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Thoroughbred horses are finely-tuned athletes with a high aerobic capacity relative to skeletal muscle mass, attributable to centuries of genetic selection for speed and stamina. Polymorphisms in the myostatin gene (MSTN), a pronounced inhibitor of skeletal muscle growth, have been shown to almost singularly account for gene-based race distance aptitude in racehorses. In Thoroughbreds, two MSTN polymorphisms, a single nucleotide variation in the first intron (SNP g.66493737C>T) and a non-coding transposable element within the promoter region (a 227 bp SINE insertion) are of particular interest. Until now, it has not been clear which of these variants affect skeletal muscle phenotypes or whether both can impact racing performance. In a large cohort of Thoroughbreds, we observed a complete concordance between the SNP and the SINE insertion. By means of in vitro assays in C2C12 myoblasts, we isolated the SNP variant from the SINE polymorphism and showed the latter is exclusively responsible for adversely affecting transcription initiation and gene expression thereby limiting myostatin protein production. Mapping the MSTN transcription start site in horse skeletal muscle likewise revealed anomalous transcription initiation in the presence of the SINE insertion. Our data provides mechanistic evidence that the SINE insertion uniquely accounts for the MSTN \"speed gene\" effect on race distance aptitude in the Thoroughbred horse.

Variants of the MSTN gene encoding myostatin are associated with muscle hypertrophy phenotypes in a range of mammalian species, most notably cattle, dogs, mice, and humans. Using a sample of registered Thoroughbred horses (n = 148), we have identified a novel MSTN sequence polymorphism that is strongly associated (g.66493737C>T, P = 4.85×10⁻⁸) with best race distance among elite racehorses (n = 79). This observation was independently validated (P = 1.91×10⁻⁶) in a resampled group of Thoroughbreds (n = 62) and in a cohort of Thoroughbreds (n = 37, P = 0.0047) produced by the same trainer. We observed that C/C horses are suited to fast, short-distance races; C/T horses compete favorably in middle-distance races; and T/T horses have greater stamina. Evaluation of retrospective racecourse performance (n = 142) and stallion progeny performance predict that C/C and C/T horses are more likely to be successful two-year-old racehorses than T/T animals. Here we describe for the first time the identification of a gene variant in Thoroughbred racehorses that is predictive of genetic potential for an athletic phenotype.

The Thoroughbred horse is a highly valued domestic animal population under strong selection for athletic phenotypes. Here we present a high resolution genomics-based analysis of inbreeding in the population that may form the basis for evidence-based discussion amid concerns in the breeding industry over the increasing use of small numbers of popular sire lines, which may accelerate a loss of genetic diversity. In the most comprehensive globally representative sample of Thoroughbreds to-date ( n  = 10,118), including prominent stallions ( n  = 305) from the major bloodstock regions of the world, we show using pan-genomic SNP genotypes that there has been a highly significant decline in global genetic diversity during the last five decades ( F IS R 2  = 0.942, P  = 2.19 × 10 −13 ; F ROH R 2  = 0.88, P  = 1.81 × 10 −10 ) that has likely been influenced by the use of popular sire lines. Estimates of effective population size in the global and regional populations indicate that there is some level of regional variation that may be exploited to improve global genetic diversity. Inbreeding is often a consequence of selection, which in managed animal populations tends to be driven by preferences for cultural, aesthetic or economically advantageous phenotypes. Using a composite selection signals approach, we show that centuries of selection for favourable athletic traits among Thoroughbreds acts on genes with functions in behaviour, musculoskeletal conformation and metabolism. As well as classical selective sweeps at core loci, polygenic adaptation for functional modalities in cardiovascular signalling, organismal growth and development, cellular stress and injury, metabolic pathways and neurotransmitters and other nervous system signalling has shaped the Thoroughbred athletic phenotype. Our results demonstrate that genomics-based approaches to identify genetic outcrosses will add valuable objectivity to augment traditional methods of stallion selection and that genomics-based methods will be beneficial to actively monitor the population to address the marked inbreeding trend.

Background Thousands of years of natural and artificial selection since the domestication of the horse has shaped the distinctive genomes of Chinese Mongolian horse populations. Consequently, genomic signatures of selection can provide insights into the human-mediated selection history of specific traits and evolutionary adaptation to diverse environments. Here, we used genome-wide SNPs from five distinct Chinese Mongolian horse populations to identify genomic regions under selection for the population-specific traits, gait, black coat colour, and hoof quality. Other global breeds were used to identify regional-specific signatures of selection. Results We first identified the most significant selection peak for the Wushen horse in the region on ECA23 harbouring DMRT3, the major gene for gait. We detected selection signatures encompassing several genes in the Baicha Iron Hoof horse that represent good biological candidates for hoof health, including the CSPG4 , PEAK1 , EXPH5 , WWP2 and HAS3 genes. In addition, an analysis of regional subgroups (Asian compared to European) identified a single locus on ECA3 containing the ZFPM1 gene that is a marker of selection for the major domestication event leading to the DOM2 horse clade. Conclusions Genomic variation at these loci in the Baicha Iron Hoof may be leveraged in other horse populations to identify animals with superior hoof health or those at risk of hoof-related pathologies. The overlap between the selection signature in Asian horses with the DOM2 selection peak raises questions about the nature of horse domestication events, which may have involved a prehistoric clade other than DOM2 that has not yet been identified.

