Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees

Abstract

Mutations in BRCA1 (ref. 1) confer an increased risk of female breast cancer2. In a genome-wide scan of linkage disequilibrium (LD), a high level of LD was detected among microsatellite markers flanking BRCA1 (ref. 3), raising the prospect that positive natural selection may have acted on this gene. We have used the predictions of evolutionary genetic theory to investigate this further. Using phylogeny-based maximum likelihood analysis of the BRCA1 sequences from primates and other mammals, we found that the ratios of replacement to silent nucleotide substitutions on the human and chimpanzee lineages were not different from one another (P=0.8), were different from those of other primate lineages (P=0.004) and were greater than 1 (P=0.04). This is consistent with the historic occurrence of positive darwinian selection pressure on the BRCA1 protein in the human and chimpanzee lineages. Analysis of genetic variation in a sample of female Australians of Northern European origin showed evidence for Hardy-Weinberg (HW) disequilibrium at polymorphic sites in BRCA1, consistent with the possibility that natural selection is affecting genotype frequencies in modern Europeans. The clustering of between-species variation in the region of the gene encoding the RAD51-interaction domain of BRCA1 suggests the maintenance of genomic integrity as a possible target of selection.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of variation along BRCA1.
Figure 2: Ratios of replacement to silent substitution (ω) estimated for the indicated branches of the primate phylogeny.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Ford, D. et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am. J. Hum. Genet. 62, 676–689 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huttley, G.A., Smith, M.W., Carrington, M. & O'Brien, S.J. A scan for linkage disequilibrium across the human genome. Genetics 152, 1711–1722 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Gowen, L.C., Avrutskaya, A.V., Latour, A.M., Koller, B.H. & Leadon, S.A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281, 1009–1012 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Somasundaram, K. et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389, 187–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Chen, J. et al. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol. Cell 2, 317–328 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Gowen, L.C., Johnson, B.L., Latour, A.M., Sulik, K.K. & Koller, B.H. BRCA1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nature Genet. 12, 191–194 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Thakur, S. et al. Localization of BRCA1 and a splice variant identifies the nuclear localization signal. Mol. Cell. Biol. 17, 444–452 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chapman, M.S. & Verma, I.M. Transcriptional activation by BRCA1. Nature 382, 678–679 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Scully, R. et al. Association of BRCA1 with RAD51 in mitotic and meiotic cells. Cell 88, 265–275 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Hacia, J.G. et al. Evolutionary sequence comparisons using high-density oligonucleotide arrays. Nature Genet. 18, 155–158 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Kreitman, M. & Akashi, H. Molecular evidence for natural selection. Annu. Rev. Ecol. Syst. 26, 403–422 (1995).

    Article  Google Scholar 

  13. Durocher, F. et al. Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum. Mol. Genet. 5, 835–842 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Dunning, A.M. et al. Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum. Mol. Genet. 6, 285–289 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Southey, M.C. et al. BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer. Br. J. Cancer 79, 34–39 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Messier, W. & Stewart, C.B. Episodic adaptive evolution of primate lysozymes. Nature 385, 151–154 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Yang, Z. Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol. Biol. Evol. 15, 568–573 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Swanson, W.J. & Vacquier, V.D. Concerted evolution in an egg receptor for a rapidly evolving abalone sperm protein. Science 281, 710–712 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Hughes, A.L. & Nei, M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335, 167–170 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Wyckoff, G.J., Wang, W. & Wu, C.I. Rapid evolution of male reproductive genes in the descent of man. Nature 403, 304–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Clark, A.G. & Civetta, A. Protamine wars. Nature 403, 261–263 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Cavalli-Sforza, L.L., Menozzi, P. & Piazza, A. The History and Geography of Human Genes 268 (Princeton University Press, Princeton, New Jersey, 1994).

    Google Scholar 

  23. Lewontin, R.C. & Cockerham, C.C. The goodness-of-fit test for detecting natural selection in random mating populations. Evolution 13, 561–564 (1959).

    Article  Google Scholar 

  24. Batterham, P., Davies, A.G., Game, A.Y. & McKenzie, J.A. Asymmetry—where evolutionary and developmental genetics meet. Bioessays 18, 841–845 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Hopper, J.L., Giles, G.G., McCredie, M.R.E. & Boyle, P. Background, rationale and protocol for case-control-family study of breast cancer. Breast 3, 79–86 (1994).

    Article  Google Scholar 

  26. McCredie, M.R.E., Dite, G., Giles, G.G. & Hopper, J.L. Breast cancer in Australian women under 40. Cancer Causes Control 9, 189–198 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Southey, M.C. et al. Estrogen receptor polymorphism at codon 325 and risk of breast cancer in women before age forty. J. Natl Cancer Inst. 90, 532–536 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Goodman, M. et al. Toward a phylogenetic classification of primates based on DNA evidence complemented by fossil evidence. Mol. Phylogenet. Evol. 9, 585–598 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Muse, S.V. & Gaut, B.S. A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. Mol. Biol. Evol. 11, 715–724 (1994).

    CAS  PubMed  Google Scholar 

  30. Li, W.H. Molecular Evolution (Sinauer Associates, Sunderland, Massachusetts, 1997).

    Google Scholar 

  31. Excoffier, L. & Slatkin, M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol. Biol. Evol. 12, 921–927 (1995).

    CAS  PubMed  Google Scholar 

  32. Smith, T.M. et al. Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. Genome Res. 6, 1029–1049 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983).

    Book  Google Scholar 

Download references

Acknowledgements

We thank Y. Zhang and B. Whittle for technical assistance; P. Board and C. Goodnow for comments on an early version of this manuscript; D. Easton and D. Goldgar for comments regarding previous studies; and the other researchers in the Australian Breast Cancer Family Study who contributed to this work, C. Andersen, K. Jennings, S. Brown, L. Porter, G. Dite and J. Maskiell.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gavin A. Huttley.

Additional information

the Australian Breast Cancer Family Study

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huttley, G., Easteal, S., Southey, M. et al. Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees. Nat Genet 25, 410–413 (2000). https://doi.org/10.1038/78092

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/78092

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing