LAUSR

Replicate lines under uniform selection often evolve in different ways. Previously, analyses using whole-genome sequence data for individual mice (Mus musculus) from four replicate High Runner (HR) lines and four non-selected control (C) lines demonstrated genomic regions that have responded consistently to selection for voluntary wheel-running behavior. Here, we ask whether the HR lines have evolved differently from each other, even though they reached selection limits at similar levels. We focus on one HR line (HR3) that became fixed for a mutation at a gene of major effect (Myh4Minimsc) that, in the homozygous condition, causes a 50% reduction in hindlimb muscle mass and many pleiotropic effects. We excluded HR3 from SNP analyses and identified 19 regions not consistently identified in analyses with all four lines. Repeating analyses while dropping each of the other HR lines identified 12, 8, and 6 such regions. (Of these 45 regions, 37 were unique.) These results suggest that each HR line indeed responded to selection somewhat uniquely, but also that HR3 is the most distinct. We then applied two additional analytical approaches when dropping HR3 only (based on haplotypes and nonstatistical tests involving fixation patterns). All three approaches identified seven new regions (as compared with analyses using all four HR lines) that include genes associated with activity levels, dopamine signaling, hippocampus morphology, heart size, and body size, all of which differ between HR and C lines. Our results illustrate how multiple solutions and "private" alleles can obscure general signatures of selection involving "public" alleles.