Gene Expression Networks Across Multiple Tissues Are Associated with Rates of Molecular Evolution in Wild House Mice
Department of Integrative Biology and Museum of Vertebrate Zoology, University of California, Berkeley, CA 94720, USA
Department of Biology, Monmouth University, West Long Branch, NJ 07764, USA
Max-Planck-Institute for Evolutionary Biology, Plön 24306, Germany
Authors to whom correspondence should be addressed.
Genes 2019, 10(3), 225; https://doi.org/10.3390/genes10030225
Received: 28 January 2018 / Revised: 10 March 2019 / Accepted: 11 March 2019 / Published: 18 March 2019
(This article belongs to the Special Issue Evolutionary Genetics of Gene Expression)
Interactions between genes can influence how selection acts on sequence variation. In gene regulatory networks, genes that affect the expression of many other genes may be under stronger evolutionary constraint than genes whose expression affects fewer partners. While this has been studied for individual tissue types, we know less about the effects of regulatory networks on gene evolution across different tissue types. We use RNA-sequencing and genomic data collected from Mus musculus domesticus to construct and compare gene co-expression networks for 10 tissue types. We identify tissue-specific expression and local regulatory variation, and we associate these components of gene expression variation with sequence polymorphism and divergence. We found that genes with higher connectivity across tissues and genes associated with a greater number of cross-tissue modules showed significantly lower genetic diversity and lower rates of protein evolution. Consistent with this pattern, “hub” genes across multiple tissues also showed evidence of greater evolutionary constraint. Using allele-specific expression, we found that genes with cis-regulatory variation had lower average connectivity and higher levels of tissue specificity. Taken together, these results are consistent with strong purifying selection acting on genes with high connectivity within and across tissues.