Abstract
Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and (2) global differentiation among four geographically diverse horse populations (FST). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P<0.01), insulin receptor signalling (5.0-fold enrichment; P<0.01) and lipid transport (2.2-fold enrichment; P<0.05) genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P<0.05) and focal adhesion pathway (1.9-fold enrichment; P<0.01) genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes within the complex molecular networks underlying obesity and its consequential pathologies, such as type 2 diabetes. Therefore, we propose Thoroughbred as a novel in vivo large animal model for understanding molecular protection against metabolic disease.
Highlights
As flight animals and grazers the wild ancestors of modern horses were naturally selected for speed and the ability to traverse long distances
This process has been uniquely augmented in Thoroughbred horses, which for four centuries have been subject to intense artificial selection for system-wide structural and functional adaptations that contribute to athletic performance phenotypes
Whereas loci lying at the negative end of the Dh/sd distribution have been subject to positive selection, the positive end of the distribution indicates the effects of balancing selection where two or more alleles are maintained at higher frequency than expected under neutral genetic drift
Summary
As flight animals and grazers the wild ancestors of modern horses were naturally selected for speed and the ability to traverse long distances. In comparison to other athletic species of similar size, the aerobic capacity or maximal oxygen uptake (VO2max) of Thoroughbreds is superior (.200 ml O2/kg/min) [2,3,4] and is achieved by a remarkable oxygen carrying capacity and delivery facilitated by structural and functional adaptations involving the respiratory and cardiovascular systems [5] Some of these adaptations include a large lung volume, high maximum haemoglobin concentration and cardiac output as well as a large muscle mass (approximately 55%) to body weight ratio, high skeletal muscle mitochondrial density and oxidative enzyme activity and large intramuscular stores of energy substrates (primarily glycogen) in which equivalent concentrations are only achieved in human skeletal muscle after carbohydrate loading [6,7,8,9]. The VO2max in horses is usually limited by oxygen supply to the mitochondria rather than by mitochondrial oxidative capacity [10], with the respiratory system in horses unable to meet the metabolic demands of exercising muscle [11,12]
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