WILD DERIVED GENETIC VARIATION

一系列远亲的小鼠物种已经进行了测试 能够与实验室菌株杂交，并产生有活力的， 有生育能力的混血儿。在这些物种中，Spretus已被证明是 作为高度分化的父母资源股票，非常有价值 来自实验室小鼠，但在F1杂交组合中仍然有效。在这些 杂交种，雌性是有生育能力的，它们可以与任何一个回交 亲本基因。相比之下，杂交雄性是不育的，几乎没有 或者在减数分裂中期I之后没有精子发生的证据。 初步工作表明，X-Y染色体配对失败是一种 这些杂交种减数分裂前期的显著特征以及它可能 是不育表型的原因。总而言之，最初的工作 指示正常的X-Y配对是 减数分裂超过中期I和不同种小鼠的研究进展 可能在X-Y配对区域中缺乏足够的序列同源性 这种相互作用就会发生。因此，不育的杂交雄性可能会提供 关于减数分裂和精子发生调控的重要信息。 从进化的角度来看，X-Y配对区域的分歧可能 是物种形成过程中的一个重要特征。这项建议 概述了解决男性不育的遗传基础的具体目标 包括X-Y染色体配对在内的小鼠物种杂交在其中的作用 并对配对失败的分子基础进行了分析。 该计划还保留了强大的研究资源，结合了 一组特定的研究问题，使用广泛的鼠标样本 基因库作为特殊的研究资源。所支持的研究资源 通过这笔赠款，包括1)一套不同的野生来源的实验室 保持近交系小鼠种，2)携带一系列同源菌株 野生来源的各种不同基因的等位基因，3)罕见的近交系 对更广泛的研究至关重要的菌株和突变种群 我们部门的几位调查员的兴趣和4)一个小系列 从本项目进行的ENU诱变研究中恢复的突变体的数量。 因此，提案的一个中心主题是延续这一资源 以及一个大纲计划，以提高其对我们和更广泛社区的价值 老鼠遗传学和医学研究。

A series of distantly related Mus species have been tested for their ability to interbreed with laboratory strains and to produce viable, fertile hybrids. Among these species, M. spretus has proved to be extremely valuable as a parental resource stock that is highly diverged from laboratory mice but still viable in F1 hybrid combinations. In these hybrids, the females are fertile and they can be backcrossed with either parental genotype. By contrast, the hybrid males are sterile with little or no evidence of spermatogenesis beyond metaphase I of meiosis. Preliminary work indicates that a failure of X-Y chromosome pairing is a prominent feature of the meiotic prophase of these hybrids and that it may be causal of the sterile phenotype. Taken together, the initial work indicates that normal X-Y pairing is an essential requisite for the progression of meiosis beyond metaphase I and that divergent Mus species may lack sufficient sequence homology in the X-Y pairing region to allow this interaction to occur. Thus, the sterile hybrid males may provide important information about the regulation of meiosis and spermatogenesis. From an evolutionary perspective, the divergence of X-Y pairing regions may be an important feature in the process of speciation. This proposal outlines specific aims to address the genetic basis of male sterility in mouse species hybrids including the role of X-Y chromosome pairing in this phenotype and an analysis of the molecular basis for the pairing failure. The program also retains a strong research resource combined with a specific set of research questions that use a broad sampling of the mouse gene pool as special research resources. The research resources supported by this grant include 1) a diverse set of wild-derived, laboratory maintained outbred Mus species, 2) a series of congenic strains carrying wild-derived alleles for a variety of different genes, 3) rare inbred strains and mutant stocks that are critical to the broader research interests of several investigators in our department and 4) a small series of mutants recovered from ENU mutagenesis studies conducted in our program. Thus a central theme of the proposal is the continuation of this resource and an outline program to improve its value to us and the broader community of mouse genetics and medical research.