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1.  Breed-specific incidence rates of canine primary bone tumors — A population based survey of dogs in Norway 
This is one of few published population-based studies describing breed specific rates of canine primary bone tumors. Incidence rates related to dog breeds could help clarify the impact of etiological factors such as birth weight, growth rate, and adult body weight/height on development of these tumors. The study population consisted of dogs within 4 large/giant breeds; Irish wolfhound (IW), Leonberger (LB), Newfoundland (NF), and Labrador retriever (LR), born between January 1st 1989 and December 31st 1998. Questionnaires distributed to owners of randomly selected dogs — fulfilling the criteria of breed, year of birth, and registration in the Norwegian Kennel Club — constituted the basis for this retrospective, population-based survey. Of the 3748 questionnaires received by owners, 1915 were completed, giving a response rate of 51%. Forty-three dogs had been diagnosed with primary bone tumors, based upon clinical examination and x-rays. The breeds IW and LB, with 126 and 72 cases per 10 000 dog years at risk (DYAR), respectively, had significantly higher incidence rates of primary bone tumors than NF and LR (P < 0.0001). Incidence rates for the latter were 11 and 2 cases per 10 000 DYAR, respectively. Pursuing a search for risk factors other than body size/weight is supported by the significantly different risks of developing primary bone tumors between similarly statured dogs, like NF and LB, observed in this study. Defining these breed-specific incidence rates enables subsequent case control studies, ultimately aiming to identify specific etiological factors for developing primary bone tumors.
PMCID: PMC3122972  PMID: 22210997
2.  A Simple Genetic Architecture Underlies Morphological Variation in Dogs 
PLoS Biology  2010;8(8):e1000451.
The largest genetic study to date of morphology in domestic dogs identifies genes controlling nearly 100 morphological traits and identifies important trends in phenotypic variation within this species.
Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (≤3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.
Author Summary
Dogs offer a unique system for the study of genes controlling morphology. DNA from 915 dogs from 80 domestic breeds, as well as a set of feral dogs, was tested at over 60,000 points of variation and the dataset analyzed using novel methods to find loci regulating body size, head shape, leg length, ear position, and a host of other traits. Because each dog breed has undergone strong selection by breeders to have a particular appearance, there is a strong footprint of selection in regions of the genome that are important for controlling traits that define each breed. These analyses identified new regions of the genome, or loci, that are important in controlling body size and shape. Our results, which feature the largest number of domestic dogs studied at such a high level of genetic detail, demonstrate the power of the dog as a model for finding genes that control the body plan of mammals. Further, we show that the remarkable diversity of form in the dog, in contrast to some other species studied to date, appears to have a simple genetic basis dominated by genes of major effect.
PMCID: PMC2919785  PMID: 20711490
3.  Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies 
PLoS Genetics  2012;8(9):e1002898.
Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.
Author Summary
The domestic dog offers a unique opportunity to study complex disorders similar to those seen in humans, but within the context of the much simpler genetic backgrounds of pure breeds, which represent closed populations. We performed a whole-genome search for genetic risk factors of adult-onset deafness in the Border Collie, a breed of herding dog that relies on acute hearing to perceive and respond to commands while working. Adult-onset deafness in Border Collies typically begins in early adulthood and is similar to age-related hearing loss in humans. This earlier onset has particular impact on the utility of working Border Collies and the livelihoods of their owners, and it appears to have a genetic cause. We identified three genetic variants that were strongly associated with adult-onset deafness in a sample of 405 Border Collies. These variants are located in two genes that have previously been linked to deafness, one involved in ear development and another that appears to mitigate tissue damage in the ear. These results provide new insight regarding genetic risk factors for age-related hearing loss in both dogs and humans.
PMCID: PMC3441646  PMID: 23028339
4.  Evaluation of three canine γ-crystallins (CRYGB, CRYGC, and CRYGS) as candidates for hereditary cataracts in the dachshund 
Molecular Vision  2007;13:125-132.
We analyzed the γ-crystallin genes CRYGB, CRYGC, and CRYGS in the dog and tested single nucleotide polymorphisms (SNPs) for linkage and association with primary noncongenital cataract (CAT) in the dachshund, a popular dog breed. The crystallin genes may be involved in the pathogenesis of canine CAT as shown in humans and mice.
We sequenced all exons and their flanking intronic regions of the CRYGB, CRYGC, and CRYGS genes and in addition, the complete cDNA of these three genes using lens tissue from CAT-affected and unaffected dogs of several breeds. After examining BLASTN analyses, we compared the gene structure with the predicted genes in the current dog genome assembly and the orthologs of humans and mice.
The search for SNPs within these crystallin genes revealed a total of five polymorphisms. As both CAT-affected and unaffected dogs shared identical haplotypes, there was no cosegregation of the SNP alleles with the affected animals. Expression did not differ among CAT-affected and unaffected dogs.
The polymorphisms reported for CRYGB, CRYGC, and CRYGS can be excluded as causative mutations for the CAT phenotype in the wire- and smooth-haired dachshund. The canine cataract gene orthologs described here may serve as a valuable resource for further studies in other dog breeds to develop a canine model. Many different dog breeds are affected by CAT. The use of the SNPs presented in this paper can facilitate the screening of more dog breeds.
