A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses

Background: Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse. Results: Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb – 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p <0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042). Conclusions: Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses

Identification of a Mutation Associated with Fatal Foal Immunodeficiency Syndrome in the Fell and Dales Pony

The Fell and Dales are rare native UK pony breeds at risk due to falling numbers, in-breeding, and inherited disease. Specifically, the lethal Mendelian recessive disease Foal Immunodeficiency Syndrome (FIS), which manifests as B-lymphocyte immunodeficiency and progressive anemia, is a substantial threat. A significant percentage (∼10%) of the Fell ponies born each year dies from FIS, compromising the long-term survival of this breed. Moreover, the likely spread of FIS into other breeds is of major concern. Indeed, FIS was identified in the Dales pony, a related breed, during the course of this work. Using a stepwise approach comprising linkage and homozygosity mapping followed by haplotype analysis, we mapped the mutation using 14 FIS–affected, 17 obligate carriers, and 10 adults of unknown carrier status to a ∼1 Mb region (29.8 – 30.8 Mb) on chromosome (ECA) 26. A subsequent genome-wide association study identified two SNPs on ECA26 that showed genome-wide significance after Bonferroni correction for multiple testing: BIEC2-692674 at 29.804 Mb and BIEC2-693138 at 32.19 Mb. The associated region spanned 2.6 Mb from ∼29.6 Mb to 32.2 Mb on ECA26. Re-sequencing of this region identified a mutation in the sodium/myo-inositol cotransporter gene (SLC5A3); this causes a P446L substitution in the protein. This gene plays a crucial role in the regulatory response to osmotic stress that is essential in many tissues including lymphoid tissues and during early embryonic development. We propose that the amino acid substitution we identify here alters the function of SLC5A3, leading to erythropoiesis failure and compromise of the immune system. FIS is of significant biological interest as it is unique and is caused by a gene not previously associated with a mammalian disease. Having identified the associated gene, we are now able to eradicate FIS from equine populations by informed selective breeding

Genetic diversity in the modern horse illustrated from genome-wide SNP data

Horses were domesticated from the Eurasian steppes 5,000-6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. F(ST) calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection

Genetic Diversity in the Modern Horse Illustrated from Genome-Wide SNP Data

Horses were domesticated from the Eurasian steppes 5,000–6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. FST calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection

Genetic Diversity in the Modern Horse Illustrated from Genome-Wide SNP Data

Peer reviewe

Genome-Wide Analysis Reveals Selection for Important Traits in Domestic Horse Breeds

Peer reviewe

Foal immunodeficiency syndrome : identification of the causal mutation

Foal Immunodeficiency Syndrome (FIS), is a disease that affects both Fell and Dales Ponies. FIS results in a profound anaemia and a severe deficiency in the number of circulating Bvlymphocytes. Consequently, FIS-affected foals begin to lose condition and suffer from multiple opportunistic infections; FIS is eventually fatal. Pedigree analysis, incorporating the knowledge of FIS-affected individuals, suggested that FIS is a genetic disorder, with an autosomal recessive mode of inheritance. Further, analysis of the Fell and Dales Pony stud book revealed a common founder stallion, in the maternal and paternal lineage of all Fell and Dales FIS-affected individuals. Based on this, the primary aim of this investigation was to characterise the genetic lesion responsible for FIS, and subsequently develop a diagnostic test which could be used to identify asymptomatic carriers. Two approaches were taken in this study to definitively map the FIS locus; a micro satellite whole-genome scan, and a genome-wide association study. Linkage analysis and homozygosity mapping of the micro satellite marker data revealed a single locus which showed significant linkage to FIS. This was then further supported with the genome-wide association study, using the EquineSNP50 Beadchip, which identified the same locus with a significant disease association. After additional fine-mapping of the associated region, four plausible candidate genes were identified and subsequently investigated, although none revealed the causative mutation. Therefore, the entire FIS critical interval was sequenced using next-generation re-sequencing. This led to the identification of a non-synonymous single nucleotide polymorphism, in the single ex on of the sodium/myo-inositol cotransporter gene (SLC5A 3) , which is highly associated with the FIS phenotype. This gene plays a crucial role in the osmoregulation of tissues, a process which has been shown to be extremely important in the development of lymphoid tissues, lymphocytes, peripheral nerves and during early embryonic development. Further functional studies are now required to assess the functional consequences of this mutation. The identification of this mutation has led to the development of a diagnostic test, which is not only used to identify asymptomatic carriers of FIS, but also to definitively diagnose foals which are suspected FIS-affected. Additionally, this test has been used to perform a population screen, to assess the prevalence of the FIS mutation and investigate possible transfer into other equine breeds. This revealed that carrier prevalence is approximately 40-50% in the Fell Pony and 10-20% in the Dales Pony. Further, this confirmed that the FIS mutation had transferred into the Coloured pony population. Global transcriptional changes in FIS-affected foals were evaluated as part of a pilot study. This revealed significant disruption of multiple pathways, including those responsible for the haematological system and its development, tissue development and cell growth. Due to the severe clinical presentation of the FIS-affected foals used in this study, this data provides limited information on primary consequences of the causal variant. Rather it provides a snapshot of the transcriptional changes associated with the downstream effects of the FIS-causal variant and the multiple pathological effects associated with this.EThOS - Electronic Theses Online ServiceGBUnited Kingdo