Evidence for reduced BRCA2 functional activity in Homo sapiens after divergence from the chimpanzee-human last common ancestor

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Memorial Sloan Kettering Statement

BRCA mutations have been implicated in pancreatic cancer, as well as breast and ovarian cancers.  Dr. Iacobuzio-Donahue and her colleagues traced the BRCA2 gene back to the chimpanzee-human last common ancestor in order to follow the evolution of the BRCA mutation in humans.

BRCA2 has remained basically unchanged throughout primate evolution. But because BRCA2 is commonly mutated in humans, MSK’s Dr. Iacobuzio-Donahue and her American Museum of Natural History colleagues asked: If we compare human BRCA to the version we find in our closest evolutionary relatives, namely non-human primates, what can we find out about the cancer-causing details of BRCA2 mutations—that is, exactly where is the mutated gene “misspelled” and, accordingly, what exactly is wrong with the BRCA2 protein?

Thanks to the Robert J and Helen C Kleberg Foundation, Dr. Iacobuzio and colleagues have conducted a tour-de force study of how combining evolutionary theory with cancer genomics can reveal the mechanics of human cancer. And they have located the single “misspelled letter,” known as a single nucleotide polymorphism, in BRCA2 that accounts for a 20 percent reduction in its ability to repair broken DNA strands compared to the non-human primate version. Further, the mutation, which affects just a single amino acid on the BRCA protein, has occurred in one of the most “conserved” (that is, unchanged through evolution) regions in BRCA2.

Perhaps even more intriguing than the study itself is the idea that its methodology applies to diseases other than cancer and has implications for new diagnostics and therapies. Indeed, the study revealed small but significant evolutionary changes in almost 400 human genes compared to those handed down to us through primate evolution. The methodology therefore likely has implications beyond cancer, such as neurodegenerative and cardiovascular diseases.