PMCID: PMC2533037  PMID: 17327821
5.  Determination of Morphological, Biometric and Biochemical Susceptibilities in Healthy Eurasier Dogs with Suspected Inherited Glaucoma 
PLoS ONE  2014;9(11):e111873.
In both humans and dogs, the primary risk factor for glaucoma is high intraocular pressure (IOP), which may be caused by iridocorneal angle (ICA) abnormalities. Oxidative stress has also been implicated in retinal ganglion cell damage associated with glaucoma. A suspected inherited form of glaucoma was recently identified in Eurasier dogs (EDs), a breed for which pedigrees are readily available. Because of difficulties in assessing ICA morphology in dogs with advanced glaucoma, we selected a cohort of apparently healthy dogsfor the investigation of ICA morphological status, IOP and plasma concentrations of oxidative stress biomarkers. We aimed to establish correlations between these factors, to identify predictive markers of glaucoma in this dog breed. A cohort of 28 subjects, volunteered for inclusion by their owners, was selected by veterinary surgeons. These dogs were assigned to four groups: young males, young females (1–3 years old), adult males and adult females (4–8 years old). Ocular examination included ophthalmoscopy, tonometry, gonioscopy, biometry and ultrasound biomicroscopy (UBM), and the evaluation of oxidative stress biomarkers consisting of measurements of plasma glutathione peroxidase (GP) activity and taurine and metabolic precursor (methionine and cysteine) concentrations in plasma. The prevalence of pectinate ligament abnormalities was significantly higher in adult EDs than in young dogs. Moreover, in adult females, high IOP was significantly correlated with a short axial globe length, and a particularly large distance between Schwalbe's line and the anterior lens capsule. GP activity levels were significantly lower in EDs than in a randomized control group of dogs, and plasma taurine concentrations were higher. Hence, ICA abnormalities were associated with weaker antioxidant defenses in EDs, potentially counteracted by higher plasma taurine concentrations. This study suggests that EDs may constitute an appropriate canine model for the development of glaucoma. This cohort will be used as a sentinel for longitudinal monitoring.
PMCID: PMC4224419  PMID: 25380252
6.  Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping 
PLoS Genetics  2011;7(10):e1002316.
The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.
Author Summary
There are hundreds of dog breeds that exhibit massive differences in appearance and behavior sculpted by tightly controlled selective breeding. This large-scale natural experiment has provided an ideal resource that geneticists can use to search for genetic variants that control these differences. With this goal, we developed a high-density array that surveys variable sites at more than 170,000 positions in the dog genome and used it to analyze genetic variation in 46 breeds. We identify 44 chromosomal regions that are extremely variable between breeds and are likely to control many of the traits that vary between them, including curly tails and sociality. Many other regions also bear the signature of strong artificial selection. We characterize one such region, known to associate with body size and ear type, in detail using “next-generation” sequencing technology to identify candidate mutations that may control these traits. Our results suggest that artificial selection has targeted genes involved in development and metabolism and that it may have increased the incidence of disease in dog breeds. Knowledge of these regions will be of great importance for uncovering the genetic basis of variation between dog breeds and for finding mutations that cause disease.
PMCID: PMC3192833  PMID: 22022279
7.  Random repeated cross sectional study on breeding site characterization of Anopheles sinensis larvae in distinct villages of Yongcheng City, People's Republic of China 
Parasites & Vectors  2012;5:58.
Characterizing the breeding site of Anopheles sinensis is of major importance for the transition from malaria control to elimination in China. However, little information is available especially regarding the characteristics and influencing factors of breeding sites of An. sinensis in Yongcheng City, a representative region of unstable malaria transmission in the Huang-Huai River region of central China. The aims of this study were to determine the breeding site characteristics of An. sinensis and related environmental and physicochemical parameters, to find out which breeding site characteristics could best explain the presence of An. sinensis larvae, and to determine whether the breeding habit of An. sinensis has changed or not.
Random repeated cross sectional study was undertaken in six villages of the Yongcheng city characterized by different levels of the historical incidence of P. vivax malaria. The potential breeding sites of An. sinensis larvae in each village were examined twice per month both in the household courtyards and the village surroundings. The larval sampling was done by the standard dipping method. Some important breeding site characterizations were recorded and characterized. The anopheline mosquito larvae and emerged adults were identified to the species level morphologically and to sub-species by the ribosomal DNA PCR technique. Chi-square analysis and logistic regression analysis were applied to determine the importance of factors for explaining the presence or absence of An. sinensis larvae.
