Cytogenetic Analysis of Recombination in the Human Male

人类男性重组的细胞遗传学分析

• 批准号: 7216237
• 负责人: TERRY J HASSOLD
• 金额: $ 39.63万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216237
• 关键词: chromosomes; clinical research; cytogenetics; disease /disorder etiology; fertility; gene expression; gene mutation; genetic recombination; human subject; laboratory mouse; linkage mapping; male; meiosis; molecular genetics; nondisjunction; patient oriented research; sperm; spermatogenesis

DESCRIPTION (provided by applicant): Segregation of homologous chromosomes at the first meiotic division is dependent on the placement of genetic exchanges along the length of the chromosomes. In most organisms, including humans, absent or mis-located exchanges dramatically increase the likelihood of nondisjunction. Despite the importance of this process, we remain remarkably ignorant of the mechanisms through which the sites of exchange are chosen and the overall level of recombination is controlled in meiocytes. In the proposed studies we will combine molecular and cytological approaches to investigate the biology of human meiotic recombination. Our studies will focus on the human male, assessing the manner in which homologous chromosomes initiate and complete the process of synapsis and characterizing recombination in normal males. These studies will allow us to test hypotheses about inter-individual and inter-chromosomal variation, the importance of the synaptonemal complex in mediating recombination levels, and the nature of cross-over interference and to ask directly whether some individuals may be predisposed to meiotic nondisjunction. In related studies, we will use the power of mouse genetics to identify the gene(s) that control the level of recombination in mammals. In a final set of studies, we will conduct meiotic studies of infertile men. We will utilize the meiotic data obtained and the clinical findings to categorize these individuals, focusing subsequent mutation detection studies on that subset of infertile male most likely to include individuals with mutations in meiotic genes. The combined data from these studies will not only provide answers to basic questions about meiotic recombination in the human, but may well lead to the identification of the first recombination-dependent causes of human infertility.

描述（由申请人提供）：第一次减数分裂时同源染色体的分离取决于沿染色体长度的遗传交换的布置。在包括人类在内的大多数生物体中，交换的缺失或错位会极大地增加不分离的可能性。 尽管这个过程很重要，但我们仍然对性母细胞中交换位点选择和重组总体水平控制的机制一无所知。在拟议的研究中，我们将结合分子和细胞学方法来研究人类减数分裂重组的生物学。我们的研究将集中于人类男性，评估同源染色体启动和完成突触过程的方式，并表征正常男性的重组。这些研究将使我们能够检验有关个体间和染色体间变异、联会复合体在介导重组水平中的重要性以及交叉干扰的性质的假设，并直接询问某些个体是否可能倾向于减数分裂不分离。在相关研究中，我们将利用小鼠遗传学的力量来识别控制哺乳动物重组水平的基因。在最后一组研究中，我们将对不育男性进行减数分裂研究。我们将利用获得的减数分裂数据和临床结果对这些个体进行分类，将随后的突变检测研究重点放在最有可能包括减数分裂基因突变个体的不育男性亚群上。这些研究的综合数据不仅将为人类减数分裂重组的基本问题提供答案，而且很可能导致人类不孕症的第一个重组依赖性原因的识别。