Cytogenetic Analysis of Recombination in the Human Male

描述(申请人提供)：同源染色体在第一次减数分裂时的分离取决于沿染色体长度的遗传交换的位置。在包括人类在内的大多数生物体中，缺少或错误定位的交换极大地增加了不分离的可能性。 尽管这一过程很重要，但我们仍然对选择交换位置和控制小母细胞重组的总体水平的机制一无所知。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。我们的研究将集中在人类男性身上，评估同源染色体启动和完成正常男性突触和重组过程的方式。这些研究将使我们能够检验关于个体间和染色体间变异的假设，联会复合体在调节重组水平中的重要性，以及交叉干扰的性质，并直接询问一些个体是否有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确定控制哺乳动物重组水平的基因(S)。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发现对这些个体进行分类，将后续的突变检测研究集中在最有可能包括减数分裂基因突变的不育男性子集上。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，而且很可能导致识别导致人类不孕不育的第一个依赖重组的原因。

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.