title: Systematic detection of polygenic cis-regulatory evolution.
abstract: The idea that most morphological adaptations can be attributed to changes in the cis-regulation of gene expression levels has been gaining increasing acceptance, despite the fact that only a handful of such cases have so far been demonstrated. Moreover, because each of these cases involves only one gene, we lack any understanding of how natural selection may act on cis-regulation across entire pathways or networks. Here we apply a genome-wide test for selection on cis-regulation to two subspecies of the mouse Mus musculus. We find evidence for lineage-specific selection at over 100 genes involved in diverse processes such as growth, locomotion, and memory. These gene sets implicate candidate genes that are supported by both quantitative trait loci and a validated causality-testing framework, and they predict a number of phenotypic differences, which we confirm in all four cases tested. Our results suggest that gene expression adaptation is widespread and that these adaptations can be highly polygenic, involving cis-regulatory changes at numerous functionally related genes. These coordinated adaptations may contribute to divergence in a wide range of morphological, physiological, and behavioral phenotypes.
authors.affiliation: Rosetta Inpharmatics, Seattle, Washington, United States of America.
authors.forename: Hunter B
authors.initials: HB
authors.lastname: Fraser
authors.forename: Tomas
authors.initials: T
authors.lastname: Babak
authors.forename: John
authors.initials: J
authors.lastname: Tsang
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Margarete
authors.initials: M
authors.lastname: Mehrabian
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics*; D000818:Animals; D030541:Databases, Genetic; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D048788:Growth and Development / Q000235:genetics; D008124:Locomotion / Q000235:genetics; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D012641:Selection, Genetic