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2.
J Assist Reprod Genet ; 36(3): 543-556, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30470961

ABSTRACT

PURPOSE: This study aims to determine if intra-ovarian injection of bone marrow-derived mesenchymal stem cells (MSCs) improves or restores ovarian function in aged females. METHODS: Prospective randomized study of eight aged mares and six young mares receiving intra-ovarian injection of MSCs or vehicle. Main outcome measures were antral follicle count and serum anti-Müllerian hormone (AMH) (aged and young mares), and for aged mares, oocyte meiotic and developmental competence; gross and histological ovarian assessment; evaluation of presence of chimerism in recovered granulosa cells and in ovarian tissue samples; and gene expression in ovarian tissue as assessed by RNA sequencing. RESULTS: Injection of MSCs was not associated with significant changes in follicle number, oocyte recovery rate on follicle aspiration, oocyte maturation rate, or blastocyst rate after ICSI in aged mares, or in changes in follicle number in young mares. There were no significant changes in peripheral AMH concentrations, indicating a lack of effect on growing follicles. MSC donor DNA was not recovered in granulosa cells or in ovarian tissue, indicating lack of persistence of injected MSC. RNA sequencing revealed significant differences in gene expression between MSC- and vehicle-injected ovaries. CONCLUSIONS: Intra-ovarian injection of bone marrow-derived MSCs altered gene expression but did not improve ovarian function in aged mares.


Subject(s)
Granulosa Cells/transplantation , Mesenchymal Stem Cell Transplantation , Ovarian Follicle/growth & development , Ovary/growth & development , Animals , Estradiol/metabolism , Female , Horses , Mesenchymal Stem Cells/cytology , Oocyte Retrieval , Oocytes/growth & development , Prospective Studies , Sequence Analysis, RNA
3.
Int J Cancer ; 141(2): 342-353, 2017 07 15.
Article in English | MEDLINE | ID: mdl-28425625

ABSTRACT

Squamous cell carcinoma (SCC) is the most common cancer of the equine eye, frequently originating at the limbus, with the potential to invade the cornea, cause visual impairment, and result in loss of the eye. Several breeds of horses have a high occurrence of limbal SCC implicating a genetic basis for limbal SCC predisposition. Pedigree analysis in the Haflinger breed supports a simple recessive mode of inheritance and a genome-wide association study (N = 23) identified a 1.5 Mb locus on ECA12 significantly associated with limbal SCC (Pcorrected = 0.04). Sequencing the most physiologically relevant gene from this locus, damage specific DNA binding protein 2 (DDB2), identified a missense mutation (c.1013 C > T p.Thr338Met) that was strongly associated with limbal SCC (P = 3.41 × 10-10 ). Genotyping 42 polymorphisms narrowed the ECA12 candidate interval to 483 kb but did not identify another variant that was more strongly associated. DDB2 binds to ultraviolet light damaged DNA and recruits other proteins to perform global genome nucleotide excision repair. Computational modeling predicts this mutation to be deleterious by altering conformation of the ß loop involved in photolesion recognition. This DDB2 variant was also detected in two other closely related breeds with reported cases of ocular SCC, the Belgian and the Percheron, suggesting it may also be a SCC risk factor in these breeds. Furthermore, in humans xeroderma pigmentosum complementation group E, a disease characterized by sun sensitivity and increased risk of cutaneous SCC and melanomas, is explained by mutations in DDB2. Cross-species comparison remains to be further evaluated.


Subject(s)
Carcinoma, Squamous Cell/veterinary , DNA-Binding Proteins/genetics , Eye Neoplasms/veterinary , Horse Diseases/genetics , Limbus Corneae/pathology , Mutation, Missense , Animals , Carcinoma, Squamous Cell/genetics , Computational Biology , DNA Damage , DNA-Binding Proteins/chemistry , Eye Neoplasms/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study/veterinary , Horses , Male , Pedigree , Protein Structure, Secondary , Sequence Analysis, DNA/veterinary
4.
G3 (Bethesda) ; 7(4): 1315-1321, 2017 04 03.
Article in English | MEDLINE | ID: mdl-28235824

