Genetic Basis of Aerobically Supported Voluntary Exercise: Results from a Selection Experiment with House Mice

Abstract

The biological basis of exercise behavior is increasingly relevant for maintaining healthy lifestyles. Various quantitative genetic studies and selection experiments have conclusively demonstrated substantial heritability for exercise behavior in both humans and laboratory rodents. In the "High Runner" selection experiment, 4 replicate lines of Mus domesticus were bred for high voluntary wheel running (HR), along with 4 non-selected control (C) lines. After 61 generations, the genomes of 79 mice (9-10 from each line) were fully sequenced and single nucleotide polymorphisms (SNPs) were identified. We used nested ANOVA with MIVQUE estimation and other approaches to compare allele frequencies between the HR and C lines for both SNPs and haplotypes. Approximately 61 genomic regions, across all somatic chromosomes, showed evidence of differentiation. Twelve of these regions were differentiated by all methods of analysis. Gene function was inferred largely using Panther gene ontology terms and KO phenotypes associated with genes of interest. Some of the differentiated genes are known to be associated with behavior/motivational systems and/or athletic ability, including Sorl1, Dach1, and Cdh10. Sorl1 is a sorting protein associated with cholinergic neuron morphology, vascular wound healing, and metabolism. Dach1 is associated with limb bud development and neural differentiation. Cdh10 is a calcium ion binding protein associated with phrenic neurons. Overall, these results indicate that selective breeding for high voluntary exercise has resulted in changes in allele frequencies for multiple genes associated with both motivation and ability for endurance exercise, providing candidate genes that may explain phenotypic changes observed in previous studies.

Physical activity and sedentary behavior; mechanistic insights and role in disease prevention

“…The LSTassociated loci yield similar tissue enrichment results, with retina being the most significantly enriched tissue. Interestingly, enrichment for genes expressed in retina was also observed in the High Runner mouse model 39 . Areas related to the reward system (e.g.…”

“…In the mouse however, a gene without an established orthologue in humans -the lncRNA 4930413E15Rik -is considered likely causal for high voluntary wheel running behavior in mice selectively bred for 61 generations 39 . Using single cell RNA-sequencing data from GTEx 55 , we show that a sequence 1.4 Mb from rs2173650 with high conservation to the mouse 4930413E15Rik is expressed in several human reproductive tissues (Supp Figure 8).…”

Coadaptation of the chemosensory system with voluntary exercise behavior in mice

“…In this study, we utilized a unique animal model: 4 replicate mouse lines that have been experimentally evolved by selectively breeding individuals showing high VWR activity (HR lines), along with their 4 independent, non-selected Control lines maintained over 88 generations [43]. The HR and Control lines provide a strong model for determining the contribution of genetics to voluntary-exercise related traits [44,51]. In addition to the exercise ability-related genetic adaptations found after selective breeding [37,44], several changes at the level of the central nervous system have also been identified, which contribute to elevation of VWR for HR mice [37,40,52].…”

Evolutionary physiology at 30+: Has the promise been fulfilled?

“…The low cost of sequencing has led to a genomic revolution that has found its way into all approaches and areas of biology, including selection experiments and experimental evolution, [ 33 ] the study of adaptation in natural populations, [ 34,35 ] and the study of human morphological and physiological evolution. [ 36 ] As one example, the killifish, Fundulus heteroclitus , has been a subject of studies in evolutionary genetics, biochemistry, and physiology since the late 1970s (e.g., see references in [12]).…”