We have used selective breeding with house mice to study coadaptation of morphology and physiology with the evolution of high daily levels of voluntary exercise. Here, we compared hindlimb bones and muscle masses from the 11th generation of four replicate High Runner (HR) lines of house mice bred for high levels of voluntary wheel running with four non‐selected control (C) lines. Mass, length, diameter, and depth of the femur, tibia‐fibula, and metatarsal bones, as well as masses of gastrocnemius and quadriceps muscles, were compared by analysis of covariance with body mass or body length as the covariate. Mice from HR lines had relatively wider distal femora and deeper proximal tibiae, suggesting larger knee surface areas, and larger femoral heads. Sex differences in bone dimensions were also evident, with males having thicker and shorter hindlimb bones when compared with females. Several interactions between sex, linetype, and/or body mass were observed, and analyses split by sex revealed several cases of sex‐specific responses to selection. A subset of the HR mice in two of the four HR lines expressed the mini‐muscle phenotype, characterized mainly by an ∼50% reduction in hindlimb muscle mass, caused by a Mendelian recessive mutation, and known to have been under positive selection in the HR lines. Mini‐muscle individuals had elongated distal elements, lighter and thinner hindlimb bones, altered 3rd trochanter muscle insertion positions, and thicker tibia‐fibula distal widths. Finally, several differences in levels of directional or fluctuating asymmetry in bone dimensions were observed between HR and C, mini‐ and normal‐muscled mice, and the sexes. This study demonstrates that skeletal dimensions and muscle masses can evolve rapidly in response to directional selection on locomotor behavior.
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Multiple solutions at the genomic level in response to selective breeding for high locomotor activity
Replicate lines under uniform selection often evolve in different ways. Previously, analyses using whole-genome sequence data for individual mice (Mus musculus) from 4 replicate High Runner lines and 4 nonselected control lines demonstrated genomic regions that have responded consistently to selection for voluntary wheel-running behavior. Here, we ask whether the High Runner lines have evolved differently from each other, even though they reached selection limits at similar levels. We focus on 1 High Runner 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 4 lines. Repeating analyses while dropping each of the other High Runner lines identified 12, 8, and 6 such regions. (Of these 45 regions, 37 were unique.) These results suggest that each High Runner line indeed responded to selection somewhat uniquely, but also that HR3 is the most distinct. We then applied 2 additional analytical approaches when dropping HR3 only (based on haplotypes and nonstatistical tests involving fixation patterns). All 3 approaches identified 7 new regions (as compared with analyses using all 4 High Runner lines) that include genes associated with activity levels, dopamine signaling, hippocampus morphology, heart size, and body size, all of which differ between High Runner and control lines. Our results illustrate how multiple solutions and “private” alleles can obscure general signatures of selection involving “public” alleles.
more » « less- Award ID(s):
- 2038528
- NSF-PAR ID:
- 10382609
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Genetics
- ISSN:
- 1943-2631
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Selection experiments can elucidate the varying course of adaptive changes across generations. We examined the appendicular skeleton of house mice from four replicate High Runner (HR) lines bred for physical activity on wheels and four non‐selected Control (C) lines. HR mice reached apparent selection limits between generations 17 and 27, running ~3‐fold more than C. Studies at generations 11, 16, and 21 found that HR mice had evolved thicker hindlimb bones, heavier feet, and larger articular surface areas of the knee and hip joint. Based on biomechanical theory, any or all of these evolved differences may be beneficial for endurance running. Here, we studied mice from generation 68, plus a limited sample from generation 58, to test whether the skeleton continued to evolve after selection limits were reached. Contrary to our expectations, we found few differences between HR and C mice for these later generations, and some of the differences in bone dimensions identified in earlier generations were no longer statistically significant. We hypothesize that the loss of apparently coadapted lower‐level traits reflects (1) deterioration related to a gradual increase in inbreeding and/or (2) additional adaptive changes that replace the functional benefits of some skeletal changes.
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Abstract Behavioral addictions can come in many forms, including overeating, gambling and overexercising. All addictions share a common mechanism involving activation of the natural reward circuit and reinforcement learning, but the extent to which motivation for natural and drug rewards share similar neurogenetic mechanisms remains unknown. A unique mouse genetic model in which four replicate lines of female mice were selectively bred (>76 generations) for high voluntary wheel running (High Runner or HR lines) alongside four non‐selected control (C) lines were used to test the hypothesis that high motivation for exercise is associated with greater reward for cocaine (20 mg/kg) and methylphenidate (10 mg/kg) using the conditioned place preference (CPP) test. HR mice run ~three times as many revolutions/day as C mice, but the extent to which they have increased motivation for other rewards is unknown. Both HR and C mice displayed significant CPP for cocaine and methylphenidate, but with no statistical difference between linetypes for either drug. Taken together, results suggest that selective breeding for increased voluntary running has modified the reward circuit in the brain in a way that increases motivation for running without affecting cocaine or methylphenidate reward.
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