

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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Authors

Contributions

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.

Corresponding authors

Correspondence to James X Sun, David Reich or Kari Stefansson.

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Competing interests

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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Supplementary Figures 1–17, Supplementary Tables 1–9 and Supplementary Note (PDF 5215 kb)

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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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