X Chromosomal Studies of Spermatogenic Failure

生精失败的 X 染色体研究

• 批准号: 8046259
• 负责人: Jacob L Mueller
• 金额: $ 10.78万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-18 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046259
• 关键词: Address; Affect; Antibodies; Architecture; Collaborations; Collection; Complex; Coupled; DNA; DNA Sequence Rearrangement; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Few genetic factors have been identified to explain the high incidence of spermatogenic failure, which affects 1-2% of all men. Understanding the location and role of X-linked genes in spermatogenic failure will help explain molecular mechanisms of spermatogenesis and important causes of infertility.

描述（由申请人提供）：该提案认为，对参与物种形成的快速进化基因的研究将为男性不育症的人类分子遗传学提供重要的见解。物种形成是两个种群生殖隔离的过程。在最近分化的物种之间，生殖隔离通常以男性不育的形式表现出来。 X 染色体上快速进化的基因是这种生殖隔离的主要驱动因素。我的初步研究已经确定了快速进化的 X 连锁基因，这些基因隐藏在大的、近乎完美的片段重复或扩增子中。我假设这些 X 扩增序列含有对精子发生至关重要的基因，并且这些序列在一个物种内的快速进化可能导致男性不育。我将对人类和小鼠进行研究来检验这个假设。在人类中，X 染色体的所有扩增子都将被精确测序以确定其基因组结构。在解析每个扩增区域后，我将确定 X-扩增缺失与生精失败显着相关的程度；最常见的男性不育症类型。为此，我将从 500 名生精障碍男性和 500 名对照人群中筛选缺失。为了测试人类 X 扩增基因是否在生精细胞中表达，我将进行 X 扩增基因的表达谱分析，以深入了解生精失败的分子发病机制。在小鼠中，12% 的 X 染色体由扩增序列组成。两个 X 扩增区域特别令人感兴趣，因为它们代表 X 染色体进化最快的区域，并且与杂交小鼠的生精失败有关。因此，这两个 X 扩增区域代表了研究 X 扩增基因生精功能的极有前景的候选区域。为了测试这两个 X 扩增区域是否在生精失败中发挥作用，我将对这两个区域进行独立的靶向敲除。小鼠 X 扩增区域的敲除提供了进行受控功能丧失和拯救实验的机会，而这在人类中是不可行的。人类 DNA 研究与小鼠 X 扩增基因的分子特征相结合，对于增进我们对人类精子发生和生殖中 X 扩增基因功能的理解至关重要。 公共健康相关性：很少有遗传因素能够解释生精失败的高发生率，这种情况影响着所有男性的 1-2%。了解X连锁基因在生精失败中的位置和作用将有助于解释生精的分子机制和不育的重要原因。