According to the ribosomal DNA PCR assay, all sampled anopheline mosquito larvae and emerged adults belonged to An. sinensis. Only 3 containers that were sampled from the household courtyards were found to contain An. sinensis larvae. There were no differences in the species composition of mosquito larvae among containers that contained water in the household courtyards (P > 0.05). An. sinensis larvae were shown to be present in a total of 60 breeding sites in the village surroundings, this included 8 (13.3%) river fringes, 26 (43.3%) ponds, 23 (38.3%) puddles, and 3 (5.0%) irrigation/drainage ditches. Logistic regression analysis revealed that the breeding site type, water depth, chemical oxygen demand (COD), ammonia nitrogen, and sulphate were found to be the key factors determining the presence of An. sinensis larvae. Approximately 94.9% of An. sinensis larvae inhabited relatively large and medium-sized water bodies, with depths between 0.5 m and 1.0 m (73.3%), COD lower than 2 mg/L (75%), ammonia nitrogen lower than 0.4 mg/L (86.7%), and sulphate lower than 150 mg/L (58.3%), respectively.
These results indicate that the majority of An. sinensis larval breeding sites were relatively large and medium-sized water bodies with depths between 0.5 m and 1.0 m, and containing low levels of COD, ammonia nitrogen, and sulphate, respectively. For effective An. sinensis larval control, the type of breeding site, water depth, COD, ammonia nitrogen, and sulphate should be given higher priority over other factors in areas where it is the primary vector.
PMCID: PMC3323357  PMID: 22444032
Breeding site; Characterization; Mosquito; Anopheles vectors; Ecology, Malaria elimination
8.  Ten inherited disorders in purebred dogs by functional breed groupings 
Analysis of 88,635 dogs seen at the University of California, Davis Veterinary Medical Teaching Hospital from 1995 to 2010 identified ten inherited conditions having greater prevalence within the purebred dog population as compared to the mixed-breed dog population: aortic stenosis, atopy/allergic dermatitis, gastric dilatation volvulus (GDV), early onset cataracts, dilated cardiomyopathy, elbow dysplasia, epilepsy, hypothyroidism, intervertebral disk disease (IVDD), and hepatic portosystemic shunt. The objective of the present study was to ascertain if disorders with higher prevalence in purebreds were restricted to particular breed group classifications within the purebred population, specifically the American Kennel Club breed grouping or groups with genomic similarities based upon allele sharing. For each disorder, healthy controls seen at the hospital during that same time period were matched for age, weight, and sex to each affected dog to determine risk of disease presentation in the purebred group as compared to that of the mixed-breed population. To enhance reliability of the analyses, sampling of matched healthy to affected dogs was repeated 50 times. For each comparison, the purebred subgroups to mixed-breed odds ratio was determined as was the mean P value used to test this ratio.
For aortic stenosis, GDV, early onset cataracts, dilated cardiomyopathy, elbow dysplasia, epilepsy, and portosystemic shunt, most purebred groups were not statistically distinct from the mixed-breed population with higher prevalence in purebreds restricted to distinct subsets of purebred dogs. The conditions of atopy/allergic dermatitis, hypothyroidism, and IVDD were more pervasive across the purebred population with many groups having higher prevalence than the mixed-breed population. The prevalence of IVDD in purebred terrier groups was statistically lower than that observed for mixed-breed dogs.
The results offer an assessment of the distribution of inherited disorders within purebred dogs and illustrate how mixed-breed and subpopulations of purebred dogs do not differ statistically in prevalence for certain disorders. Some disorders appear linked to common ancestors providing insight into disease allele origin whereas others may be due to selection for common structural morphology. Knowledge of the origin of a condition may aid in reducing its prevalence in the dog population as a whole.
Electronic supplementary material
The online version of this article (doi:10.1186/s40575-015-0021-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4579393  PMID: 26401337
Purebred dog; Mixed-breed dog; Inherited disorders; Allele sharing
9.  MtDNA diversity among four Portuguese autochthonous dog breeds: a fine-scale characterisation 
BMC Genetics  2005;6:37.
The picture of dog mtDNA diversity, as obtained from geographically wide samplings but from a small number of individuals per region or breed, has revealed weak geographic correlation and high degree of haplotype sharing between very distant breeds. We aimed at a more detailed picture through extensive sampling (n = 143) of four Portuguese autochthonous breeds – Castro Laboreiro Dog, Serra da Estrela Mountain Dog, Portuguese Sheepdog and Azores Cattle Dog-and comparatively reanalysing published worldwide data.
Fifteen haplotypes belonging to four major haplogroups were found in these breeds, of which five are newly reported. The Castro Laboreiro Dog presented a 95% frequency of a new A haplotype, while all other breeds contained a diverse pool of existing lineages. The Serra da Estrela Mountain Dog, the most heterogeneous of the four Portuguese breeds, shared haplotypes with the other mainland breeds, while Azores Cattle Dog shared no haplotypes with the other Portuguese breeds.
A review of mtDNA haplotypes in dogs across the world revealed that: (a) breeds tend to display haplotypes belonging to different haplogroups; (b) haplogroup A is present in all breeds, and even uncommon haplogroups are highly dispersed among breeds and continental areas; (c) haplotype sharing between breeds of the same region is lower than between breeds of different regions and (d) genetic distances between breeds do not correlate with geography.
