Stem cell transcriptional profiles from mouse subspecies reveal cis-regulatory evolution at ribosomal large-subunit genes

Abstract A key goal of evolutionary genomics is to harness molecular data to draw inferences about selective forces that have acted on genomes. The field progresses in large part through the development and benchmarking of advanced molecular-evolution analysis methods. Here we evaluated the rigor and performance of a test of directional, cis-regulatory evolution across genes in pathways, using stem cells from Mus musculus subspecies as a model. We discovered a unique program of induction of ribosomal large-subunit genes in stem cells of the Southeast Asian mouse M. m. castaneus relative to its sister taxa, driven in part by cis-regulatory variation. As a complement, we used sequence analyses to find population- and comparative-genomic signatures of selection in M. m. castaneus, at the upstream regions of the ribosomal gene cohort. The unique high-expression program for these loci in M. m. castaneus was recapitulated in stem cell-derived neurons. We interpret our data under a model of changes in lineage-specific pressures across Mus musculus in stem cells with high translational capacity. Together, our findings underscore the rigor of integrating expression and sequence-based methods to generate hypotheses about evolutionary events from long ago.