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

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          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.

          Author Summary

          Foal Immunodeficiency Syndrome (FIS) is a genetic disease that affects two related British pony breeds, namely the Fell and the Dales. Foals with FIS appear to be normal at birth but within a few weeks develop evidence of infection such as diarrhoea, pneumonia, etc. The infections are resistant to treatment, and the foals die or are euthanized before three months of age. The foals also suffer from a severe progressive anemia. Being a recessive condition, the disease is difficult to control without a diagnostic DNA test to identify symptom-free carrier parents. Within the last few years the horse genome has been sequenced, and this has allowed the development of tools to identify genetic mutations in the horse at high resolution. In this article we demonstrate the use of these new tools to identify the location of the FIS mutation. The presumptive causal lesion was then identified by sequencing this region. This has enabled us to develop a test that can be used to identify carrier ponies, allowing breeders to avoid FIS in their foal crop.

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          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                July 2011
                July 2011
                7 July 2011
                : 7
                : 7
                [1 ]Animal Health Trust, Newmarket, United Kingdom
                [2 ]Department of Infection Biology, School of Veterinary Science, University of Liverpool, Liverpool, United Kingdom
                [3 ]Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
                [4 ]Department of Veterinary Clinical Science, Equine Hospital, University of Liverpool, Liverpool, United Kingdom
                [5 ]Townhead Veterinary Centre, Townhead Farm, Penrith, United Kingdom
                [6 ]Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom
                Cornell University, United States of America
                Author notes

                Conceived and designed the experiments: SDC WEO JES. Performed the experiments: LYF-C IG JES. Analyzed the data: LYF-C IG JES. Contributed reagents/materials/analysis tools: NH DCK PDFM. Wrote the paper: JES.

                Fox-Clipsham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 8
                Research Article
                Animal Genetics
                Genetics of Disease
                Immune System
                Bone Marrow
                Lymphoid Organs
                Genetics of the Immune System
                Veterinary Science
                Animal Types
                Large Animals
                Veterinary Medicine
                Veterinary Diagnostics
                Veterinary Immunology



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