Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
BMC Evol Biol. 2014 Jul 11;14:155. doi: 10.1186/1471-2148-14-155.
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.
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.
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.
维持染色体完整性是每个生物体的基本任务，细胞修复机制的存在是为了防止 DNA 受到损伤。鉴于这个过程的重要性，人们期望 DNA 修复蛋白在进化上是保守的，随着时间的推移，其序列变化非常小。然而，BRCA1 是参与 DNA 修复的必需基因，尽管该基因内的许多改变蛋白质的突变会显著增加乳腺癌和卵巢癌的风险，但据报道，它的进化速度非常快。
为了更深入地了解 BRCA1 的进化轨迹，我们分析了来自 23 种灵长类动物的完整 BRCA1 基因序列。我们表明，特定的氨基酸位点在灵长类动物进化过程中经历了多次针对氨基酸替换的选择。这种选择特别集中在人类和我们最亲近的亲属——黑猩猩（Pan troglodytes）和倭黑猩猩（Pan paniscus）身上。在对 7 只倭黑猩猩、44 只黑猩猩和 44 只恒河猴（Macaca mulatta）个体的 BRCA1 多态性进行研究后，我们发现每个物种都存在相当大的变异，并在黑猩猩种群中发现了近期选择的证据。最后，我们还对来自 24 种灵长类动物的 BRCA2 进行了测序和分析，发现该基因也受到了正选择的影响。
虽然导致 BRCA1 截断形式的突变显然与人类的癌症表型有关，但该基因中也存在有利于氨基酸改变取代的潜在选择压力。讨论了一种假设，即病毒是这种自然选择的驱动因素。