Thoroughbred horses are bred for competitive racing and undergo intense training regimes. The maintenance of physical soundness and desirable behavioural characteristics are critical to the longevity of a racing career. Horses intended for Flat racing generally enter training as yearlings and undergo introductory training prior to exercise conditioning for racing. This period requires rapid adjustment to a novel environment. As a prey animal, a horse’s ‘fight-or-flight’ response is highly adapted, in which a well-understood component of this response, the hypothalamic-pituitary-axis, is activated in response to a stress stimulus, releasing cortisol. In the Thoroughbred, a significant difference in salivary cortisol concentrations between pre- and post-first time ridden (i.e., first backing) by a jockey have previously been identified. Here, to test the hypothesis that salivary cortisol concentrations may be used to objectively detect individual variations in the acute physiological stress response we investigate individual variation in cortisol response to training milestones. Saliva samples were collected from a cohort of n = 96 yearling Flat racehorses, at the same training yard, across three timepoints at rest: before entering the training yard ( n = 66), within three days of entry to the training yard ( n = 67) and following 2–3 weeks in the training yard ( n = 50). Salivary cortisol concentration was measured using an ELISA. There was no significant difference in cortisol concentration (ANOVA, P > 0.05) across the samples collected at timepoints at rest. Samples were also collected before and 30 minutes after exposure to three novel training events: first time long-reined ( n = 6), first time backed by a jockey ( n = 34), and first time ridden on the gallops ( n = 10). Mean salivary cortisol concentration after all three novel training events was significantly higher than prior to the training event (Paired t-test, P <0.005). The ranges of post-event salivary cortisol concentration across all timepoints suggest individual variation in the measured stress response, reflecting individual differences in stress response to the early training environment. This measure may be used as an objective assessment of the stress response of Thoroughbred racehorses during training.

Background Thoroughbred horses have been selected for traits contributing to speed and stamina for centuries. It is widely recognized that inherited variation in physical and physiological characteristics is responsible for variation in individual aptitude for race distance, and that muscle phenotypes in particular are important. Results A genome-wide SNP-association study for optimum racing distance was performed using the EquineSNP50 Bead Chip genotyping array in a cohort of n = 118 elite Thoroughbred racehorses divergent for race distance aptitude. In a cohort-based association test we evaluated genotypic variation at 40,977 SNPs between horses suited to short distance (≤ 8 f) and middle-long distance (> 8 f) races. The most significant SNP was located on chromosome 18: BIEC2-417495 ~690 kb from the gene encoding myostatin ( MSTN ) [ P unadj. = 6.96 × 10 -6 ]. Considering best race distance as a quantitative phenotype, a peak of association on chromosome 18 (chr18:65809482-67545806) comprising eight SNPs encompassing a 1.7 Mb region was observed. Again, similar to the cohort-based analysis, the most significant SNP was BIEC2-417495 ( P unadj. = 1.61 × 10 -9 ; P Bonf. = 6.58 × 10 -5 ). In a candidate gene study we have previously reported a SNP (g.66493737C>T) in MSTN associated with best race distance in Thoroughbreds; however, its functional and genome-wide relevance were uncertain. Additional re-sequencing in the flanking regions of the MSTN gene revealed four novel 3' UTR SNPs and a 227 bp SINE insertion polymorphism in the 5' UTR promoter sequence. Linkage disequilibrium was highest between g.66493737C>T and BIEC2-417495 ( r 2 = 0.86). Conclusions Comparative association tests consistently demonstrated the g.66493737C>T SNP as the superior variant in the prediction of distance aptitude in racehorses (g.66493737C>T, P = 1.02 × 10 -10 ; BIEC2-417495, P unadj. = 1.61 × 10 -9 ). Functional investigations will be required to determine whether this polymorphism affects putative transcription-factor binding and gives rise to variation in gene and protein expression. Nonetheless, this study demonstrates that the g.66493737C>T SNP provides the most powerful genetic marker for prediction of race distance aptitude in Thoroughbreds.

