Collaborative Cross: A system genetics approach to the study of male infertility

描述（由申请人提供）：本研究的长期目标是了解男性不育的遗传学。协作交叉是一个哺乳动物参考种群，旨在为最流行的哺乳动物模式生物（小鼠）的系统遗传学提供一个跨学科平台，并克服现有平台的局限性。在十字架的衍生过程中，大约一半的系正在灭绝，男性不育是丢失系的主要原因。对已灭绝系的雄性进行特征分析，为研究男性不育提供了一个短暂但独特的机会。我们已经召集了一个专家小组，他们在生殖生物学、遗传学/基因组学和计算生物学方面具有互补的优势，并在富有成效的合作方面有着良好的记录，以充分利用这一机会之窗。协作杂交的幸存系为验证和深入的生理和分子分析提供了额外的资源。我们的具体目标是：1)完成灭绝CC系雄性的表型鉴定，并利用高密度基因分型阵列对其进行基因分型；2)鉴定与主要男性生殖性状表型变异相关的位点，包括睾丸组织学异常、睾丸重量、精子数量、精子活力和不育；3)对绝迹漏斗中定位的不育位点进行独立验证，对男性不育相关基因型的男性进行深入的表型分析，确定导致男性不育的潜在分子机制。

DESCRIPTION (provided by applicant): The long-term objectives of this research are to understand the genetics of male infertility. The Collaborative Cross is a mammalian reference population that was designed to provide a cross-disciplinary platform for systems genetics in the most popular mammalian model organism, the mouse, and to overcome limitations of existing platforms. During the derivation of the Cross, approximately half of the lines are becoming extinct and male infertility is a major cause of lost lines. Characterization of males from the extinct lines provides a transient, but unique opportunity, for substantial genetic dissection of male infertility. We have assembled an expert group of scientists with complementary strengths in reproductive biology, genetics/genomics and computational biology and a strong record of productive collaborations to take full advantage of this window of opportunity. The surviving lines of the Collaborative Cross provide additional resources for validation and in-depth physiological and molecular analyses. Our specific aims are to: 1) complete the phenotypic characterization of males from extinct CC lines and genotype them with the high-density genotyping array; 2) identify loci associated with phenotypic variation for major male reproductive traits including abnormal testis histology, testis weight, sperm count, sperm motility and infertility; and 3) provide independent validation of the infertility loci mapped in the extinct funnels, conduct in-depth phenotypic analysis of males with genotypes associated with male infertility and identify the underlying molecular mechanisms leading to male infertility. )