ABSTRACT

Naked foal syndrome (NFS) is a genodermatosis in the Akhal-Teke horse breed. We provide the first scientific description of this phenotype. Affected horses have almost no hair and show a mild ichthyosis. So far, all known NFS affected horses died between a few weeks and 3 yr of age. It is not clear whether a specific pathology caused the premature deaths. NFS is inherited as a monogenic autosomal recessive trait. We mapped the disease causing genetic variant to two segments on chromosomes 7 and 27 in the equine genome. Whole genome sequencing of two affected horses, two obligate carriers, and 75 control horses from other breeds revealed a single nonsynonymous genetic variant on the chromosome 7 segment that was perfectly associated with NFS. The affected horses were homozygous for ST14:c.388G>T, a nonsense variant that truncates >80% of the open reading frame of the ST14 gene (p.Glu130*). The variant leads to partial nonsense-mediated decay of the mutant transcript. Genetic variants in the ST14 gene are responsible for autosomal recessive congenital ichthyosis 11 in humans. Thus, the identified equine ST14:c.388G>T variant is an excellent candidate causative variant for NFS, and the affected horses represent a large animal model for a known human genodermatosis. Our findings will enable genetic testing to avoid the nonintentional breeding of NFS-affected foals.


Subject(s)
Codon, Nonsense/genetics , Horse Diseases/genetics , Horses/genetics , Tumor Suppressor Proteins/genetics , Animals , Base Sequence , Chromosome Mapping , Female , Genetic Linkage , Genetic Predisposition to Disease , Heterozygote , Horse Diseases/pathology , Male , Phenotype , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Analysis, DNA , Syndrome , Tumor Suppressor Proteins/metabolism
5.
G3 (Bethesda) ; 6(9): 2963-70, 2016 09 08.
Article in English | MEDLINE | ID: mdl-27449517

ABSTRACT

We investigated a family of horses exhibiting irregular vertical stripes in their hair coat texture along the neck, back, hindquarters, and upper legs. This phenotype is termed "brindle" by horse breeders. We propose the term "brindle 1 (BR1)" for this specific form of brindle. In some BR1 horses, the stripes were also differentially pigmented. Pedigree analyses were suggestive of a monogenic X-chromosomal semidominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of four BR1 and 60 nonbrindle horses identified 61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBTPS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBTPS2 transcripts in skin, and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBTPS2:c1437+4T>C variant showed perfect cosegregation with the brindle phenotype in the investigated family, and was absent from 457 control horses of diverse breeds. Altogether, our genetic data, and previous knowledge on MBTPS2 function in the skin, suggest that the identified MBTPS2 intronic variant leads to partial exon skipping, and causes the BR1 phenotype in horses.


Subject(s)
Hair/metabolism , Horses/genetics , Metalloendopeptidases/genetics , RNA Splicing/genetics , Animals , Exons/genetics , Hair/growth & development , Humans , Introns/genetics , Phenotype , Skin Diseases/genetics , Skin Diseases/pathology , X Chromosome/genetics
6.
Genet Sel Evol ; 45: 35, 2013 Sep 30.
Article in English | MEDLINE | ID: mdl-24079454

ABSTRACT

BACKGROUND: Determining the value of livestock breeds is essential to define conservation priorities, manage genetic diversity and allocate funds. Within- and between-breed genetic diversity need to be assessed to preserve the highest intra-specific variability. Information on genetic diversity and risk status is still lacking for many Creole cattle breeds from the Americas, despite their distinct evolutionary trajectories and adaptation to extreme environmental conditions. METHODS: A comprehensive genetic analysis of 67 Iberoamerican cattle breeds was carried out with 19 FAO-recommended microsatellites to assess conservation priorities. Contributions to global diversity were investigated using alternative methods, with different weights given to the within- and between-breed components of genetic diversity. Information on Iberoamerican plus 15 worldwide cattle breeds was used to investigate the contribution of geographical breed groups to global genetic diversity. RESULTS: Overall, Creole cattle breeds showed a high level of genetic diversity with the highest level found in breeds admixed with zebu cattle, which were clearly differentiated from all other breeds. Within-breed kinships revealed seven highly inbred Creole breeds for which measures are needed to avoid further genetic erosion. However, if contribution to heterozygosity was the only criterion considered, some of these breeds had the lowest priority for conservation decisions. The Weitzman approach prioritized highly differentiated breeds, such as Guabalá, Romosinuano, Cr. Patagonico, Siboney and Caracú, while kinship-based methods prioritized mainly zebu-related breeds. With the combined approaches, breed ranking depended on the weights given to the within- and between-breed components of diversity. Overall, the Creole groups of breeds were generally assigned a higher priority for conservation than the European groups of breeds. CONCLUSIONS: Conservation priorities differed significantly according to the weight given to within- and between-breed genetic diversity. Thus, when establishing conservation programs, it is necessary to also take into account other features. Creole cattle and local isolated breeds retain a high level of genetic diversity. The development of sustainable breeding and crossbreeding programs for Creole breeds, and the added value resulting from their products should be taken into consideration to ensure their long-term survival.


Subject(s)
Cattle/genetics , Chromosomes, Mammalian , Genetic Variation , Microsatellite Repeats , Animals , Breeding , Evolution, Molecular , Genetic Markers , Genotype , Phylogeny
7.
PLoS One ; 8(1): e54997, 2013.
Article in English | MEDLINE | ID: mdl-23383025

ABSTRACT

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.


Subject(s)
Genomics , Horses/genetics , Polymorphism, Single Nucleotide , Animals , Breeding , Cluster Analysis , Horses/classification , Principal Component Analysis
8.
PLoS Genet ; 9(1): e1003211, 2013.
Article in English | MEDLINE | ID: mdl-23349635

ABSTRACT

Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.


Subject(s)
Genome-Wide Association Study , Horses/genetics , Myostatin/genetics , Selection, Genetic , Animals , Biological Evolution , Breeding , Genotype , Haplotypes , Phenotype , Polymorphism, Single Nucleotide
9.
PLoS One ; 7(11): e49066, 2012.
Article in English | MEDLINE | ID: mdl-23155451

ABSTRACT

BACKGROUND: American Creole cattle presumably descend from animals imported from the Iberian Peninsula during the period of colonization and settlement, through different migration routes, and may have also suffered the influence of cattle directly imported from Africa. The introduction of European cattle, which began in the 18th century, and later of Zebu from India, has threatened the survival of Creole populations, some of which have nearly disappeared or were admixed with exotic breeds. Assessment of the genetic status of Creole cattle is essential for the establishment of conservation programs of these historical resources. METHODOLOGY/PRINCIPAL FINDINGS: We sampled 27 Creole populations, 39 Iberian, 9 European and 6 Zebu breeds. We used microsatellite markers to assess the origins of Creole cattle, and to investigate the influence of different breeds on their genetic make-up. The major ancestral contributions are from breeds of southern Spain and Portugal, in agreement with the historical ports of departure of ships sailing towards the Western Hemisphere. This Iberian contribution to Creoles may also include some African influence, given the influential role that African cattle have had in the development of Iberian breeds, but the possibility of a direct influence on Creoles of African cattle imported to America can not be discarded. In addition to the Iberian influence, the admixture with other European breeds was minor. The Creoles from tropical areas, especially those from the Caribbean, show clear signs of admixture with Zebu. CONCLUSIONS/SIGNIFICANCE: Nearly five centuries since cattle were first brought to the Americas, Creoles still show a strong and predominant signature of their Iberian ancestors. Creole breeds differ widely from each other, both in genetic structure and influences from other breeds. Efforts are needed to avoid their extinction or further genetic erosion, which would compromise centuries of selective adaptation to a wide range of environmental conditions.


Subject(s)
Cattle/genetics , Genetic Variation , Animals , Breeding , Microsatellite Repeats
10.
PLoS One ; 7(6): e38601, 2012.
Article in English | MEDLINE | ID: mdl-22685589