Although inspiratory muscle training (IMT) is reported to improve inspiratory muscle strength in humans little has been reported for horses. We tested the hypothesis that IMT would maintain and/or improve inspiratory muscle strength variables measured in Thoroughbreds during detraining. Thoroughbreds from one training yard were placed into a control (Con, n = 3 males n = 7 females; median age 2.2±0.4 years) or treatment group (Tr, n = 5 males, n = 5 females; median age 2.1±0.3 years) as they entered a detraining period at the end of the racing/training season. The Tr group underwent eight weeks of IMT twice a day, five days per week using custom-made training masks with resistance valves and an incremental threshold of breath-loading protocol. An inspiratory muscle strength test to fatigue using an incremental threshold of breath-loading was performed in duplicate before (T0) and after four (T1) and eight weeks (T2) of IMT/no IMT using a custom-made testing mask and a commercial testing device. Inspiratory measurements included the total number of breaths achieved during the test, average load, peak power, peak volume, peak flow, energy and the mean peak inspiratory muscle strength index (IMSi). Data were analysed using a linear mixed effects model, P≤0.05 significant. There were no differences for inspiratory measurements between groups at T0. Compared to T0, the total number of breaths achieved (P = 0.02), load (P = 0.003) and IMSi (P = 0.01) at T2 had decreased for the Con group while the total number of breaths achieved (P<0.001), load (P = 0.03), volume (P = 0.004), flow (P = 0.006), energy (P = 0.01) and IMSi (P = 0.002) had increased for the Tr group. At T2 the total number of breaths achieved (P<0.0001), load (P<0.0001), volume (P = 0.02), energy (P = 0.03) and IMSi (P<0.0001) were greater for the Tr than Con group. In conclusion, our results support that IMT can maintain and/or increase aspects of inspiratory muscle strength for horses in a detraining programme.

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease caused by infection with trypanosome parasites ( Trypanosoma spp.). These are transmitted by infected tsetse flies ( Glossina spp.) and cause a similar disease in animals, known as African animal trypanosomosis (AAT), which is one of the largest constraints to livestock production in sub-Saharan Africa and causes a financial burden of approximately $4.5 billion annually. Some African Bos taurus cattle populations have an important evolutionary adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites ( Trypanosoma spp.). Trypanotolerant African B. taurus N’Dama and trypanosusceptible Bos indicus Boran cattle responded in largely similar ways during trypanosome infection when gene expression was examined using blood, liver, lymph node, and spleen samples with peaks and troughs of gene expression differences following the cyclic pattern of parasitaemia exhibited during trypanosome infection. However, differences in response to infection between the two breeds were reflected in differential expression of genes related to the immune system such as those encoding antimicrobial peptides and cytokines, including, for example, the antimicrobial peptide encoding genes LEAP2 , CATHL3 , DEFB4A , and S100A7 and the cytokine genes CCL20 , CXCL11 , CXCL13 , CXCL16 , CXCL17 , IL33 , and TNFSF13B . In addition, transcriptional profiling of peripheral blood identified expression differences in genes relating to coagulation and iron homeostasis, which supports the hypothesis that the dual control of parasitaemia and the anaemia resulting from the innate immune response to trypanosome parasites is key to trypanotolerance and provide new insights into the molecular mechanisms underlying this phenomenon.

Thoroughbred horse racing is a global sport with major hubs in Europe, North America, Australasia and Japan. Regional preferences for certain traits have resulted in phenotypic variation that may result from adaptation to the local racing ecosystem. Here, we test the hypothesis that genes selected for regional phenotypic variation may be identified by analysis of selection signatures in pan-genomic SNP genotype data. Comparing Australian to non-Australian Thoroughbred horses (n = 99), the most highly differentiated loci in a composite selection signals (CSS) analysis were on ECA6 (34.75-34.85 Mb), ECA14 (33.2-33.52 Mb and 35.52-36.94 Mb) and ECA16 (24.28-26.52 Mb) in regions containing candidate genes for exercise adaptations including cardiac function (ARHGAP26, HBEGF, SRA1), synapse development and locomotion (APBB3, ATXN7, CLSTN3), stress response (NR3C1) and the skeletal muscle response to exercise (ARHGAP26, NDUFA2). In a genome-wide association study for field-measured speed in two-year-olds (n = 179) SNPs contained within the single association peak (33.2-35.6 Mb) overlapped with the ECA14 CSS signals and spanned a protocadherin gene cluster. Association tests using higher density SNP genotypes across the ECA14 locus identified a SNP within the PCDHGC5 gene associated with elite racing performance (n = 922). These results indicate that there may be differential selection for racing performance under racing and management conditions that are specific to certain geographic racing regions. In Australia breeders have principally selected horses for favourable genetic variants at loci containing genes that modulate behaviour, locomotion and skeletal muscle physiology that together appear to be contributing to early two-year-old speed.

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 (F(ST)). 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.