Genetic mechanisms of hybrid sterility in house mice (Mus musculus)

当以前自由杂交的有机体群体之间形成繁殖障碍时，新物种就产生了。识别导致生殖隔离的基因揭示了物种形成过程的机制。已经采取了两种方法来识别导致生殖障碍的基因--实验室中物种之间的遗传杂交，以及对自然杂交区域的研究。家鼠(Mus Musculus)罕见地将复杂的遗传工具和亚种之间的自然杂交区域结合在一起--提供了将这两种方法的优势结合在一起的机会。亚种之间的雄性杂交通常表现出生育力下降，这是初生种之间常见的生殖障碍。这项拟议的研究的目标是确定杂交雄性不育的遗传和发育原因，以之前的研究为基础，确定与实验室杂交小鼠和杂交区小鼠生育力降低有关的遗传变异。我们将使用一组独特的近亲繁殖小鼠品系，它们携带与杂交区不育症相关的变异；每个品系的个体在基因上是相同的，使我们能够在多个时间点通过复制来研究相同的特征。我们将结合系统生物学、进化生物学和生殖生物学的方法来(1)识别不育杂交中被破坏的相互作用的基因网络，(2)确定精子发生过程中缺陷出现的地点和时间，以及(3)识别和功能评估候选不育基因。这里提出的新的、综合的研究计划将确定小鼠杂交雄性不育的精确分子机制。此外，这项工作将更好地理解导致杂交缺陷的网络和基因的变化类型，并确定受影响的生物途径。这些特征更有可能在不同的生物体之间共享，而不是特定的不育基因。总而言之，这些结果将大大促进人们对自然界中一个关键的生殖障碍的理解，并为物种形成过程提供新的见解。

New species are created when barriers to reproduction form between groups of organisms that formerly interbred freely. Identifying the genes that cause reproductive isolation reveals mechanisms of the speciation process. Two approaches have been taken to identify the genes that cause reproductive barriers - genetic crosses between species in the laboratory, and studies of natural zones of hybridization. The house mouse (Mus musculus) features a rare combination of sophisticated genetic tools and natural hybrid zones between subspecies - providing the opportunity to combine the advantages of these two approaches. Male hybrids between subspecies often show reduced fertility, a common type of reproductive barrier between incipient species. The goal of the proposed research is to determine genetic and developmental causes of hybrid male sterility, building on previous studies identifying genetic variants associated with reduced fertility in a laboratory cross and in hybrid zone mice. We will use a unique set of inbred mouse strains, which carry variants associated with sterility in the hybrid zone; individuals from each strain are genetically identical, enabling us to investigate the same trait with replication and at multiple time points. We will integrate approaches from systems biology, evolutionary biology, and reproductive biology to (1) identify networks of interacting genes disrupted in sterile hybrids, (2) determine where and when defects appear during spermatogenesis, and (3) identify and functionally evaluate candidate sterility genes. The novel, integrative research programme proposed here will identify precise molecular mechanisms of hybrid male sterility in mice. Furthermore, this work will provide a better understanding of the types of changes in networks and genes that cause hybrid defects and identify the biological pathways affected. These characteristics are more likely to be shared among different organisms than specific sterility genes. Together these results will significantly advance understanding of a key reproductive barrier in nature, and provide novel insight into the speciation process.