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Unexpectedly similar rates of nucleotide substitution found in male and female hominids

Nature volume 406, pages 622–625 (2000)Cite this article

Abstract

In 1947, it was suggested that, in humans, the mutation rate is dramatically higher in the male germ line than in the female germ line1. This hypothesis has been supported by the observation that, among primates, Y-linked genes evolved more rapidly than homologous X-linked genes2,3,4,5,6. Based on these evolutionary studies, the ratio (αm) of male to female mutation rates in primates was estimated to be about 5. However, selection could have skewed sequence evolution in introns and exons7,8,9,10. In addition, some of the X–Y gene pairs studied lie within chromosomal regions with substantially divergent nucleotide sequences7,11,12. Here we directly compare human X and Y sequences within a large region with no known genes. Here the two chromosomes are 99% identical, and X–Y divergence began only three or four million years ago, during hominid evolution13,14,15. In apes, homologous sequences exist only on the X chromosome. We sequenced and compared 38.6 kb of this region from human X, human Y, chimpanzee X and gorilla X chromosomes. We calculated αm to be 1.7 (95% confidence interval 1.15–2.87), significantly lower than previous estimates in primates. We infer that, in humans and their immediate ancestors, male and female mutation rates were far more similar than previously supposed.

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Figure 1: Phylogenetic tree of nucleotide sequences.

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References

  1. Haldane, J. B. S. The mutation rate of the gene for haemophilia, and its segregation ratios in males and females. Ann. Eugen. 13, 262 –271 (1947).

    Article  MathSciNet  CAS  Google Scholar 

  2. Miyata, T., Hayashida, H., Kuma, K., Mitsuyasu, K. & Yasunaga, T. Male-driven molecular evolution: A model and nucleotide sequence analysis. Cold Spring Harbor Symp. Quant. Biol. 52, 863–867 (1987).

    Article  CAS  Google Scholar 

  3. Shimmin, L. C., Chang, B. H. -J. & Li, W. -H. Male-driven evolution of DNA sequences. Nature 362, 745–747 ( 1993).

    Article  ADS  CAS  Google Scholar 

  4. Shimmin, L. C., Chang, B. H. -J. & Li, W. -H. Contrasting rates of nucleotide substitution in the X-linked and Y-linked zinc finger genes. J. Mol. Evol. 39, 569–578 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Chang, B. H.-J., Hewett-Emmett, D. & Li, W.-H. Male-to-female ratios of mutation rate in higher primates estimated from intron sequences. Zool. Stud. 35, 36–48 (1996).

    CAS  Google Scholar 

  6. Huang, W., Chang, B. H.-J., Gu, X., Hewett-Emmett, D. & Li, W.-H. Sex differences in mutation rate in higher primates estimated from AMG intron sequences. J. Mol. Evol. 44, 463–465 (1997).

    Article  ADS  CAS  Google Scholar 

  7. Shimmin, L. C., Chang, B. H.-J., Hewett-Emmett, D. & Li, W.-H. Potential problems in estimating the male-to-female mutation rate ratio from DNA sequence data. J. Mol. Evol. 37, 160 –166 (1993).

    Article  ADS  CAS  Google Scholar 

  8. Charlesworth, B. The effect of background selection against deleterious alleles on weakly selected, linked variants. Genet. Res. 63, 213– 227 (1994).

    Article  CAS  Google Scholar 

  9. Li, W.-H. Molecular Evolution (Sinauer, Sunderland, 1997).

    Google Scholar 

  10. McVean, G. T. & Hurst, L. D. Evidence for a selectively favourable reduction in the mutation rate of the X chromosome. Nature 386, 388–392 (1997).

    Article  ADS  CAS  Google Scholar 

  11. Bulmer, M. Neighboring base effects on substitution rates in pseudogenes. Mol. Biol. Evol. 3, 322–329 (1986).

    CAS  PubMed  Google Scholar 

  12. Wolfe, K. H., Sharp, P. M. & Li, W.-H. Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989).

    Article  ADS  CAS  Google Scholar 

  13. Page, D. C., Harper, M. E., Love, J. & Botstein, D. Occurrence of a transposition from the X-chromosome long arm to the Y-chromosome short arm during human evolution. Nature 311, 119– 123 (1984).