MtDNA haplotype sharing occurred between Serra da Estrela Mountain dogs (with putative origin in the centre of Portugal) and two breeds in the north and south of the country-with the Castro Laboreiro Dog (which behaves, at the mtDNA level, as a sub-sample of the Serra da Estrela Mountain Dog) and the southern Portuguese Sheepdog. In contrast, the Azores Cattle Dog did not share any haplotypes with the other Portuguese breeds, but with dogs sampled in Northern Europe. This suggested that the Azores Cattle Dog descended maternally from Northern European dogs rather than Portuguese mainland dogs. A review of published mtDNA haplotypes identified thirteen non-Portuguese breeds with sufficient data for comparison. Comparisons between these thirteen breeds, and the four Portuguese breeds, demonstrated widespread haplotype sharing, with the greatest diversity among Asian dogs, in accordance with the central role of Asia in canine domestication.
PMCID: PMC1180824  PMID: 15972107
10.  Genome-Wide Analysis of the World's Sheep Breeds Reveals High Levels of Historic Mixture and Strong Recent Selection 
PLoS Biology  2012;10(2):e1001258.
Genomic structure in a global collection of domesticated sheep reveals a history of artificial selection for horn loss and traits relating to pigmentation, reproduction, and body size.
Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep populations contain high SNP diversity and have retained an effective population size much higher than most cattle or dog breeds, suggesting domestication occurred from a broad genetic base. Extensive haplotype sharing and generally low divergence time between breeds reveal frequent genetic exchange has occurred during the development of modern breeds. A scan of the genome for selection signals revealed 31 regions containing genes for coat pigmentation, skeletal morphology, body size, growth, and reproduction. We demonstrate the strongest selection signal has occurred in response to breeding for the absence of horns. The high density map of genetic variability provides an in-depth view of the genetic history for this important livestock species.
Author Summary
During the process of domestication, mankind recruited animals from the wild into a captive environment, changing their morphology, behaviour, and genetics. In the case of sheep, domestication and subsequent selection by their animal handlers over thousands of years has produced a spectrum of breeds specialised for the production of wool, milk, and meat. We sought to use this population history to search for the genes that directly underpin phenotypic variation. We collected DNA from 2,819 sheep, belonging to 74 breeds sampled from around the world, and assessed the genotype of each animal at nearly 50,000 locations across the genome. Our results show that sheep breeds have maintained high levels of genetic diversity, in contrast to other domestic animals such as dogs. We also show that particular regions of the genome contain strong evidence for accelerated change in response to artificial selection. The most prominent example was identified in response to breeding for the absence of horns, a trait now common across many modern breeds. Furthermore, we demonstrate that other genomic regions under selection in sheep contain genes controlling pigmentation, reproduction, and body size.
PMCID: PMC3274507  PMID: 22346734
11.  A genetic dissection of breed composition and performance enhancement in the Alaskan sled dog 
BMC Genetics  2010;11:71.
The Alaskan sled dog offers a rare opportunity to investigate the development of a dog breed based solely on performance, rather than appearance, thus setting the breed apart from most others. Several established breeds, many of which are recognized by the American Kennel Club (AKC), have been introduced into the sled dog population to enhance racing performance. We have used molecular methods to ascertain the constitutive breeds used to develop successful sled dog lines, and in doing so, determined the breed origins of specific performance-related behaviors.
One hundred and ninety-nine Alaskan sled dogs were genotyped using 96 microsatellite markers that span the canine genome. These data were compared to that from 141 similarly genotyped purebred dog breeds. Sled dogs were evaluated for breed composition based on a variety of performance phenotypes including speed, endurance and work ethic, and the data stratified based on population structure.
We observe that the Alaskan sled dog has a unique molecular signature and that the genetic profile is sufficient for identifying dogs bred for sprint versus distance. When evaluating contributions of existing breeds we find that the Alaskan Malamute and Siberian Husky contributions are associated with enhanced endurance; Pointer and Saluki are associated with enhanced speed and the Anatolian Shepherd demonstrates a positive influence on work ethic.
We have established a genetic breed profile for the Alaskan sled dog, identified profile variance between sprint and distance dogs, and established breeds associated with enhanced performance attributes. These data set the stage for mapping studies aimed at finding genes that are associated with athletic attributes integral to the high performing Alaskan sled dog.
PMCID: PMC2920855  PMID: 20649949
12.  Cigarette smoking, body mass index associated with the risks of age-related cataract in male patients in northeast China 
To determine the association between cigarettes smoking, body mass index (BMI) and the risk of age-related cataract (ARC) in middle-aged and elderly men in Northeast China.
A hospital-based case control study was conducted. Cases (n =362) were men who had surgically treated ARC, 45-85 years old; controls frequency-matched (n =362) were men who had been admitted to the same hospital as cases for other diseases not related with eye diseases. Cases and controls were matched with 1:1. The cases and controls were interviewed during their hospital stay, using a structured interviewer-administrated questionnaire that included information on sociodemographic characteristics, socioeconomic, lifestyle habits (tobacco smoking and alcohol consumption, etc.), anthropometric measures, personal medical history, and family history of ARC in first-degree relatives, and simultaneously BMI was calculated. The odds ratios (OR) and 95% confidence intervals (CI) of ARC were estimated using multiple logistic regression models.
