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症的遗传学。 Collaborative Cross 是一个哺乳动物参考群体，旨在为最流行的哺乳动物模型生物（小鼠）的系统遗传学提供跨学科平台，并克服现有平台的局限性。在十字架的衍生过程中，大约一半的血统正在灭绝，而男性不育是血统消失的主要原因。对灭绝系雄性的鉴定为对雄性不育症进行实质性基因剖析提供了短暂但独特的机会。我们组建了一个由科学家组成的专家组，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优势，并且拥有良好的富有成效的合作记录，以充分利用这一机会之窗。协作杂交的幸存品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）完成已灭绝CC系雄性的表型表征，并使用高密度基因分型阵列对其进行基因分型； 2) 识别与主要男性生殖性状表型变异相关的基因座，包括异常睾丸组织学、睾丸重量、精子计数、精子活力和不育症； 3）对灭绝漏斗中绘制的不育位点进行独立验证，对具有与男性不育相关的基因型的男性进行深入的表型分析，并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. )