Utsunomiya-shi, Japan
Utsunomiya-shi, Japan

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McCue M.E.,University of Minnesota | Bannasch D.L.,University of California at Davis | Petersen J.L.,University of Minnesota | Gurr J.,University of Sydney | And 18 more authors.
PLoS Genetics | Year: 2012

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. © 2012 McCue et al.

Hauswirth R.,University of Bern | Haase B.,University of Sydney | Blatter M.,Swiss National Stud | Brooks S.A.,Cornell University | And 16 more authors.
PLoS Genetics | Year: 2012

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. © 2012 Hauswirth et al.

Tozaki T.,Laboratory of Racing Chemistry | Miyake T.,Kyoto University | Kakoi H.,Laboratory of Racing Chemistry | Gawahara H.,Laboratory of Racing Chemistry | And 3 more authors.
Journal of Animal Breeding and Genetics | Year: 2012

This study evaluated the differences between linear and non-linear modelled heritability estimates of racing performance based on lifetime earnings (LE) and lifetime ranking (LR) in Japanese Thoroughbred racehorses. The heritability estimate (h2=0.25) obtained from a non-linear model based on formal Japan Racing Association ranking was much higher than that obtained from a linear model based on the original trait phenotype (h2=0.11). The linear models showed slightly higher heritability estimates under the trait categorizations than under the original phenotypes, while the non-linear categorical trait models showed much higher heritability estimates than the linear models, especially for binary trait categorizations (h2=0.34) with non-winning and winning horses. The binary trait categorizations were consistent with the case and control classifications in the previous genome-wide association study (GWAS), which identified possible sequence variants on ECA18 that affect racing performance in Japanese Thoroughbred racehorses. Those findings suggested that the different heritability estimates obtained from several trait categorizations would reflect the possible presence of susceptibility gene segregations in the analyzed population, indicating that heritability estimates from non-linear models are useful for the selection of case and control populations in GWAS. © 2011 Blackwell Verlag GmbH.

Tozaki T.,Laboratory of Racing Chemistry | Hill E.W.,University College Dublin | Hirota K.,Laboratory of Racing Chemistry | Kakoi H.,Laboratory of Racing Chemistry | And 7 more authors.
Animal Genetics | Year: 2012

Using 1710 Thoroughbred racehorses in Japan, a cohort study was performed to evaluate the influence of genotypes at four single nucleotide polymorphisms (SNPs) on equine chromosome 18 (ECA18), which were associated in a previous genome-wide association study for racing performance with lifetime earnings and performance rank. In males, both g.65809482T>C and g.65868604G>T were related to performance rank (P = 0.005). In females, g.65809482T>C (P = 1.76E-6), g.65868604G>T (P = 6.81E-6) and g.66493737C>T (P = 4.42E-5) were strongly related to performance rank and also to lifetime earnings (P < 0.05). When win-race distance (WRD) among all winning racehorses and best race distance (BRD) among elite racehorses were considered as the phenotypes, significant associations (P < 0.001) were observed for all four SNPs. The favourable race distance of both elite (BRD) and novice racehorses (WRD) was also associated with genotypes in the ECA18 region, indicating the presence of a gene in this region influencing optimum race distance in Thoroughbred racehorses. Therefore, the association with performance rank is likely due to the bias in the race distances. The location of the SNPs within and proximal to the gene encoding myostatin (MSTN) strongly suggests that regulation of the MSTN gene affects racing performance. In particular, the g.65809482T>C, g.65868604G>T and g.66493737C>T SNPs, or their combinations, may be genetic diagnostic markers for racing performance indicators such as WRD and BRD. © 2011 Stichting International Foundation for Animal Genetics.

Ishii H.,Tohoku University | Ishii H.,Laboratory of Racing Chemistry | Yamaguchi H.,Tohoku University | Mano N.,Tohoku University
Chemical and Pharmaceutical Bulletin | Year: 2016

The goal of this study was to demonstrate the utility of in-source collision-induced dissociation for shifting the linear range in liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). The linear ranges for uracil, deoxyuridine, and uridine were shifted from 0.3-300, 1-100, and 10-1000 ng/mL to 10-1000, 30-3000, and 100-10000 ng/mL, respectively, by changing the declustering potential controlling in-source collision-induced dissociation. This technique should be considered for control of linear range in simultaneous quantitative measurements of extremely different amounts of compounds, drugs, and metabolites using LC/ESI-MS/MS. © 2016 The Pharmaceutical Society of Japan.