ABSTRACT

BACKGROUND: Most genetic studies on modern cattle have established a common origin for all taurine breeds in the Near East, during the Neolithic transition about 10 thousand years (ka) ago. Yet, the possibility of independent and/or secondary domestication events is still debated and is fostered by the finding of rare mitochondrial DNA (mtDNA) haplogroups like P, Q and R. Haplogroup T1, because of its geographic distribution, has been the subject of several investigations pointing to a possible independent domestication event in Africa and suggesting a genetic contribution of African cattle to the formation of Iberian and Creole cattle. Whole mitochondrial genome sequence analysis, with its proven effectiveness in improving the resolution of phylogeographic studies, is the most appropriate tool to investigate the origin and structure of haplogroup T1. METHODOLOGY: A survey of >2200 bovine mtDNA control regions representing 28 breeds (15 European, 10 African, 3 American) identified 281 subjects belonging to haplogroup T1. Fifty-four were selected for whole mtDNA genome sequencing, and combined with ten T1 complete sequences from previous studies into the most detailed T1 phylogenetic tree available to date. CONCLUSIONS: Phylogenetic analysis of the 64 T1 mitochondrial complete genomes revealed six distinct sub-haplogroups (T1a-T1f). Our data support the overall scenario of a Near Eastern origin of the T1 sub-haplogroups from as much as eight founding T1 haplotypes. However, the possibility that one sub-haplogroup (T1d) arose in North Africa, in domesticated stocks, shortly after their arrival from the Near East, can not be ruled out. Finally, the previously identified "African-derived American" (AA) haplotype turned out to be a sub-clade of T1c (T1c1a1). This haplotype was found here for the first time in Africa (Egypt), indicating that it probably originated in North Africa, reached the Iberian Peninsula and sailed to America, with the first European settlers.


Subject(s)
Cattle/genetics , Genome, Mitochondrial/genetics , Haplotypes , Phylogeny , Africa , Americas , Animals , Cattle/classification , DNA, Mitochondrial/chemistry , DNA, Mitochondrial/genetics , Europe , Evolution, Molecular , Genetic Variation , Molecular Sequence Data , Sequence Analysis, DNA , Species Specificity , Time Factors
11.
PLoS Genet ; 8(4): e1002653, 2012.
Article in English | MEDLINE | ID: mdl-22511888

ABSTRACT

During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The "splashed white" pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes.


Subject(s)
Horses/genetics , Microphthalmia-Associated Transcription Factor/genetics , Mutation , Paired Box Transcription Factors/genetics , Pigmentation/genetics , Animals , Base Sequence , Chromosome Mapping , Color , Genetic Linkage , Genome , Genome-Wide Association Study , Hair Color , Lod Score , Melanocytes/metabolism , Microphthalmia-Associated Transcription Factor/metabolism , Molecular Sequence Data , Phenotype , Promoter Regions, Genetic
12.
Proc Natl Acad Sci U S A ; 109(7): 2449-54, 2012 Feb 14.
Article in English | MEDLINE | ID: mdl-22308342

ABSTRACT

Archaeological and genetic evidence concerning the time and mode of wild horse (Equus ferus) domestication is still debated. High levels of genetic diversity in horse mtDNA have been detected when analyzing the control region; recurrent mutations, however, tend to blur the structure of the phylogenetic tree. Here, we brought the horse mtDNA phylogeny to the highest level of molecular resolution by analyzing 83 mitochondrial genomes from modern horses across Asia, Europe, the Middle East, and the Americas. Our data reveal 18 major haplogroups (A-R) with radiation times that are mostly confined to the Neolithic and later periods and place the root of the phylogeny corresponding to the Ancestral Mare Mitogenome at ~130-160 thousand years ago. All haplogroups were detected in modern horses from Asia, but F was only found in E. przewalskii--the only remaining wild horse. Therefore, a wide range of matrilineal lineages from the extinct E. ferus underwent domestication in the Eurasian steppes during the Eneolithic period and were transmitted to modern E. caballus breeds. Importantly, now that the major horse haplogroups have been defined, each with diagnostic mutational motifs (in both the coding and control regions), these haplotypes could be easily used to (i) classify well-preserved ancient remains, (ii) (re)assess the haplogroup variation of modern breeds, including Thoroughbreds, and (iii) evaluate the possible role of mtDNA backgrounds in racehorse performance.


Subject(s)
Animals, Domestic/genetics , DNA, Mitochondrial/genetics , Genome , Haplotypes , Horses/genetics , Animals , Horses/classification , Phylogeny
13.
Exp Clin Psychopharmacol ; 20(3): 173-80, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22250657

ABSTRACT

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is used in anesthetic, abuse, and therapeutic contexts. Recent evidence suggests that ketamine may affect not only glutamate systems, but may also act on receptors in the dopamine and serotonin systems. Because monoamine neurotransmitters play important trophic roles in prenatal development, we hypothesized that the behavioral consequences of prenatal exposure to ketamine may be moderated by genotype of the promoter in the monoamine oxidase-A (MAOA) gene. Eighty-two infant rhesus monkeys were identified that had known dates of conception and exposures to ketamine during gestation. Animals were tested at 3-4 months of age on a battery of tests assessing responsiveness to maternal separation, recognition memory, and contact with novel objects. Animals were classified by putative activity levels for the MAOA genotype. The effects of prenatal ketamine exposure were seen only in the context of MAOA genotype. Greater exposure to ketamine resulted in increased activity, less willingness to perform in the memory task, and reduced emotionality and novel-object contact, but only for individuals with the low-activity genotype. Nearly all effects of ketamine were the result of first- and second-trimester exposure. MAOA genotype moderates the role of prenatal ketamine exposure at time points in gestation earlier than have been shown in past research, and is particularly evident for measures of emotionality. These results support the idea that ketamine's use might be best considered in light of individuals' genetic characteristics.


Subject(s)
Emotions/drug effects , Ketamine/adverse effects , Monoamine Oxidase/genetics , Prenatal Exposure Delayed Effects/genetics , Prenatal Exposure Delayed Effects/psychology , Animals , Exploratory Behavior/drug effects , Female , Genotype , Macaca mulatta , Male , Maternal Deprivation , Pregnancy , Recognition, Psychology/drug effects
14.
PLoS Genet ; 8(1): e1002451, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22253606

ABSTRACT

An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of ∼43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50-100 kb and reached background levels within 1-2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of ∼750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species.


Subject(s)
Genotyping Techniques , Horses/genetics , Perissodactyla/genetics , Polymorphism, Single Nucleotide/genetics , Animals , Biological Evolution , Breeding , Chromosome Mapping , Gene Frequency , Genetic Linkage , Genetic Variation , Haplotypes , Linkage Disequilibrium , Phylogeny
15.
Am J Vet Res ; 72(7): 940-4, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21728855

ABSTRACT

OBJECTIVE: To determine the mode of inheritance for cerebellar abiotrophy (CA), a neurologic disease in Arabians. ANIMALS: 804 Arabians, including 29 horses (15 males and 14 females) with CA. PROCEDURES: Most horses (n = 755) belonged to 1 of 4 paternal families. Among the 29 CA-affected horses, all had clinical signs consistent with the disease; the disease was confirmed histologically following euthanasia in 8 horses. From the pedigree information, inbreeding coefficients were calculated for 16 affected horses and compared with coefficients for a subgroup of 16 unaffected horses. Complex segregation analysis was used to determine the effect of a putative Mendelian locus on the development of the disease and the probable mode of inheritance of CA. RESULTS: The mean inbreeding coefficient was 0.0871 for CA-affected and unaffected horses, suggesting that all of the Arabians were inbred to the same degree and that affected horses were not more inbred than were unaffected horses. Results of the complex segregation analysis were consistent with a single Mendelian autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL RELEVANCE: Knowledge of the mode of inheritance of CA should help breeders to make informed decisions regarding the selection of animals for mating when closely related horses have developed CA or produced CA-affected foals.


Subject(s)
Cerebellar Diseases/veterinary , Genetic Variation , Horse Diseases/genetics , Horses/genetics , Animals , Atrophy/genetics , Atrophy/veterinary , Cerebellar Diseases/genetics , Cerebellar Diseases/pathology , Cerebellum/pathology , Female , Male , Pedigree
16.
BMC Ecol ; 11: 5, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21284886

ABSTRACT

BACKGROUND: A key challenge for conservation biologists is to determine the most appropriate demographic and genetic management strategies for wildlife populations threatened by disease. We explored this topic by examining whether genetic background and previous pathogen exposure influenced survival of translocated animals when captive-bred and free-ranging bighorn sheep (Ovis canadensis) were used to re-establish a population that had been extirpated in the San Andres Mountains in New Mexico, USA. RESULTS: Although the free-ranging source population had significantly higher multi-locus heterozygosity at 30 microsatellite loci than the captive bred animals, neither source population nor genetic background significantly influenced survival or cause of death. The presence of antibodies to a respiratory virus known to cause pneumonia was associated with increased survival, but there was no correlation between genetic heterozygosity and the presence of antibodies to this virus. CONCLUSIONS: Although genetic theory predicts otherwise, increased heterozygosity was not associated with increased fitness (survival) among translocated animals. While heterosis or genetic rescue effects may occur in F1 and later generations as the two source populations interbreed, we conclude that previous pathogen exposure was a more important marker than genetic heterozygosity for predicting survival of translocated animals. Every wildlife translocation is an experiment, and whenever possible, translocations should be designed and evaluated to test hypotheses that will further improve our understanding of how pathogen exposure and genetic variability influence fitness.


Subject(s)
Animal Diseases/genetics , Animal Diseases/virology , Animals, Wild/genetics , Sheep/genetics , Animal Diseases/immunology , Animal Diseases/mortality , Animal Migration , Animals , Animals, Wild/immunology , Animals, Wild/virology , Antibodies, Viral/immunology , Conservation of Natural Resources , Heterozygote , Host-Pathogen Interactions , New Mexico , Sheep/immunology , Sheep/virology , Viruses/immunology
17.
PLoS One ; 6(1): e15922, 2011 Jan 06.
Article in English | MEDLINE | ID: mdl-21253012

ABSTRACT

BACKGROUND: Diversity patterns of livestock species are informative to the history of agriculture and indicate uniqueness of breeds as relevant for conservation. So far, most studies on cattle have focused on mitochondrial and autosomal DNA variation. Previous studies of Y-chromosomal variation, with limited breed panels, identified two Bos taurus (taurine) haplogroups (Y1 and Y2; both composed of several haplotypes) and one Bos indicus (indicine/zebu) haplogroup (Y3), as well as a strong phylogeographic structuring of paternal lineages. METHODOLOGY AND PRINCIPAL FINDINGS: Haplogroup data were collected for 2087 animals from 138 breeds. For 111 breeds, these were resolved further by genotyping microsatellites INRA189 (10 alleles) and BM861 (2 alleles). European cattle carry exclusively taurine haplotypes, with the zebu Y-chromosomes having appreciable frequencies in Southwest Asian populations. Y1 is predominant in northern and north-western Europe, but is also observed in several Iberian breeds, as well as in Southwest Asia. A single Y1 haplotype is predominant in north-central Europe and a single Y2 haplotype in central Europe. In contrast, we found both Y1 and Y2 haplotypes in Britain, the Nordic region and Russia, with the highest Y-chromosomal diversity seen in the Iberian Peninsula. CONCLUSIONS: We propose that the homogeneous Y1 and Y2 regions reflect founder effects associated with the development and expansion of two groups of dairy cattle, the pied or red breeds from the North Sea and Baltic coasts and the spotted, yellow or brown breeds from Switzerland, respectively. The present Y1-Y2 contrast in central Europe coincides with historic, linguistic, religious and cultural boundaries.


Subject(s)
Cattle/genetics , Dairying , Genetic Variation , Y Chromosome/genetics , Animals , Europe , Founder Effect , Haplotypes , Male
18.
Genomics ; 97(2): 121-9, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21126570

ABSTRACT

Equine Cerebellar Abiotrophy (CA) is a neurological disease found in Arabian horses. CA is characterized by post-natal degeneration of the Purkinje cells of the cerebellum. Signs of CA include ataxia, head tremors, and a lack of balance equilibrium. We have discovered a linkage of the CA phenotype to a microsatellite marker on ECA2 and identified a region of conserved homozygosity spanning approximately 142 kb. Complete sequencing of the four genes in this region identified one SNP found only in Arabian horses, located in exon 4 of TOE1 and approximately 1200 base pairs upstream of MUTYH, adjacent to a possible binding site for the transcription factor GATA2. qPCR analysis of cDNA from the cerebella of affected and unaffected horses suggested that MUTYH expression is down-regulated in affected horses. This SNP may therefore have a function effect on TOE1, or a regulatory effect on MUTYH by negatively affecting the binding affinity of GATA2.