After adjusting for age and multiple potential confounders, higher BMI was associated with an increased risk of ARC. Cigarette smoking, years smoking or moderate cigarette smoking (1-29 cigarettes per day) had no relation with the risk of ARC (P>0.05), although patients smoking ≥30 cigarettes per day had an elevated risk of ARC as compared with the non-smokers (OR=1.55, 95% CI; 1.16-2.85, P=0.026). Higher BMI was associated with an increased risk of ARC. Both overweight and obesity was associated with an obviously increased risk for surgically ARC (OR=1.55, 95% CI: 1.02-1.98, P=0.015 and OR=1.71, 95% CI: 1.32-2.39, P=0.013 respectively) compared to normal BMI. Then participants were grouped into quartiles of BMI (Q1 to Q4), compared to controls in the lowest quartile, the OR for cases in the highest quartile of BMI was 1.54 (OR=1.54, 95% CI: 1.08-2.46, P=0.022). The results of univariate analysis showed cigarette smoking was not associated with ARC formation for men with lower or normal BMI (P>0.05). Compared to the non-smokers, for men of overweight or obesity, cigarette smoking was associated with a significantly increased risk for surgically ARC (OR=2.00, 95% CI: 1.49-6.65, P=0.003 and OR=1.66, 95% CI: 1.63-13.21, P=0.002 respectively). Similarly, smokers in the highest quartile of BMI had approximately 1.5 times the risk of ARC as non-smokers in the lowest quartile (OR=1.46, 95% CI: 1.06-5.29, P<0.001). Followed multivariate models revealed that the association had never changed.
Current cigarette smoking is positively related to ARC only among those who smoking 30 or more cigarettes per day. For men who are both overweight and obesity, cigarette smoking is associated with a significantly increased risk for ARC.
PMCID: PMC3388400  PMID: 22773980
age-related cataract; male; smoking; body mass index; risk
13.  Searching for “monogenic diabetes” in dogs using a candidate gene approach 
Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility.
Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds.
Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds.
Electronic supplementary material
The online version of this article (doi:10.1186/2052-6687-1-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4579387  PMID: 26401325
Diabetes mellitus; Dog breeds; Candidate genes
14.  Connecting serum IGF-1, body size, and age in the domestic dog 
Age  2010;33(3):475-483.
Many investigations in recent years have targeted understanding the genetic and biochemical basis of aging. Collectively, genetic factors and biological mechanisms appear to influence longevity in general and specifically; reduction of the insulin/IGF-1 signaling cascade has extended life span in diverse species. Genetic alteration of mammals for life extension indicates correlation to serum IGF-1 levels in mice, and IGF-1 levels have been demonstrated as a physiological predictor of frailty with aging in man. Longevity and aging data in the dog offer a close measure of the natural multifactorial longevity interactions of genetic influence, IGF-1 signaling, and environmental factors such as exposure, exercise, and lifestyle. The absence of genetic alteration more closely represents the human longevity status, and the unique species structure of the canine facilitates analyses not possible in other species. These investigations aimed to measure serum IGF-1 in numerous purebred and mixed-breed dogs of variable size and longevity in comparison to age, gender, and spay/neuter differences. The primary objective of this investigation was to determine plasma IGF-1 levels in the adult dog, including a wide range of breeds and adult body weight. The sample set includes animals ranging from just a few months of age through 204 months and ranging in size from 5 to 160 lb. Four groups were evaluated for serum IGF-1 levels, including intact and neutered males, and intact and spayed females. IGF-1 loss over time, as a function of age, decreases in all groups with significant differences between males and females. The relationship between IGF-1 and weight differs depending upon spay/neuter status, but there is an overall increase in IGF-1 levels with increasing weight. The data, currently being interrogated further for delineation of IGF-1 receptor variants and sex differences, are being collected longitudinally and explored for longevity associations previously unavailable in non-genetically modified mammals.
PMCID: PMC3168604  PMID: 20865338
Longevity; IGF-1; Canine; Aging; Insulin signaling
15.  Selenium and Mercury in the Brazilian Amazon: Opposing Influences on Age-Related Cataracts 
Environmental Health Perspectives  2010;118(11):1584-1589.
Age-related cataracts (ARCs) are an important cause of blindness in developing countries. Although antioxidants may be part of the body’s defense to prevent ARC, environmental contaminants may contribute to cataractogenesis. In fish-eating populations of the lower Tapajós region, elevated exposure to mercury (Hg) has been reported, and blood levels of selenium (Se) range from normal to very high (> 1,000 μg/L).
We examined ARCs in relation to these elements among adults (≥ 40 years of age) from 12 riverside communities.
Participants (n = 211) provided blood samples and underwent an extensive ocular examination. Inductively coupled plasma mass spectrometry was used to assess Hg and Se in blood and plasma.
