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Equine genomics and athletic performance

Published: August 12, 2007
By: EMMELINE W. HILL - University College Dublin, Belfield, Dublin, Ireland (Courtesy of Alltech Inc.)
All health, performance, and disease traits in horses are fundamentally influenced by a subset of the approximately 25,000 genes that comprise the equine genome. Athletic ability and physical fitness in humans and animals are complex traits manifested by the interaction of a number of factors including genetics, environment/management and training, and it is well recognised that these traits have a strong inherited component.

Genetic analyses have shown that in Thoroughbreds 30% of variation in racetrack performance is due to heritable components (Gaffney and Cunningham, 1988). Therefore this genetic variation can be dissected to identify genes conferring breeding and racing performance advantage in Thoroughbreds.


The genetics of performance


Domestic animals are valuable models for dissecting the molecular genetic basis of complex traits (Andersson and Georges, 2004), because the genomes of livestock and other domesticates have been artificially shaped by selection for thousands of years leading to distinct phenotypic characteristics that clearly distinguish them from their wild ancestors. In addition, unlike other animals, an enormous amount of phenotypic data has been gathered for domestic species.

Although the precise timing and nature of horse domestication has not yet been resolved, it is understood that horses have been associated with human cultures for over 6,000 years. Since domestication, horses have been selected for various traits including draught power, temperament, endurance, speed and adaptation to adverse climatic conditions. It is likely that throughout the domestication process ancillary traits such as disease tolerance were also naturally favoured. As flight animals, horses have been exposed to continual selection pressure for speed and stamina.

Thus, the background level of natural selection will have been significantly augmented by the intense selection for competitive track performance during the 400-year development of the Thoroughbred.

This performance selection, coupled with the intense management of Thoroughbreds, provides a unique opportunity to better understand the influence of genetic and environmental factors in athleticism. Management of training and nutrition have significant effects on the development of elite athletes, however these factors alone are insufficient to guarantee success. Breeders understand the importance of genetics in success since pedigrees reflect inherited variables and considerable weight is given to pedigrees in the selection of horses.


CANDIDATE GENES FOR PERFORMANCE


By 2006, more than 150 candidate genes for performance and health-related fitness traits had been identified in humans (Rankinen et al., 2006), almost five times the number reported in 2001 (Rankinen et al., 2001).

A well-characterised example of variation in a performance-related gene is an insertion allele at the angiotensin-converting enzyme (ACE) gene, which has been encountered more frequently in elite rowers, mountaineers and long-distance runners than in samples of the general population (Montgomery et al., 1998; Myerson et al., 1999).

On the other hand, the deletion allele has recently been found at higher frequencies in elite sprinters and short distance swimmers than endurance athletes (Tsianos et al., 2004). Other genes have been shown to be associated with physiological variables linked to cardiorespiratory function and skeletal muscle energetics (MacArthur and North, 2005).

Variant forms of candidate genes for athletic performance in Thoroughbreds are being investigated in order to provide information to breeders, owners and trainers about the genetic potential of their horses.


THE HORSE GENOME SEQUENCING PROJECT


In the horse, sequence variants have until now been detected in candidate genes by resequencing DNA fragments after amplification from different individuals sometimes following pre-screening and this approach has been effective for exploring sequence variation of individual genes in depth. Single nucleotide polymorphisms (SNPs) are stable, bi-allelic sequence variants that are distributed throughout the genome that can be assayed using high-throughput automated methods in order to investigate association with a particular trait.

In February 2007, the first assembly of the approximately 2.7 billion DNA base pairs in the genome of the horse was made public. The Horse Genome Sequencing project was funded by the National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH).

A team led by Kerstin Lindblad-Toh, Ph.D., at the Eli and Edythe L. Broad Institute of the Massachusetts Institute of Technology and Harvard University, in Cambridge, Massachusetts, in cooperation with the international horse genome mapping community, carried out the sequencing and assembly of the horse genome. This work included the identification and mapping of more than one million SNPs that can be interrogated in the search for genetic association with performance.

The availability of the Horse Genome Sequence will revolutionise equine genomics research towards identifying specific genes, mutations, and patterns of gene expression that impact both highly heritable and genetically complex diseases as well as athletic performance traits in horses.

