The maintenance of genomic integrity is an essential task of every living organism and several repair mechanisms exist to guard against insults to DNA. Therefore, it is expected that DNA repair proteins are evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, a sentinel for genome maintenance, has been evolving very rapidly during primate evolution. This evolutionary phenomenon has been focused specifically on humans and our closest living relatives, chimpanzees and bonobos. In addition, specific amino acid sites have experienced incredibly dynamic change over the last 33 million years of primate evolution. However, the selective pressures that are driving evolutionary change at this locus have yet to be described. Interestingly, the second most common cancer-causing mutation in BRCA1 conveys significant resistance to retroviral infection. This indicates that at least some cancer-linked mutations in BRCA1 may protect against retroviral infection but disrupt normal BRCA1 function, manifesting as cancer later in life. Therefore, the evolution of BRCA1 may have been shaped by retroviruses and at least some cancer-causing mutations in BRCA1 may reflect an ongoing genetic conflict with these pathogens. The goal of this proposal is to uncover the selective pressures that have driven the rapid evolutionary changes seen in BRCA1.
The specific aims of this research proposal are to: (1) Determine if viruses have exerted an evolutionary pressure for BRCA1 sequence innovation. Several evolutionary BRCA1 forms and the most common human variants will be tested for susceptibility to retroviral infection. (2) Determine the consequences of BRCA1 sequence variation on DNA repair activities. BRCA1 variants that under positive selection, regardless of the driving force behind it may have impaired functions that could potentially lead to cancer later in life. (3) Determine whether genes encoding proteins known to interact with BRCA1 are also evolving rapidly. It is important to delineate the breadth of this unusual evolutionary phenomenon in BRCA1 pathways because mutations in several BRCA1 interacting proteins can lead to cancer formation. Uncovering the selective pressures that have shaped BRCA1 evolution may help us define the etiology of hereditary breast and ovarian cancers. This will also help us understand why "cancer-linked" BRCA1 polymorphisms are maintained in the human population and may uncover previously unidentified roles for this multi-functional protein. !
Evolutionary analysis of medically-important genes that cause inherited diseases, such as breast and/or ovarian cancers, can provide an explanation as to why devastating genetic diseases plague the human population. Understanding why these genes have evolved to their current state may lead to innovative approaches in eradicating illnesses that are generally thought to be incurable.
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