One-third (n = 69; 32.7%) of the participants had ARC. Lower plasma Se (P-Se; < 25th percentile, 110 μg/L) and higher blood Hg (B-Hg; ≥ 25th percentile, 25 μg/L) were associated with a higher prevalence odds ratio (POR) of ARC [adjusted POR (95% confidence interval), 2.69 (1.11–6.56) and 4.45 (1.43–13.83), respectively]. Among participants with high P-Se, we observed a positive but nonsignificant association with high B-Hg exposure, whereas among those with low B-Hg, we observed no association for P-Se. However, compared with the optimum situation (high P-Se, low B-Hg), the POR for those with low P-Se and high B-Hg was 16.4 (3.0–87.9). This finding suggests a synergistic effect.
Our results suggest that persons in this population with elevated Hg, the cataractogenic effects of Hg may be offset by Se. Because of the relatively small sample size and possible confounding by other dietary nutrients, additional studies with sufficient power to assess multiple nutrient and toxic interactions are required to confirm these findings.
PMCID: PMC2974697  PMID: 20716509
age-related cataract; Brazilian Amazon; fish consumption; mercury; selenium
16.  Epidemiology, Pathology, and Genetics of Histiocytic Sarcoma in the Bernese Mountain Dog Breed 
Journal of Heredity  2009;100(Suppl 1):S19-S27.
Histiocytic sarcoma (HS) refers to a highly aggressive and frequently disseminated neoplastic disease belonging to the class of canine histiocytic proliferative disorders. Disseminated HS (previously called malignant histiocytosis) is highly breed specific, with Bernese mountain dogs (BMDs), rottweilers, and retrievers having a high prevalence with a frequency of approximately 25% in the BMD breed. We collected DNA samples and clinical information from 800 BMDs, of which 200 are affected by HS. To better characterize the physiopathology and epidemiology, an in-depth analysis of 89 BMD cases has been performed. The mean age of onset was 6.5 years, males and females being equally affected. The clinical features, biochemical parameters, and pathological features have been determined. The life span after diagnosis has been estimated to be 49 days. A large BMD pedigree of 327 dogs, 121 of which are affected, was assembled. Using a subset of 160 BMDs, encompassing 21 complete sibships, we now propose an oligogenic transmission mode of the disease. Whole-genome linkage scans as well as association studies using a case/control analysis, in parallel with expression profiling of neoplastic versus normal histiocytes, are all underway. Altogether, these complementary approaches are expected to localize the genes for HS in the BMD, leading to advances in our knowledge of histiocyte diseases in dogs and humans.
PMCID: PMC3139364  PMID: 19531730
Bernese mountain dogs; cancer; dog; genetics; histiocytic sarcoma
17.  A longitudinal study on diarrhoea and vomiting in young dogs of four large breeds 
Prospective studies to document the occurrence of canine diarrhoea and vomiting are relatively scarce in dogs, and the majority of published studies are based on information from clinical records. This study investigates the incidence risk of diarrhoea and vomiting as well as potential risk factors.
A cohort study of 585 privately owned dogs of four breeds: Newfoundland, Labrador retriever, Leonberger, and Irish wolfhound. The owners maintained a continuous log regarding housing, exercise, nutrition, and health of their dogs. Episodes of diarrhoea and vomiting were recorded in a consecutive manner in a booklet. The owners completed the questionnaires and reported information at three, four, six, 12, 18, and 24/25 months of age, called observational ages.
Associations with potential risk factors for diarrhoea and vomiting were investigated in separate generalized estimating equation analyses.
The incidence of both diarrhoea and vomiting was influenced by breed. Both diarrhoea and vomiting were relatively common in young dogs, occurring most frequently during the first months of life. After three months of age, the odds of diarrhoea were significantly lower when compared to the observational period seven weeks to three months (OR ranging from 0.31 to 0.70 depending on the period). More males than females suffered from diarrhoea (OR = 1.42). The occurrence of diarrhoea was more common in dogs that also experienced episode(s) of vomiting during the study period (OR = 5.43) and vice versa (OR = 5.50). In the majority of dogs episodes of diarrhoea and vomiting did not occur at the same time. Dogs in urban areas had higher odds (OR = 1.88) of getting diarrhoea compared to dogs living in rural areas. The occurrence of both diarrhoea and vomiting demonstrated a seasonal variation with higher incidence during the summer months.
Both diarrhoea and vomiting occurred most frequently during the first months of life. The incidence of diarrhoea and vomiting was significantly different between breeds. Diarrhoea occurred more frequently in males and in dogs living in urban areas. Also, a positive association between the occurrence of diarrhoea and vomiting in the same dog was found.
