Rapid evolution of genes critical for genome integrity

描述（申请人提供）：将研究灵长类动物DNA双链断裂修复基因的分子进化。这些基因对基因组稳定性很重要，许多癌症综合征都与这些基因的突变有关。有趣的是，这个基因家族的许多成员都具有反复正选择的特征。正在测试的假设是，这些签名是由这些DNA修复基因和灵长类动物进化过程中普遍存在的寄生逆转录病毒和逆转录转座子之间的长期共同进化造成的。这可能影响了灵长类动物DNA修复基因的多态性和固定的遗传变异。在这项拟议的研究中，将为参与人类双链断裂修复的基因生成大型灵长类动物序列数据集，并将测试这些数据集是否具有复发性正选择的特征。然后将使用逆转录病毒感染检测来测试这些DNA修复基因中的适应性序列变化是否导致对感染的易感性改变。这种序列变化对细胞DNA修复的影响也将被探讨。细胞培养模型系统中的初步数据显示，最知名的癌症易感基因之一BRCA1可能在DNA修复保真度和逆转录病毒抗性的双重选择压力下进化。基于此，DNA修复基因进化可能对癌症产生深远的影响，因此，阐明这些基因进化的进化力量非常重要。这项拟议中的研究对于理解遗传寄生虫如何通过它们施加的选择压力来塑造与它们相互作用的人类基因序列这一总体目标至关重要。

DESCRIPTION (provided by applicant): The molecular evolution of primate DNA double-strand break repair genes will be studied. These genes are important for genome stability, and many cancer syndromes have been linked to mutations in these genes. Interestingly, many members of this gene family bear signatures of recurrent positive selection. The hypothesis being tested is that these signatures result from the long-term co-evolution between these DNA repair genes and the pervasive, parasitic retroviruses and retrotransposons with which primates have evolved. This may have influenced primate DNA repair genes with respect to both polymorphic and fixed genetic variation. In this proposed research, large primate sequence datasets will be generated for genes involved in human double-strand break repair, and these will be tested for signatures of recurrent positive selection. Retroviral infection assays will then be used to test whether adaptive sequence change in these DNA repair genes has resulted in altered susceptibility to infection. The consequences of this sequence change to cellular DNA repair will also be explored. Preliminary data in a cell culture model system shows that one of the most well-known cancer susceptibility genes, BRCA1, may be evolving under the dual selective pressures of DNA repair fidelity and retroviral resistance. Based on this, DNA repair gene evolution can have a profound effect on cancer, and for this reason, it is of great importance that the evolutionary forces that define the evolution of these genes be elucidated. This proposed research is central to the overarching goal of understanding how genetic parasites, through the selective pressures that they exert, shape the sequence of human genes with which they interact.