X Chromosomal Studies of Spermatogenic Failure

生精失败的 X 染色体研究

• 批准号: 8820079
• 负责人: Jacob L Mueller
• 金额: $ 21.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-08 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820079
• 关键词: Address; Affect; Antibodies; Architecture; Collaborations; Collection; Complex; Coupled; DNA; Data; Defect; Disease; Evolution; Exhibits; Failure; Genes; Genetic; Genomics; Health; Human; Hybrids; Incidence; Infertility; Knock-out; Knockout Mice; Laboratories; Lead; Link; Location; Male Infertility; Maps; Mediating; Mediator of activation protein; Mentors; Molecular; Molecular Genetics; Molecular Profiling; Mus; Organism; Pathogenesis; Pattern; Phase; Population; Population Control; Process; Proteins; Publishing; Reproduction; Research Personnel; Resolution; Resources; Role; Spermatogenesis; Spermatogenic Cell; Testing; Universities; Washington; Work; X Chromosome; base; gene function; genome sequencing; human male; insight; interest; loss of function; men; novel strategies; protein expression; reproductive; research study; spatiotemporal; sperm cell

PROJECT SUMMARY This proposal posits that the study of rapidly evolving genes involved in speciation will provide significant insights into the human molecular genetics of male infertility. Speciation is the process by which two populations become reproductively isolated. Between recently diverged species, reproductive isolation typically manifests itself in the form of male infertility. Rapidly evolving genes on the X chromosome are primary drivers of this reproductive isolation. My preliminary studies have identified rapidly evolving X-linked genes which are harbored in large, near-perfect, segmental duplications, or amplicons. I hypothesize that these X-ampliconic sequences contain genes critical for spermatogenesis and that the rapid evolution of these sequences within a species can lead to male infertility. I will perform studies in humans and mice to test this hypothesis. In humans, all amplicons of the X chromosome will be accurately sequenced to determine their genomic architecture. Upon resolution of each ampliconic region, I will determine the extent to which X- ampliconic deletions are significantly associated with spermatogenic failure; the most common type of male infertility. To do this I will screen for deletions in a collection of 500 men with spermatogenic failure and 500 men from a control population. To test whether human X-ampliconic genes are expressed in spermatogenic cells, I will perform expression profiling of X-ampliconic genes to provide insight into the molecular pathogenesis of spermatogenic failure. In mice, 12% of the X chromosome is comprised of ampliconic sequences. Two X-ampliconic regions are of particular interest because they represent the most rapidly evolving regions of the X chromosome and have been linked to spermatogenic failure in hybrid mice. Thus, these two X-ampliconic regions represent highly promising candidates to study the spermatogenic functions of X-ampliconic genes. To test whether these two X-ampliconic regions have a role in spermatogenic failure, I will generate independent targeted knockouts of both regions. The knockout of X-ampliconic regions in mice offers opportunities to perform controlled loss-of-function and rescue experiments not feasible in humans. The DNA studies in humans coupled with molecular characterizations of X-ampliconic genes in mice will be essential to advance our understanding of X-ampliconic gene functions in human spermatogenesis and reproduction.

项目总结 这一建议认为，对涉及物种形成的快速进化基因的研究将提供重要的 对男性不育的人类分子遗传学的洞察。物种形成是一个过程，通过这个过程， 种群在生殖上变得孤立。在最近分化的物种之间，生殖隔离 通常表现为男性不育。X染色体上快速进化的基因是 这种生殖隔离的主要驱动力。我的初步研究发现了快速进化的X连锁 隐藏在大的、近乎完美的、节段性复制或扩增中的基因。我假设 这些X扩增序列包含对精子发生至关重要的基因，这些基因的快速进化 物种内的序列可能导致男性不育。我将在人类和老鼠身上进行研究来测试这一点 假设。在人类中，X染色体的所有扩增片段都将被准确测序，以确定它们的 基因组结构。根据每个扩增区域的分辨率，我将确定X- 扩增片段缺失与生精失败显著相关；最常见的男性 不孕不育。为了做到这一点，我将在500名生精障碍男性和500名男性中筛查缺失 来自控制人口的男性。检测人类X扩增基因是否在生精过程中表达 细胞，我将进行X扩增基因的表达谱分析，以提供对分子的洞察 生精功能衰竭的发病机制。在小鼠中，12%的X染色体由扩增片段组成 序列。两个X扩增区域特别令人感兴趣，因为它们代表了最快的 X染色体的进化区域，并与杂交小鼠的生精失败有关。因此， 这两个X-扩增区是研究精子发生功能的极有希望的候选区域。 X扩增基因。为了测试这两个X扩增区域是否在生精失败中起作用，我 将对这两个地区产生独立的、有针对性的击倒。小鼠X扩增区的基因敲除 提供了进行受控功能丧失和抢救实验的机会，这在人类身上是不可行的。这个 人类的DNA研究与小鼠X扩增基因的分子特征相结合将是 对促进我们对X扩增基因在人类精子发生和发育中的功能的理解是必不可少的 繁殖。