Rapid evolution of genes critical for genome integrity

描述（申请人提供）：研究灵长类动物DNA双链断裂修复基因的分子进化。这些基因对基因组的稳定性很重要，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的正选择的特征。正在测试的假设是，这些特征是这些DNA修复基因与普遍存在的寄生逆转录病毒和反转录转座子之间长期共同进化的结果，灵长类动物就是与这些病毒一起进化的。这可能影响了灵长类动物DNA修复基因的多态性和固定遗传变异。在这项拟议的研究中，将为涉及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，并对这些数据集进行反复阳性选择的特征测试。然后，逆转录病毒感染试验将用于测试这些DNA修复基因的适应性序列变化是否导致了对感染易感性的改变。这种序列改变对细胞DNA修复的影响也将被探讨。细胞培养模型系统的初步数据表明，最著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修复基因的进化可以对癌症产生深远的影响，因此，阐明定义这些基因进化的进化力量是非常重要的。这项拟议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其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. PUBLIC HEALTH RELEVANCE: Human cells contain a complex network of DNA repair pathways, which have evolved to protect the integrity of chromosomes. However, the evolution and function of DNA repair proteins may be influenced by retroviral pathogens, like HIV, which use these proteins for their own benefit. Understanding the evolution of DNA repair genes is important to understanding both the formation of cancers and susceptibility to retroviral infection.