Tozaki T.,Laboratory of Racing Chemistry | Miyake T.,Kyoto University | Kakoi H.,Laboratory of Racing Chemistry | Gawahara H.,Laboratory of Racing Chemistry | And 5 more authors.
Animal Genetics | Year: 2010

Using 1400 microsatellites, a genome-wide association study (GWAS) was performed to identify genomic regions associated with lifetime earnings and performance ranks, as determined by the Japan Racing Association (JRA). The minimum heritability (h2) was estimated at 7-8% based on the quantitative trait model, suggesting that the racing performance is heritable. Following GWAS with microsatellites, fine mapping led to identification of three SNPs on ECA18, namely, g.65809482T>C (P?=?1.05E-18), g.65868604G>T (P?=?6.47E-17), and g.66539967A>G (P?=?3.35E-14) associated with these performance measures. The haplotype of these SNPs, together with a recently published nearby SNP, g.66493737C>T (P?=?9.06E-16) in strong linkage disequilibrium, also showed a very clear association with the performance (P?

Tozaki T.,Laboratory of Racing Chemistry | Hirota K.,Laboratory of Racing Chemistry | Sugita S.,Equine Research Institute | Ishida N.,Equine Research Institute | And 3 more authors.
Animal Genetics | Year: 2010

Tying-up syndrome, also known as recurrent exertional rhabdomyolysis in Thoroughbreds, is a common muscle disorder for racehorses. In this study, we performed a multipoint linkage analysis using LOKI based on the Bayesian Markov chain Monte Carlo method using 5 half-sib families (51 affected and 277 nonaffected horses in total), and a genome-wide association study (GWAS) using microsatellites (144 affected and 144 nonaffected horses) to map candidate regions for tying-up syndrome in Japanese Thoroughbreds. The linkage analysis identified one strong L-score (82.45) between the loci UCDEQ411 and COR058 (24.9-27.9?Mb) on ECA12. The GWAS identified two suggestive genomic regions on ECA12 (24.9-27.8?Mb) and ECA20 (29.3-33.5?Mb). Based on both results, the genomic region between UCDEQ411 and TKY499 (24.9-27.8?Mb) on ECA12 was the most significant and was considered as a candidate region for tying-up syndrome in Japanese Thoroughbreds. © 2010 Stichting International Foundation for Animal Genetics.

PubMed | Racehorse Hospital, Japan Racing Association and Laboratory of Racing Chemistry
Type: Journal Article | Journal: Journal of veterinary pharmacology and therapeutics | Year: 2016

Procaterol (PCR) is a beta-2-adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 g/kg) and oral (2.0 g/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography-mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 0.16 L/h/kg, the steady-state volume of the distribution was 1.21 0.23 L/kg, and the elimination half-life was 2.85 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses.

PubMed | DNA Chip Research Inc., Laboratory of Racing Chemistry and Equine Research Institute
Type: Journal Article | Journal: Journal of equine science | Year: 2016

Transcriptome analyses based on DNA microarray technology have been used to investigate gene expression profiles in horses. In this study, we aimed to identify exercise-induced changes in the expression profiles of genes in the peripheral blood of Thoroughbred horses using DNA microarray technology (15,429 genes on 43,603 probes). Blood samples from the jugular vein were collected from six horses before and 1 min, 4 hr, and 24 hr after all-out running on a treadmill. After the normalization of microarray data, a total of 26,830 probes were clustered into four groups and 11 subgroups showing similar expression changes based on k-mean clustering. The expression level of inflammation-related genes, including interleukin-1 receptor type II (IL-1R2), matrix metallopeptidase 8 (MMP8), protein S100-A8 (S100-A8), and serum amyloid A (SAA), increased at 4 hr after exercise, whereas that of c-Fos (FOS) increased at 1 min after exercise. These results indicated that the inflammatory response increased in the peripheral blood cells after exercise. Our study also revealed the presence of genes that may not be affected by all-out exercise. In conclusion, transcriptome analysis of peripheral blood cells could be used to monitor physiological changes induced by various external stress factors, including exercise, in Thoroughbred racehorses.

PubMed | Laboratory of Racing Chemistry and Musashino University
Type: Journal Article | Journal: Journal of equine science | Year: 2016

In the doping tests currently used in horse racing, prohibited substances or their metabolites are usually directly detected in urine or blood samples. However, despite their lasting pharmaceutical effects, some prohibited substances are rapidly eliminated from horse urine and blood, making them difficult to detect. Therefore, new indirect biomarkers for doping, such as plasma proteins that are increased by the prohibited substances, have recently attracted much attention. Here, a fluorogenic derivatization-liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS) method was adopted for horse plasma proteomics analysis, in order to identify plasma proteins whose concentrations were altered in response to xylazine in Thoroughbred horses. Xylazine, which is rapidly absorbed and eliminated and has possibility of the change in the levels of plasma proteins, was selected as a model drug. Of the ten plasma proteins identified, four proteins, including three acute phase proteins (haptoglobin, ceruloplasmin, and -2-macroglobulin-like), were significantly increased after xylazine administration. Therefore, our present approach might be useful in identifying indirect biomarkers of drug administration.

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