1. Rapid evolution of BRCA1 and BRCA2 in humans and other primates
- Author
-
Anne C. Stone, Ross M. McBee, Gregory K. Wilkerson, Sara L. Sawyer, Ann Demogines, Uyen Q Le, and Dianne I. Lou
- Subjects
Models, Molecular ,Primates ,DNA Repair ,DNA repair ,Simian primates ,Genes, BRCA2 ,Molecular Sequence Data ,Genes, BRCA1 ,Breast Neoplasms ,Cell cycle ,DNA damage response ,medicine.disease_cause ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Selection, Genetic ,Gene ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,BRCA2 Protein ,Ovarian Neoplasms ,Genetics ,0303 health sciences ,Mutation ,Polymorphism, Genetic ,Natural selection ,biology ,BRCA1 Protein ,Bonobo ,Exons ,biology.organism_classification ,Positive selection ,Pan paniscus ,Rhesus macaque ,Essential gene ,Evolutionary biology ,030220 oncology & carcinogenesis ,Female ,Sequence Alignment ,Research Article - Abstract
Background The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers. Results To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection. Conclusions While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.
- Full Text
- View/download PDF