Subject(s)
Cerebellar Diseases/veterinary , DNA Glycosylases/genetics , Gene Expression Regulation , Horse Diseases/genetics , Horses/genetics , Animals , Cerebellar Diseases/genetics , Cerebellar Diseases/pathology , Cerebellum/metabolism , Cerebellum/pathology , Chromosome Mapping , GATA2 Transcription Factor/metabolism , Genetic Association Studies , Genetic Linkage , Homozygote , Horse Diseases/pathology , Mutation , Polymorphism, Single Nucleotide , Purkinje Cells/metabolism , Purkinje Cells/pathology
19.
Blood ; 116(24): 5403-18, 2010 Dec 09.
Article in English | MEDLINE | ID: mdl-20833977

ABSTRACT

We have developed a major histocompatibility complex-defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8(+) and CD4(+) granzyme B(+) effector cells and FoxP3(pos)/CD27(high)/CD25(pos)/CD127(low) CD4(+) T cells. CD8(+) cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL-18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-γ, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-resistant CD28(-) CD8(+) T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control.


Subject(s)
CD28 Antigens , CD8-Positive T-Lymphocytes/immunology , Graft vs Host Disease/prevention & control , Immunosuppression Therapy/methods , Sirolimus/therapeutic use , Animals , Cell Proliferation , Graft vs Host Disease/etiology , Graft vs Host Disease/pathology , Haplotypes , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphocyte Activation , Macaca mulatta , Sirolimus/immunology
20.
J Am Vet Med Assoc ; 234(1): 120-5, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19119976

ABSTRACT

OBJECTIVE: To estimate allele frequencies of the hyperkalaemic periodic paralysis (HYPP), lethal white foal syndrome (LWFS), glycogen branching enzyme deficiency (GBED), hereditary equine regional dermal asthenia (HERDA), and type 1 polysaccharide storage myopathy (PSSM) genes in elite performance subgroups of American Quarter Horses (AQHs). DESIGN: Prospective genetic survey. ANIMALS: 651 elite performance AQHs, 200 control AQHs, and 180 control American Paint Horses (APHs). PROCEDURES: Elite performance AQHs successful in 7 competitive disciplines (barrel racing, cutting, halter, racing, reining, western pleasure, and working cow horse) were geno- typed for 5 disease-causing alleles. Age-matched control AQHs and APHs were used to establish comparative whole-breed estimates of allele frequencies. RESULTS: Highest allele frequencies among control AQHs were for type 1 PSSM (0.055) and GBED (0.054), whereas HERDA (0.021) and HYPP (0.008) were less prevalent. Control APHs uniquely harbored LWFS (0.107) and had high prevalence of HYPP (0.025), relative to AQHs. Halter horse subgroups had significantly greater allele frequencies for HYPP (0.299) and PSSM (0.155). Glycogen branching enzyme deficiency, HERDA, and PSSM were found broadly throughout subgroups; cutting subgroups were distinct for HERDA (0.142), and western pleasure subgroups were distinct for GBED (0.132). Racing and barrel racing subgroups had the lowest frequencies of the 5 disease genes. CONCLUSIONS AND CLINICAL RELEVANCE: Accurate estimates of disease-causing alleles in AQHs and APHs may guide use of diagnostic genetic testing, aid management of genetic diseases, and help minimize production of affected foals.


Subject(s)
Gene Frequency , Genetic Diseases, Inborn/veterinary , Horse Diseases/genetics , Pedigree , 1,4-alpha-Glucan Branching Enzyme/deficiency , 1,4-alpha-Glucan Branching Enzyme/genetics , Animals , Asthenia/genetics , Asthenia/veterinary , Female , Fetal Death/genetics , Fetal Death/veterinary , Genes, Lethal , Genetic Diseases, Inborn/genetics , Genetic Predisposition to Disease , Genetic Testing , Glycogen Storage Disease Type IV/genetics , Glycogen Storage Disease Type IV/veterinary , Hair Color/genetics , Horses , Male , Paralysis, Hyperkalemic Periodic/genetics , Paralysis, Hyperkalemic Periodic/veterinary , Pregnancy , Prospective Studies , Syndrome
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