PMCID: PMC3293024  PMID: 22300688
longitudinal study; diarrhoea; vomiting; incidence; risk factors; dog
18.  Do avian cooperative breeders live longer? 
Cooperative breeding is not common in birds but intriguingly over-represented in several families, suggesting that predisposing factors, similar ecological constraints or a combination of the two facilitate the evolution of this breeding strategy. The life-history hypothesis proposes that cooperative breeding is facilitated by high annual survival, which increases the local population and leads to a shortage of breeding opportunities. Clutch size in cooperative breeders is also expected to be smaller. An earlier comparative analysis in a small sample of birds supported the hypothesis but this conclusion has been controversial. Here, I extend the analysis to a larger, worldwide sample and take into account potential confounding factors that may affect estimates of a slow pace of life and clutch size. In a sample of 81 species pairs consisting of closely related cooperative and non-cooperative breeders, I did not find an association between maximum longevity and cooperative breeding, controlling for diet, body mass and sampling effort. However, in a smaller sample of 37 pairs, adult annual survival was indeed higher in the cooperative breeders, controlling for body mass. There was no association between clutch size and cooperative breeding in a sample of 93 pairs. The results support the facilitating effect of high annual survival on the evolution of cooperative breeding in birds but the effect on clutch size remains elusive.
PMCID: PMC4071557  PMID: 24898375
birds; cooperative breeding; lifespan; life history
19.  Epidemiological associations between brachycephaly and upper respiratory tract disorders in dogs attending veterinary practices in England 
Brachycephalic dog breeds are increasingly common. Canine brachycephaly has been associated with upper respiratory tract (URT) disorders but reliable prevalence data remain lacking. Using primary-care veterinary clinical data, this study aimed to report the prevalence and breed-type risk factors for URT disorders in dogs.
The sampling frame included 170,812 dogs attending 96 primary-care veterinary clinics participating within the VetCompass Programme. Two hundred dogs were randomly selected from each of three extreme brachycephalic breed types (Bulldog, French Bulldog and Pug) and three common small-to medium sized breed types (moderate brachycephalic: Yorkshire Terrier and non-brachycephalic: Border Terrier and West Highland White Terrier). Information on all URT disorders recorded was extracted from individual patient records. Disorder prevalence was compared between groups using the chi-squared test or Fisher’s test, as appropriate. Risk factor analysis used multivariable logistic regression modelling.
During the study, 83 (6.9 %) study dogs died. Extreme brachycephalic dogs (median longevity: 8.6 years, IQR: 2.4-10.8) were significantly younger at death than the moderate and non-brachycephalic group of dogs (median 12.7 years, IQR 11.1-15.0) (P < 0.001). A higher proportion of deaths in extreme brachycephalic breed types were associated with URT disorders (4/24 deaths, 16.7 %) compared with the moderate and non-brachycephalic group (0/59 deaths, 0.0 %) (P = 0.001).
The prevalence of having at least one URT disorder in the extreme brachycephalic group was higher (22.0 %, 95 % confidence interval (CI): 18.0-26.0) than in the moderate and non-brachycephalic group (9.7 %, 95 % CI: 7.1-12.3, P < 0.001). The prevalence of URT disorders varied significantly by breed type: Bulldogs 19.5 %, French Bulldogs 20.0 %, Pugs 26.5 %, Border Terriers 9.0 %, West Highland White Terriers 7.0 % and Yorkshire Terriers 13.0 % (P < 0.001). After accounting for the effects of age, bodyweight, sex, neutering and insurance, extreme brachycephalic dogs had 3.5 times (95 % CI: 2.4-5.0, P < 0.001) the odds of at least one URT disorder compared with the moderate and non-brachycephalic group.
In summary, this study reports that URT disorders are commonly diagnosed in Bulldog, French Bulldog, Pug, Border Terrier, WHWT and Yorkshire Terrier dogs attending primary-care veterinary practices in England. The three extreme brachycephalic breed types (Bulldog, French Bulldog and Pug) were relatively short-lived and predisposed to URT disorders compared with three other small-to-medium size breed types that are commonly owned (moderate brachycephalic Yorkshire Terrier and non-brachycephalic: Border Terrier and WHWT).
PMCID: PMC4579368  PMID: 26401338
Extreme brachycephalic; Moderate brachycephalic; Non-brachycephalic; Upper respiratory; Breed type; Dog; primary-care; VetCompass
20.  Genetic diversity of canine olfactory receptors 
BMC Genomics  2009;10:21.
Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations.
We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47%) of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently.
Our demonstration of a high overall level of polymorphism, likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested, is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why, in a context in which most OR genes are highly polymorphic, a subset of these genes is not? This phenomenon may be related to the nature of their ligands and their importance in everyday life.
