Gene regulation and speciation in house mice

Abstract

One approach to understanding the process of speciation is to characterize the genetic architecture of post-zygotic isolation. As gene regulation requires interactions between loci, negative epistatic interactions between divergent regulatory elements might underlie hybrid incompatibilities and contribute to reproductive isolation. Here, we take advantage of a cross between house mouse subspecies, where hybrid dysfunction is largely unidirectional, to test several key predictions about regulatory divergence and reproductive isolation. Regulatory divergence between Mus musculus musculus and M. m. domesticus was characterized by studying allele-specific expression in fertile hybrid males using mRNA-sequencing of whole testes. We found extensive regulatory divergence between M. m. musculus and M. m. domesticus, largely attributable to cis-regulatory changes. When both cis and trans changes occurred, they were observed in opposition much more often than expected under a neutral model, providing strong evidence of widespread compensatory evolution. We also found evidence for lineage-specific positive selection on a subset of genes related to transcriptional regulation. Comparisons of fertile and sterile hybrid males identified a set of genes that were uniquely misexpressed in sterile individuals. Lastly, we discovered a nonrandom association between these genes and genes showing evidence of compensatory evolution, consistent with the idea that regulatory interactions might contribute to Dobzhansky-Muller incompatibilities and be important in speciation.

Gene Regulation and Speciation

“…Novel interactions between divergent cis and trans variants are one way misexpression can arise in hybrids. Consistent with this prediction, a number of studies have associated misexpression with cis–trans compensatory evolution ([40,41,46,53,54], but see also [44,55]). Misexpression is commonly seen in sterile interspecific hybrids [56–61] and has been shown to accumulate with phylogenetic distance in Drosophila [44].…”

“…When cis and trans variants act in opposition, their effects may buffer one another in a compensatory fashion. Consistent with stabilizing selection, such cis–trans compensation appears to play a prominent role in regulatory evolution [38,41,42,45,46]. …”

Contrasting Levels of Molecular Evolution on the Mouse X Chromosome

“…For faster-X expression divergence, this would require that differences in transcript abundances are due to divergence in cis-regulatory elements and/or X-linked trans-regulatory elements (Kayserili et al 2012;Meisel et al 2012a;Meisel and Connallon 2013). Several studies suggest that divergence in transcript abundances is largely determined by evolution in cis (Wittkopp et al 2004;Landry et al 2005;Wittkopp et al 2008;Graze et al 2009;Goncalves et al 2012;Shi et al 2012;Shen et al 2014;Mack et al 2016), while other research indicates that trans-regulatory divergence is more common (Emerson et al 2010;McManus et al 2010;Schaefke et al 2013;Coolon et al 2014;Meiklejohn et al 2014;Combes et al 2015) or that the inferred mode of regulatory divergence is dependent on taxon and experimental design (Coolon and Wittkopp 2013;Guerrero et al 2016). The mechanisms underlying the evolution of DNA methylation are even more poorly understood, but levels of DNA methylation within a given genomic region appear strongly Faster-X sequence evolution also assumes that beneficial mutations are on average at least partially recessive (Charlesworth et al 1987), while theory (Gibson and Weir 2005) and several empirical studies (Lemos et al 2008;McManus et al 2010;Schaefke et al 2013) suggest that cis-regulatory elements should on average act additively.…”

Gene Regulatory Evolution During Speciation in a Songbird

“…Although the two zebra finch subspecies are relatively divergent, they are young relative to some species pairs previously tested for misexpression (e.g., D. simulans · D. melanogaster, 2.5 million years, Landry et al 2005; Sacchromyces cerevisiae · S. paradoxus, 5 million years, Tirosh et al 2009). On the other hand, even crosses between relatively young mouse subspecies (, 0.5 million years) exhibit hybrid sterility and misexpression (Mack et al 2016). Given that there is no evidence of reproductive incompatibility between the zebra finch subspecies and that postzygotic isolation takes a relatively long time to evolve in birds (Prager and Wilson 1975), our results suggest that misexpression may accumulate after the origin of reproductive incompatibilities or may directly contribute to the origin of incompatibilities.…”

“…One caveat, which appears to be common to various tests of regulatory divergence and requires further examination, is that cis and trans tests may differ in statistical power (e.g., Suvorov et al 2013). Divergence (spread) along the cis axis tends to be greater (Figure 3, see also Mack et al 2016), even in cases of abundant trans divergence (e.g., McManus et al 2010). Furthermore, due to the incorporation of biological variation, a large number of sites and genes are left with ambiguity in their mode of inheritance.…”