BRCA1 mutations have been linked to an increased risk of breast and ovarian cancer. Most of the highly penetrant alleles identified encode truncated proteins but missense alleles have also been recorded — their impact on cancer susceptibility is particularly difficult to assess because of low penetrance and the lack of adequate functional assays. In their paper, Fleming et al. describe an evolutionary approach to identify the missense alleles that are most likely to be associated with a disease phenotype.

The rationale behind this study is that mutations in functionally important amino acids are most likely to be associated with an increased risk of cancer. These key amino acids can be identified on the basis of their conservation in mammals, or from evidence of recent positive selection in the human lineage. To find conserved BRCA1 regions, the authors aligned Genbank sequences for exon 11 of BRCA1 from 57 mammals. Considering five amino-acid sites at a time, regions were defined as conserved if the first and last residues were fixed or conservative (that is, identical in all species or all residues sharing similar biochemical properties) and at least 80% of the sites were also fixed or conserved. Seven out of eight conserved regions were located in regions known to interact with other proteins. In addition, a conserved stretch of amino acids was identified in a region of unknown function that is also conserved in BRCA1 homologues from clawed frog and chicken.

If site conservation is a good indicator of its functional importance, one would predict that missense mutations affecting fixed sites, or resulting in non-conservative substitutions at conservative sites, are most likely to be associated with a disease phenotype. In fact, 38 of the 139 documented missense alleles in exon 11 fall into one of these categories. The authors argue that these sites should be the priority for future studies, along with three missense mutations in residues that show signs of recent positive selection in human and primate lineages. Interestingly, these three amino acids lie in the region of BRCA1 that interacts with RAD51—a protein involved in double-stranded break repair.

The authors present a promising approach for prioritizing the study of missense mutations in BRCA1, as well as in other genes associated with heritable diseases. Indeed, the authors show that this method can be used to predict the β-globin amino-acid residues that, when mutated, are associated with various globin pathologies. The true test of this approach, however, will be to determine how many of the 41 missense mutations highlighted by Fleming et al. are associated with an increased risk of breast and ovarian cancer.