Rapid evolution of genes critical for genome integrity

对基因组完整性至关重要的基因的快速进化

• 批准号: 8122066
• 负责人: Sara Sawyer
• 金额: $ 2.24万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122066
• 关键词: Affect; Alleles; Animal Model; Apoptosis; BRCA1 gene; Biological Assay; Biological Models; Cancer Etiology; Cancer-Predisposing Gene; Cell Culture Techniques; Cell Line; Cells; Chimera organism; Chromosomal Breaks; Chromosomal Instability; Chromosomal Rearrangement; Chromosomes; Complex; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA lesion; DNA repair protein; Data; Data Set; Disease; Double Strand Break Repair; Evolution; Gene Family; Gene Mutation; Genes; Genetic; Genetic Variation; Genome; Genome Stability; Goals; HIV; Hereditary Breast Carcinoma; Human; Infection; Lead; Left; Ligase; Link; Malignant Neoplasms; Measures; Modeling; Molecular Evolution; Mutation; NBS1 gene; Natural Selections; Nonhomologous DNA End Joining; Organism; Parasites; Pathway interactions; Plants; Population; Predisposition; Primates; Process; Proteins; Race; Recurrence; Research; Resistance; Retrotransposon; Retroviridae; Rodent; Shapes; Site; Syndrome; Testing; Ursidae Family; Work; XRCC4 gene; Yeasts; arm; base; cost; fly; genetic pedigree; homologous recombination; member; mutant; pathogen; pressure; public health relevance; reconstruction; repaired; research study

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.

描述（由申请人提供）：将研究灵长类动物DNA双链修复基因的分子演化。这些基因对于基因组稳定性很重要，许多癌症综合征与这些基因的突变有关。有趣的是，该基因家族的许多成员都带有反复出现的积极选择的签名。测试的假设是这些特征是由这些DNA修复基因与普遍的寄生虫逆转录病毒和逆转座子之间的长期共同进化而产生的。这可能影响了有关多态性和固定遗传变异的灵长类动物DNA修复基因。在这项拟议的研究中，将生成大型灵长类动物序列数据集，以针对人类双链破裂修复的基因生成，并将测试这些数据集的重复阳性选择签名。然后，将使用逆转录病毒感染测定法测试这些DNA修复基因中的自适应序列是否改变导致感染的敏感性改变。还将探索此序列变为细胞DNA修复的后果。细胞培养模型系统中的初步数据表明，在DNA修复保真度和逆转录病毒抗性的双重选择压力下，最著名的癌症敏感性基因BRCA1可能正在发展。基于此，DNA修复基因演化可以对癌症产生深远的影响，因此，重要的是要阐明定义这些基因演变的进化力。这项提出的研究是理解遗传寄生虫如何通过其施加的选择性压力，塑造与之相互作用的人类基因的顺序的总体目标的核心。 公共卫生相关性：人类细胞包含复杂的DNA修复途径网络，该网络已进化以保护染色体的完整性。但是，DNA修复蛋白的演变和功能可能受HIV等逆转录病毒病原体的影响，这些病原体使用这些蛋白质为其自身受益。了解DNA修复基因的演变对于理解癌症的形成和逆转录病毒感染的易感性很重要。