Cardiovascular gene variants of the Australian thoroughbred population: occurrence, genetic diversity, and racing success

Abstract

Athletic performance, regardless of activity or mammalian species, is determined by a combination of many genetic and environmental factors. Indeed, the functions of mammalian cardiovascular systems are greatly influenced by genetic factors that can have substantial phenotype variations between individuals and consequently variations in athletic performance. While many human studies have identified genomic regions of significance to cardiac-specific genes potentially involved in athletic performance, equine research linking genotype to particular equine phenotypes is deficient.It is currently thought that the abnormally large heart sizes (a non-disease state cardiac hypertrophy) seen in some Thoroughbred horses may contribute positively to athletic performance. Preliminary pedigree analysis suggests that the larger-than-average heart size and altered electrocardiograms (ECG) observed in some Thoroughbred horses may be a familial and/or breed-specific trait and thus have a genetic component, however to date no further molecular genetic analysis has been performed. Genes responsible for, or associated with, cardiac development, regulation, size, and function have been identified in both human and laboratory animal model species. These genes include MYH7, CASQ2, AKT1, PTEN, and PI3K. These genes are conserved across vertebrate and invertebrate species and have been shown to play crucial, equivalent roles in determining cardiac rhythm, growth, and function. Furthermore, these genes have not previously been characterised in Thoroughbred horses.It is hypothesised that genetic variation within these orthologous genes plays a major role in breedspecific equine cardiac size determination, regulation, and function. Therefore, this study aims to determine the genetic variation in genes involved in cardiovascular function, development, and size in the Australian Thoroughbred horse population, and investigate whether this variation may contribute on a molecular level to the high level of athletic performance characteristic of this breed.We determined the novel sequence variants of the above five equine orthologues in a panel of nonrelated Thoroughbred horses (n = 93). This has revealed several novel INDELs and SNPs that are potentially responsible for the large heart phenotype and the classification of previously undocumented variations. Key findings include novel SNPs that result in nonsense mutations in MYH7 suggesting multiple allele variants at several locations, and several insertions of premature stop codons (locations 40, 63, 64, 94, and 97) resulting in premature protein truncation. Also found was a non-conservative amino acid change in CASQ2 affecting calcium binding and protein polarity; a 3-base pair deletion in the 5' UTR (un-translated region) of AKT1 possibly resulting in iii changes to transcription factor binding regions or other regulatory binding sites; several variants in both 5' and 3' UTR of PTEN and a PI3K variant causing substitution of glutamine with a STOP codon, resulting in complete loss o...