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.

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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.

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References

  1. 1

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

  2. 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).

  3. 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).

  4. 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).

  5. 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).

  6. 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).

  7. 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).

  8. 8

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

  9. 9

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

  10. 10

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

  11. 11

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

  12. 12

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

  13. 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).

  14. 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).

  15. 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).

  16. 16

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

  17. 17

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

  18. 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).

  19. 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).

  20. 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).

  21. 21

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

  22. 22

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

  23. 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).

  24. 24

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

  25. 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).

  26. 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).

  27. 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).

  28. 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).

  29. 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).

  30. 30

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

  31. 31

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

  32. 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).

  33. 33

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

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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.

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Correspondence to Gavin A. Huttley.

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the Australian Breast Cancer Family Study

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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

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