Stem cell transcriptional profiles from mouse subspecies revealcis-regulatory evolution at translation 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.

A general principle governing neuronal evolution reveals a human-accelerated neuron type potentially underlying the high prevalence of autism in humans

“…In contrast, natural selection that favors lower expression of these genes in one lineage will lead to a pattern of biased expression, with most of the 20 genes expressed lower in that lineage 67 . This framework, which has been applied extensively to gene expression and other quantitative traits [64][65][66]68,69 , is known as the sign test. Because the ASE of each gene in hybrid cells is generally independent of that of other genes, facilitating statistical analysis, hybrid ASE is ideally suited for detecting selection with the sign test whereas data from non-hybrids cannot be used in this manner.…”

“…Overall, this strongly suggests that many ASD-linked genes were down-regulated specifically in the human lineage. This coordinated down-regulation of 25 ASD-linked genes could conceivably be due to either positive selection or loss of constraint, as both of these types of lineage-specific selection could lead to down-regulation 67,69 . To determine if ASD-associated genes might be evolving under relaxed constraint in humans, we tested several predictions of the relaxed constraint model.…”