    Article  ADS  CAS  Google Scholar 

  14. Mumm, S., Molini, B., Terrell, J., Srivastava, A. & Schlessinger, D. Evolutionary features of the 4-Mb Xq21. 3 XY homology region revealed by a map at 60-kb resolution. Genome Res. 7, 307–314 (1997).

    Article  CAS  Google Scholar 

  15. Schwartz, A. et al. Reconstructing hominid Y evolution: X-homologous block, created by X-Y transposition, was disrupted by Yp inversion through LINE-LINE recombination. Hum. Mol. Genet. 7, 1– 11 (1998).

    Article  MathSciNet  CAS  Google Scholar 

  16. Tajima, F. & Nei, M. Estimation of evolutionary distance between nucleotide sequences. Mol. Biol. Evol. 1, 269–285 (1984).

    CAS  PubMed  Google Scholar 

  17. Kaessmann, H., Heissig, F., von Haeseler, A. & Paabo, S. DNA sequence variation in a non-coding region of low recombination on the human X chromosome. Nature Genet. 22, 78 –81 (1999).

    Article  CAS  Google Scholar 

  18. Kaessmann, H., Wiebe, V. & Paabo, S. Extensive nuclear DNA sequence diversity among chimpanzees. Science 286, 1159–1162 (1999).

    Article  CAS  Google Scholar 

  19. Ellegren, H. & Fridolfsson, A. K. Male-driven evolution of DNA sequences in birds. Nature Genet. 17, 182–184 (1997).

    Article  CAS  Google Scholar 

  20. Vogel, F. & Motulsky, A. G. Human Genetics (Springer, Berlin, 1997).

    Book  Google Scholar 

  21. Crow, J. The high spontaneous mutation rate: Is it a health risk? Proc. Natl Acad. Sci. USA 94, 8380–8386 (1997).

    Article  ADS  CAS  Google Scholar 

  22. Wilkin, D. J. et al. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am. J. Hum. Genet. 63, 711– 716 (1998).

    Article  ADS  CAS  Google Scholar 

  23. Shizuya, H. B. et al. Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector. Proc. Natl Acad. Sci. USA 89, 8794– 8797 (1992).

    Article  ADS  CAS  Google Scholar 

  24. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

    Article  CAS  Google Scholar 

  25. Uberbacher, E. C. & Mural, R. J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl Acad. Sci. USA 88, 11261– 11265 (1991).

    Article  ADS  CAS  Google Scholar 

  26. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  27. Rozen, S. & Skaletsky, H. in Bioinformatics Methods and Protocols (eds Misener, S. & Krawetz, S. A.) (Humana, Totowa, 1999).

    Google Scholar 

  28. Agresti, A. Categorical Data Analysis (Wiley, New York, 1990).

    MATH  Google Scholar 

  29. Li, W. -H. A statistical test of phylogenies estimated from sequence data. Mol. Biol. Evol. 6, 424–435 (1989).

    CAS  PubMed  Google Scholar 

  30. Bishop, Y. V. V., Feinberg, S. E. & Holland, P. W. Discrete Multivariate Analysis (MIT Press, Cambridge, Massachusetts, 1975).

    Google Scholar 

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Acknowledgements

We thank A. Schwartz for identifying homologous X and Y-chromosomal BACs, colleagues at the Whitehead Institute/MIT Centre for Genome Research for sequencing those BACs, and J. Bradley, A. Chakravarti, B. Charlesworth, A. Clark, D. Haig, T. Kawaguchi, L. Kruglyak, F. Lewitter, Y.-F. Lim, D. Reich, W. Rice, S. Rozen, C. Tilford and J. Wang for comments on the manuscript. Supported in part by the NIH.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Whitehead Institute,

    Hacho B. Bohossian, Helen Skaletsky & David C. Page

  2. Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Hacho B. Bohossian, Helen Skaletsky & David C. Page

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  1. Hacho B. Bohossian
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Correspondence to David C. Page.

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Bohossian, H., Skaletsky, H. & Page, D. Unexpectedly similar rates of nucleotide substitution found in male and female hominids. Nature 406, 622–625 (2000). https://doi.org/10.1038/35020557

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