Gene regulation and the genomic basis of speciation and adaptation in house mice (Mus musculus)

Gene expression is a molecular phenotype that is essential to organismal form and fitness. However, how gene regulation evolves over evolutionary time and contributes to phenotypic differences within and between species is still not well understood. In my dissertation, I examined the role of gene regulation in adaptation and speciation in house mice (Mus musculus)./nIn chapter 1, I reviewed theoretical models and empirical data on the role of gene regulation in the origin of new species. I discuss how regulatory divergence between species can result in hybrid dysfunction and point to areas that could benefit from future research./nIn chapter 2, I characterized regulatory divergence between M. m. domesticus and M. m. musculus associated with male hybrid sterility. The major model for the evolution of post-zygotic isolation proposes that hybrid sterility or inviability will evolve as a product of deleterious interactions (i.e., negative epistasis) between alleles at different loci when joined together in hybrids. As the regulation of gene expression is inherently based on interactions between loci, disruption of gene regulation in hybrids may be a common mechanism for post-zygotic isolation. To test this question, I compared expression differences between house mouse subspecies with expression patterns in sterile and fertile male F1 hybrids. I identified extensive regulatory divergence between the subspecies in the testis and found that compensatory cis-and trans- changes were non-randomly associated with genes that were misexpressed in sterile hybrids, but not in fertile hybrids. These results support the idea that such regulatory interactions may contribute to hybrid incompatibilities and may be major drivers of speciation./nIn my third chapter, I used expression quantitative trait locus (eQTL) mapping in tandem with a genome scan for selection to identify adaptive regulatory variation in house mice (M. m. domesticus) on the east coast of North America. Mice on the east coast of North America show adaptive differences in body mass in response to latitudinal variation in temperature. I identified genes with clinally varying cis-eQTL for which expression level is correlated with latitude. Among these clinal outliers, I identified two genes (Adam17 and Bcat2) with cis-eQTL of large effect that are associated with adaptive body mass variation and for which expression is correlated with body mass both within and between populations. Adam17 and Bcat2 deletions affect body mass in mice and these genes have also been linked to obesity in humans. These findings provide strong evidence for cis- regulatory elements as essential loci of environmental adaptation in natural populations./nIn chapter 4, I used low-coverage whole genome sequencing data from the same individuals to identify and characterize copy number variation in natural populations of house mice on the east coast of North America. Consistent with a role for copy number variation in local adaptation, I identified two regions where copy number is significantly correlated with latitude. One of these regions contains the gene Trpm8, which has previously been shown to affect physiological responses to environmental cold in other species. These results suggest that copy number variation significantly contributes to genetic variation in North American house mice and that copy number variation may play an important role in local adaptation./nFinally, in my fifth chapter, I examined the relationship between gene co-expression networks and molecular evolution in natural populations of M. m. domesticus. I found that genes that are more central to their co-expression networks (i.e., have more and greater associations with other genes) and genes whose co-expression relationships are conserved across tissues show lower rates of protein evolution, have fewer polymorphisms, and are less likely show regulatory variation. Together, these results are consistent with gene co-expression network structure being a source of evolutionary constraint.

Advisor: Nachman, Michael W