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

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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.