Abstract
While over ten thousand genetic loci have been associated with phenotypic traits and inherited diseases in genome-wide association studies, in most cases only a relatively small proportion of the trait heritability is explained and biological mechanisms underpinning these traits have not been clearly identified. Expression quantitative trait loci (eQTL) are subsets of genomic loci shown experimentally to influence gene expression. Since gene expression is one of the primary determinants of phenotype, the identification of eQTL may reveal biologically relevant loci and provide functional links between genomic variants, gene expression and ultimately phenotype. Skeletal muscle (gluteus medius) gene expression was quantified by RNA-seq for 111 Thoroughbreds (47 male, 64 female) in race training at a single training establishment sampled at two time-points: at rest (n = 92) and four hours after high-intensity exercise (n = 77); n = 60 were sampled at both time points. Genotypes were generated from the Illumina Equine SNP70 BeadChip. Applying a False Discovery Rate (FDR) corrected P-value threshold (P FDR < 0.05), association tests identified 3,583 cis-eQTL associated with expression of 1,456 genes at rest; 4,992 cis-eQTL associated with the expression of 1,922 genes post-exercise; 1,703 trans-eQTL associated with 563 genes at rest; and 1,219 trans-eQTL associated with 425 genes post-exercise. The gene with the highest cis-eQTL association at both time-points was the endosome-associated-trafficking regulator 1 gene (ENTR1; Rest: P FDR = 3.81 × 10-27, Post-exercise: P FDR = 1.66 × 10-24), which has a potential role in the transcriptional regulation of the solute carrier family 2 member 1 glucose transporter protein (SLC2A1). Functional analysis of genes with significant eQTL revealed significant enrichment for cofactor metabolic processes. These results suggest heritable variation in genomic elements such as regulatory sequences (e.g. gene promoters, enhancers, silencers), microRNA and transcription factor genes, which are associated with metabolic function and may have roles in determining end-point muscle and athletic performance phenotypes in Thoroughbred horses. The incorporation of the eQTL identified with genome and transcriptome-wide association may reveal useful biological links between genetic variants and their impact on traits of interest, such as elite racing performance and adaptation to training.
Highlights
In the 6,000 years since horses were first domesticated on the Eurasian steppe, there has been strong artificial selection for various athletic traits (Levine, 1999)
untrained at rest (UR) horses had a mean age of 611.7 days, untrained four hours post-exercise (UE) horses had a mean age of 757.5 days
UR horses had an average of 41.5 days submaximal training and UE had on average 48.6 (Table 1)
Summary
In the 6,000 years since horses were first domesticated on the Eurasian steppe, there has been strong artificial selection for various athletic traits (Levine, 1999). As a result the Thoroughbred has a highly developed musculature, with a skeletal muscle mass ~10% greater than other horse breeds (~55% compared to ~42%) (Gunn, 1987), accompanied by decreased body fat (Kearns et al, 2002), superior glycogen storage capacity (Votion et al, 2012), increased mitochondrial volume (compared to other mammals) (Kayar et al, 1989) and a high degree of plasticity in skeletal muscle fibre composition (Rivero, 2004). Training elicits an increase in skeletal muscle mass (Rivero et al, 1996), mediated through hyperplastic growth as opposed to marked hypertrophy (Rivero et al, 1996; Rivero et al, 2002)
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