In particular the availability of state-of-the-art molecular genomics tools will provide clinicians and scientists the means to study the normal cellular processes and devastating diseases of all physiological systems, and will offer new diagnostic and therapeutic approaches to improve management, reduce operating costs, improve animal welfare and greatly enhance prospects of success within the entire horse industry.


Functional genomics of performance

In recent years, gene expression studies at the pan-genomic level have revolutionised biological research. Fundamental advances in the area of functional genomics have enabled a massively greater understanding of genetic regulatory networks and molecular interactions in many biological realms — particularly in relation to disease phenotype (The Chipping Forecast II, 2002). For example, functional genomics approaches have already provided remarkable insights into the biology of cancer and promise to provide sophisticated new tools for diagnosis and treatment (van’t Veer et al., 2002).

Transcriptional profiling using cDNA microarrays allows measurement of the expression of thousands of genes simultaneously in a massively parallel fashion. Production of messenger RNA (mRNA) is the precursor to protein production, and differences in mRNA expression have clear phenotypic consequences. Gene expression can vary between cell types and cellular states, and in response to environmental stimuli. For example, resting muscle cells will have a different transcriptional profile from active muscle cells.

Although functional genomics has primarily focused on human biomolecular research, it is beginning to be applied to questions concerning disease and production traits in livestock (Hill et al., 2005). One application of these novel technologies is towards an understanding of the molecular networks that control cellular function. These technologies are now being used to address questions relating to muscle physiology in the horse.


MUSCULAR RESPONSES TO EXERCISE

Skeletal muscle, in particular, has a marked ability to respond to alterations in functional and environmental demands (Fluck, 2006). Cellular responses to exercise are under genetic control and reports on gene expression changes in human muscle tissue are rapidly increasing in the scientific literature (Mahoney et al., 2004; Pilegaard et al., 2000; Schmutz et al., 2006; Zoll et al., 2006).

Although studies of the genomics of exercise in the horse are also beginning to emerge (Poso et al., 2002; Jose-Cunilleras et al., 2005), this field is still in its infancy. Exercise-induced local hypoxia has been postulated to be the main signal for muscular adaptations (Hoppeler and Vogt, 2001).

Mostly these adaptations result in mitochondrial biogenesis and improved ATP provision (Irrcher et al., 2003) and an increased musculature via coordinated molecular events that support the growth of pre-existing muscle cells (Fluck and Hoppeler, 2003).

Exercise training involving repeated exposure of skeletal muscle to exercise conditions results in training-induced adaptations and consequently an accumulation of specific proteins in skeletal muscle (Hansen et al., 2005). Therefore, altered gene expression following single bouts of exercise cumulatively affects the resulting proteome. In this way for instance, proportions of muscle fibre types can be altered, e.g. training induces an increase in Type IIa (‘fast’ twitch) muscle fibre proteins (Rivero et al., 2007).

Currently we have an investigation underway to study muscular responses to exercise in the horse. Eight untrained 4-year-old Thoroughbred geldings from the same stables and destined for National Hunt training with the same trainer were exercised in an incremental step test to HRmax or fatigue on an equine high-speed treadmill.

Prior to inclusion in the study, all horses underwent a thorough physical examination and blood biochemistries were completed. Muscle biopsy samples (100 mg) were collected before, immediately after and 4 hrs after exercise for transcriptomics investigations. Heart rates were recorded for each velocity. Blood samples were collected before, immediately after and 5 min after exercise for lactate and PCV measurements. Microarray experiments and qRTPCR analysis of a panel of candidate genes are underway.


Integrating novel technologies in the equine industry

Genomic research studies are underway to investigate genome-wide and muscle-specific variation to identify genes contributing to racing performance variables in Thoroughbreds. This work will inform on performance potential in young Thoroughbreds and will also have implications for animal welfare. Introducing novel genomics technologies will contribute to a better understanding of fitness, responses to training, individualizing training programmes and minimizing injury risk.

In particular, the integration of genomics information into the Thoroughbred racing and breeding industries has massive potential for early ‘talent identification.’ Thoroughbreds are traditionally selected for racing and breeding based on pedigree information as well as numerous phenotypic characteristics. Early identification of genetic potential, by traditional or novel means, is paramount to success.

Within the industry the quest to find an ‘edge’ pushes those involved to constantly consider new methods and techniques. Therefore, novel genomics information has the potential to directly assist breeders and trainers to fine-tune often multi-million dollar decisions by providing previously inaccessible information.


References
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