Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees

Mutations in BRCA1 (ref. 1) confer an increased risk of female breast cancer. 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.

[1]  G. Giles,et al.  Estrogen receptor polymorphism at codon 325 and risk of breast cancer in women before age forty. , 1998, Journal of the National Cancer Institute.

[2]  D. Clayton,et al.  Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. , 1997, Human molecular genetics.

[3]  Paolo Menozzi,et al.  The History and Geography of Human Genes. Princeton, NJ (Princeton University Press) 1994. , 1994 .

[4]  I. Verma,et al.  Transcriptional activation by BRCA1 , 1996, Nature.

[5]  A. Clark,et al.  Evolutionary biology: Protamine wars , 2000, Nature.

[6]  D. F. Roberts,et al.  The History and Geography of Human Genes , 1996 .

[7]  Yonghong Xiao,et al.  Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells , 1997, Cell.

[8]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[9]  S. Muse,et al.  A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. , 1994, Molecular biology and evolution.

[10]  M. Nei,et al.  Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection , 1988, Nature.

[11]  F. Couch,et al.  Localization of BRCA1 and a splice variant identifies the nuclear localization signal , 1997, Molecular and cellular biology.

[12]  R. Lewontin,et al.  THE GOODNESS–OF–FIT TEST FOR DETECTING NATURAL SELECTION IN RANDOM MATING POPULATIONS , 1959 .

[13]  J. A. Mckenzie,et al.  Asymmetry--where evolutionary and developmental genetics meet. , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.

[14]  B. Koller,et al.  BRCA1 required for transcription-coupled repair of oxidative DNA damage. , 1998, Science.

[15]  J Chang-Claude,et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. , 1998, American journal of human genetics.

[16]  G. Giles,et al.  BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer , 1999, British Journal of Cancer.

[17]  Z. Hall.  Cancer , 1906, The Hospital.

[18]  P. Boyle,et al.  Background, rationale and protocol for a case-control-family study of breast cancer , 1994 .

[19]  Z. Yang,et al.  Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. , 1998, Molecular biology and evolution.

[20]  T. Jukes,et al.  The neutral theory of molecular evolution. , 2000, Genetics.

[21]  Y. Houvras,et al.  Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiPl , 1997, Nature.

[22]  F. Couch,et al.  Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. , 1998, Molecular cell.

[23]  M. Carrington,et al.  A scan for linkage disequilibrium across the human genome. , 1999, Genetics.

[24]  B. Koller,et al.  Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities , 1996, Nature Genetics.

[25]  W. Swanson,et al.  Concerted evolution in an egg receptor for a rapidly evolving abalone sperm protein. , 1998, Science.

[26]  F. Couch,et al.  Localization of BRCA 1 and a Splice Variant Identifies the Nuclear Localization Signal , 1996 .

[27]  C. Groves,et al.  Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence. , 1998, Molecular phylogenetics and evolution.

[28]  W. Messier,et al.  Episodic adaptive evolution of primate lysozymes , 1997, Nature.

[29]  Gerald J. Wyckoff,et al.  Rapid evolution of male reproductive genes in the descent of man , 2000, Nature.

[30]  S. P. Fodor,et al.  Evolutionary sequence comparisons using high-density oligonucleotide arrays , 1998, Nature Genetics.

[31]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[32]  L. Hood,et al.  Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. , 1996, Genome research.

[33]  Hiroshi Akashi,et al.  Molecular Evidence for Natural Selection , 1995 .

[34]  M. Kimura.  The Neutral Theory of Molecular Evolution: Introduction , 1983 .

[35]  M. Skolnick,et al.  Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. , 1996, Human molecular genetics.