Genome-Wide Patterns of Differentiation Among House Mouse Subspecies

Abstract

One approach to understanding the genetic basis of speciation is to scan the genomes of recently diverged taxa to identify highly differentiated regions. The house mouse, Mus musculus, provides a useful system for the study of speciation. Three subspecies (M. m. castaneus, M. m. domesticus, and M. m. musculus) diverged 350 KYA, are distributed parapatrically, show varying degrees of reproductive isolation in laboratory crosses, and hybridize in nature. We sequenced the testes transcriptomes of multiple wild-derived inbred lines from each subspecies to identify highly differentiated regions of the genome, to identify genes showing high expression divergence, and to compare patterns of differentiation among subspecies that have different demographic histories and exhibit different levels of reproductive isolation. Using a sliding-window approach, we found many genomic regions with high levels of sequence differentiation in each of the pairwise comparisons among subspecies. In all comparisons, the X chromosome was more highly differentiated than the autosomes. Sequence differentiation and expression divergence were greater in the M. m. domesticus-M. m. musculus comparison than in either pairwise comparison with M. m. castaneus, which is consistent with laboratory crosses that show the greatest reproductive isolation between M. m. domesticus and M. m. musculus. Coalescent simulations suggest that differences in estimates of effective population size can account for many of the observed patterns. However, there was an excess of highly differentiated regions relative to simulated distributions under a wide range of demographic scenarios. Overlap of some highly differentiated regions with previous results from QTL mapping and hybrid zone studies points to promising candidate regions for reproductive isolation. U NDERSTANDING the genetic basis of speciation is a fundamental goal of evolutionary biology. This problem has primarily been approached in two ways: through laboratory studies using crosses and through studies of genetic variation in natural populations. Laboratory studies control for genetic background and environment, and they make it possible to connect genotype and phenotype. These types of studies have produced some spectacular successes including the identification of individual genes underlying postzygotic isolation in Drosophila (e.g., Ting et al. 1998;Presgraves et al. 2003;Brideau et al. 2006;Masly et al. 2006), Arabidopsis (Bomblies et al. 2007;Bikard et al. 2009), Mus (Mihola et al. 2009), and others (reviewed in Presgraves 2010 and Nosil and Schluter 2011).Studies of natural populations rely on the idea that regions of the genome that are important in reproductive isolation may be more differentiated than other regions of the genome. Therefore, by studying patterns of differentiation, one may gain insight into the genomic regions that underlie isolation. The idea that the genomes of closely related species are mosaics of differentiated and less differentiated regions is not new and first e...

Gene regulation and speciation in house mice

“…Thus, some of the regulatory differences observed between inbred strains could still be polymorphic in one or both subspecies. Finally, overlap between our data and those of Phifer-Rixey et al (2014) is greatest for genes associated with cis changes and cis + trans changes (where variants act in the same direction), suggesting that these two regulatory categories may contribute disproportionately to regulatory divergence between subspecies compared to within-subspecies variation.…”

“…While Phifer-Rixey et al (2014) included more lines, coverage per line was lower than in our analysis. Still, overlap between the two data sets is high: 77% of the genes in Phifer-Rixey et al (2014) were represented in our data. We reanalyzed the data of Phifer-Rixey et al (2014) for this subset of 9779 genes that were shared between the two studies.…”

“…Importantly, genes that were differentially expressed in the data of Phifer-Rixey et al (2014) overlap significantly with genes that have significant parental ratios in our analysis (hypergeometric test, P = 1.749 × 10…”

“…This approach, which is rarely used in studies of expression evolution, eliminates differences in gene expression that arise between subspecies as a result of differences in inbreeding depression, and it eliminates expression differences between the subspecies and hybrids as a result of heterosis. We also compared our results to an independent expression study that included more inbred lines (Phifer-Rixey et al 2014). Without population level sampling, it is impossible to distinguish between line-specific effects and subspecific differences.…”

“…This limits the extent to which our conclusions speak to regulatory divergence between M. m. musculus and M. m. domesticus in general as opposed to regulatory divergence between these particular lines. To expand this analysis and look more generally at expression divergence between the subspecies, we took advantage of data from a recent study that analyzed the testis transcriptomes from seven lines of M. m. domesticus and eight lines of M. m. musculus (Phifer-Rixey et al 2014). While Phifer-Rixey et al (2014) included more lines, coverage per line was lower than in our analysis.…”