PMCID: PMC2635374  PMID: 19144169
21.  Cooperative breeding in birds: a comparative test of the life history hypothesis 
In approximately 3.2% of bird species individuals regularly forgo the opportunity to breed independently and instead breed cooperatively with other conspecifics, either as non-reproductive 'helpers' or as co-breeders. The traditional explanation for cooperative breeding is that the opportunities for breeding independently are limited owing to peculiar features of the species' breeding ecology. However, it has proved remarkably difficult to find any common ecological correlates of cooperative breeding in birds. This difficulty has led to the 'life history hypothesis', which suggests that the common feature of cooperatively breeding birds is their great longevity, rather than any particular feature of their breeding ecology. Here, we use a comparative method to test the life history hypothesis by looking for correlations between life history variation and variation in the frequency of cooperative breeding. First, we find that cooperative breeding in birds is not randomly distributed, but concentrated in certain families, thus supporting the idea that there may be a common basis to cooperative breeding in birds. Second, increases in the level of cooperative breeding are strongly associated with decreases in annual adult mortality and modal clutch size. Third, the proportion of cooperatively breeding species per family is correlated with a low family-typical value of annual mortality, suggesting that low mortality predisposes cooperative breeding rather than vice versa. Finally, the low rate of mortality typically found in cooperatively breeding species is associated with increasing sedentariness, lower latitudes, and decreased environmental fluctuation. We suggest that low annual mortality is the key factor that predisposes avian lineages to cooperative breeding, then ecological changes, such as becoming sedentary, further slow population turnover and reduce opportunities for independent breeding. As the traditional explanation suggests, the breeding habitat of cooperatively breeding species is saturated, but this saturation is not owing to any peculiar feature of the breeding ecology of cooperative breeders. Rather, the saturation arises because the local population turnover in these species is unusually slow, as predicted by the life history hypothesis.
PMCID: PMC1689041
22.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs 
Science (New York, N.Y.)  2007;316(5821):112-115.
The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.
PMCID: PMC2789551  PMID: 17412960
23.  Polymorphisms within the Telomerase Reverse Transcriptase gene (TERT) in four breeds of dogs selected for difference in lifespan and cancer susceptibility 
Enzymatic activity of Telomerase Reverse Transcriptase (TERT) is important in maintaining the telomere length and has been implicated in cancer and aging related pathology. Since cancer susceptibility as well as longevity of dogs vary between breeds, this study involved sequencing the entire TERT gene of Canis familiaris from DNA samples obtained from forty dogs, with ten dogs each of four breeds: Shih Tzu, Dachshund, Irish Wolfhound, and Newfoundland, each with different life expectancies and susceptibility to cancer.
We compared the sequences of all forty individuals amongst one another and with the published sequence of canine TERT, and analyzed relationships between members of the same or different breeds. Two separate phylogenetic trees were generated and analyzed from these individuals. Polymorphisms were found most frequently in intronic regions of the gene, although exonic polymorphisms also were observed. In many locations genotypes were observed that were either homozygous for the reference sequence or heterozygous, but the variant homozygous genotype was not observed.
We propose that these homozygous variants are likely to have adverse effects in dogs. It was also found that the polymorphisms did not segregate by breed. Because the four breeds chosen come from geographically and physiologically distinct backgrounds, it can be inferred that the polymorphic diversification of TERT preceded breed derivation.
PMCID: PMC3904191  PMID: 24423165
24.  Molecular cytogenetic characterization of canine histiocytic sarcoma: A spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior 
BMC Cancer  2011;11:201.
Histiocytic malignancies in both humans and dogs are rare and poorly understood. While canine histiocytic sarcoma (HS) is uncommon in the general domestic dog population, there is a strikingly high incidence in a subset of breeds, suggesting heritable predisposition. Molecular cytogenetic profiling of canine HS in these breeds would serve to reveal recurrent DNA copy number aberrations (CNAs) that are breed and/or tumor associated, as well as defining those shared with human HS. This process would identify evolutionarily conserved cytogenetic changes to highlight regions of particular importance to HS biology.
Using genome wide array comparative genomic hybridization we assessed CNAs in 104 spontaneously occurring HS from two breeds of dog exhibiting a particularly elevated incidence of this tumor, the Bernese Mountain Dog and Flat-Coated Retriever. Recurrent CNAs were evaluated further by multicolor fluorescence in situ hybridization and loss of heterozygosity analyses. Statistical analyses were performed to identify CNAs associated with tumor location and breed.
Almost all recurrent CNAs identified in this study were shared between the two breeds, suggesting that they are associated more with the cancer phenotype than with breed. A subset of recurrent genomic imbalances suggested involvement of known cancer associated genes in HS pathogenesis, including deletions of the tumor suppressor genes CDKN2A/B, RB1 and PTEN. A small number of aberrations were unique to each breed, implying that they may contribute to the major differences in tumor location evident in these two breeds. The most highly recurrent canine CNAs revealed in this study are evolutionarily conserved with those reported in human histiocytic proliferations, suggesting that human and dog HS share a conserved pathogenesis.
The breed associated clinical features and DNA copy number aberrations exhibited by canine HS offer a valuable model for the human counterpart, providing additional evidence towards elucidation of the pathophysiological and genetic mechanisms associated with histiocytic malignancies. Extrapolation of data derived from canine histiocytic disorders to human histiocytic proliferation may help to further our understanding of the propagation and cancerization of histiocytic cells, contributing to development of new and effective therapeutic modalities for both species.
PMCID: PMC3121728  PMID: 21615919
25.  Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs 
Aging Cell  2009;8(6):752-755.
To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine ‘centenarians’– exceptionally long-lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest-old Rottweilers (age at death, ≥ 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0–10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2–3.3; P= 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary-sensitive biological processes that promote healthy human longevity.
PMCID: PMC2805875  PMID: 19732047
anti-aging; estrogen; ovarian conservation; ovariohysterectomy; sex difference in health

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