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Abstract

Understanding how the genome evolves in response to selection is a central challenge in evolutionary genetics. I will introduce a unique selection experiment dubbed “Longshanks” created by Campbell Rolian in Calgary (see Longshanks Mouse I abstract for details). This increase in tibia length has evolved rapidly, despite a breeding population of only 32 mice per replicate line. This result clashes with population and quantitative genetics theory, which holds that small populations should experience strong random drift, making selection inefficient. To determine the genomic response to selection, we sequenced the entire founder and 17 th generations of both Longshanks selection lines and the random‐bred Control line. In contrast to theory, we found clear signature of selection in both Longshanks lines, with widespread parallel and independent loci associated with genes expressed in the developing limb bud. By intersecting population genetics signatures of selection, limb bud chromatin profiles and chromosome domain data, we found seven candidate enhancers at two major developmental regulators, Nkx3.2/Bapx1 and Gli3, harbouring SNPs that show large changes in allele frequencies consistent with selection. We tested three enhancers using transgenic reporter assays and confirmed limb enhancer activity. Importantly, by substituting 13 SNPs that differ between the founder and the 17 th generations, we found that they either strongly boost (Gli3), or nearly abolish enhancer activity (two enhancers for Bapx1). We note that these shifts (gain‐of‐function at Gli3 and loss‐of‐function at Bapx1, a negative regulator of longitudinal bone growth) are both consistent with increased tibia length, and with observed differences between Longshanks and Control in growth plate chondrocyte dynamics. Taken together, our results suggest that it is possible to identify specific basepairs in non‐coding regions that contribute to selectable phenotypic variation in a complex trait. With basepair resolution, we can show that both gain‐of‐function and loss‐of‐function mutations contribute to selection response at the phenotypic level. We hope to use the Longshanks experiment to demonstrate the power of a systems genetics approach to understand Evo Devo at the molecular level.