Complex disease and phenotype mapping in the domestic dog

Hayward, Jessica J.; Castelhano, Marta G.; Oliveira, Kyle C.; Corey, Elizabeth; Balkman, Cheryl E.; Baxter, Tara; Casal, Margret L.; Fang, Meiying; Garrison, Susan J.; Kalla, Sara E.; Korniliev, Pavel; Kotlikoff, Michael I.; Moise, N S; Shannon, Laura M.; Simpson, Kenneth W.; Sutter, Nathan B.; Todhunter, Rory J.; Boyko, Adam R.

doi:10.1038/ncomms10460

Cited by 228 publications

(395 citation statements)

References 70 publications

(102 reference statements)

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“…The primary locus controlling body size in the TWH is the same ECA3 LCORL/NCAPG region previously identified in other breeds of horse (37,41,56,62). Relatively few loci influencing morphological traits are also observed in dogs (14,60) and can be attributed to typically small founder populations and selective breeding (23,45), resulting in longer LD compared with humans and the subsequent use of fewer individuals for association studies (23,45,46). Additional markers genotyped in this study suggest the causative polymorphism may lie downstream of the SNP BIEC2_808543 and within the LCORL coding sequence and is not likely the BIEC2-808543 SNP as proposed by Makvandi-Nejad et al (37) and Signer-Hasler et al (56).…”

Section: Discussionmentioning

confidence: 61%

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

Staiger

Al-Abri

Pflug

et al. 2016

Physiological Genomics

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Conformation has long been a driving force in horse selection and breed creation as a predictor for performance. The Tennessee Walking Horse (TWH) ranges in size from 1.5 to 1.7 m and is often used as a trail, show, and pleasure horse. To investigate the contribution of genetics to body conformation in the TWH, we collected DNA samples, body measurements, and gait/training information from 282 individuals. We analyzed the 32 body measures with a principal component analysis. Principal component (PC)1 captured 28.5% of the trait variance, while PC2 comprised just 9.5% and PC3 6.4% of trait variance. All 32 measures correlated positively with PC1, indicating that PC1 describes overall body size. We genotyped 109 horses using the EquineSNP70 bead chip and marker association assessed the data using PC1 scores as a phenotype. Mixed-model linear analysis (EMMAX) revealed a well-documented candidate locus on ECA3 (raw P = 3.86 × 10−9) near the LCORL gene. A custom genotyping panel enabled fine-mapping of the PC1 body-size trait to the 3′-end of the LCORL gene ( P = 7.09 × 10−10). This position differs from other reports suggesting single nucleotide polymorphisms (SNPs) upstream of the LCORL coding sequence regulate expression of the gene and, therefore, body size in horses. Fluorescent in situ hybridization analysis defined the position of a highly homologous 5 kb retrogene copy of LCORL (assigned to unplaced contigs of the EquCab 2.0 assembly) at ECA9 q12-q13. This is the first study to identify putative causative SNPs within the LCORL transcript itself, which are associated with skeletal size variation in horses.

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Section: Discussionmentioning

confidence: 61%

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

Staiger

Al-Abri

Pflug

et al. 2016

Physiological Genomics

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“…However, within our data set, the total number of morbidities for each dog is dependent almost exclusively on age with no detectable effect of weight or breed. Different breeds are known to experience different morbidities, as well as to have different causes of death (10,23). In this light, we would have expected to find that certain breeds were more prone to multiple morbidities, but our study failed to identify this association.…”

Section: Discussionmentioning

confidence: 99%

Multiple morbidities in companion dogs: a novel model for investigating age-related disease

Jin

Hoffman

Creevy

et al. 2016

Pathobiology of Aging & Age-related Diseases

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The proportion of men and women surviving over 65 years has been steadily increasing over the last century. In their later years, many of these individuals are afflicted with multiple chronic conditions, placing increasing pressure on healthcare systems. The accumulation of multiple health problems with advanced age is well documented, yet the causes are poorly understood. Animal models have long been employed in attempts to elucidate these complex mechanisms with limited success. Recently, the domestic dog has been proposed as a promising model of human aging for several reasons. Mean lifespan shows twofold variation across dog breeds. In addition, dogs closely share the environments of their owners, and substantial veterinary resources are dedicated to comprehensive diagnosis of conditions in dogs. However, while dogs are therefore useful for studying multimorbidity, little is known about how aging influences the accumulation of multiple concurrent disease conditions across dog breeds. The current study examines how age, body weight, and breed contribute to variation in multimorbidity in over 2,000 companion dogs visiting private veterinary clinics in England. In common with humans, we find that the number of diagnoses increases significantly with age in dogs. However, we find no significant weight or breed effects on morbidity number. This surprising result reveals that while breeds may vary in their average longevity and causes of death, their age-related trajectories of morbidities differ little, suggesting that age of onset of disease may be the source of variation in lifespan across breeds. Future studies with increased sample sizes and longitudinal monitoring may help us discern more breed-specific patterns in morbidity. Overall, the large increase in multimorbidity seen with age in dogs mirrors that seen in humans and lends even more credence to the value of companion dogs as models for human morbidity and mortality.

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“…Genotyping was performed using genomic DNA as described in Hayward et al (2016) using Illumina CanineHD BeadChips that include more than 170,000 SNPs. All positions reported are given in canFam3.1 coordinates.…”

Section: Methodsmentioning

confidence: 99%

A Pedigree-Based Map of Recombination in the Domestic Dog Genome

Campbell

Bhérer

Morrow

et al. 2016

G3 Genes|Genomes|Genetics

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Meiotic recombination in mammals has been shown to largely cluster into hotspots, which are targeted by the chromatin modifier PRDM9. The canid family, including wolves and dogs, has undergone a series of disrupting mutations in this gene, rendering PRDM9 inactive. Given the importance of PRDM9, it is of great interest to learn how its absence in the dog genome affects patterns of recombination placement. We have used genotypes from domestic dog pedigrees to generate sex-specific genetic maps of recombination in this species. On a broad scale, we find that placement of recombination events in dogs is consistent with that in mice and apes, in that the majority of recombination occurs toward the telomeres in males, while female crossing over is more frequent and evenly spread along chromosomes. It has been previously suggested that dog recombination is more uniform in distribution than that of humans; however, we found that recombination in dogs is less uniform than in humans. We examined the distribution of recombination within the genome, and found that recombination is elevated immediately upstream of the transcription start site and around CpG islands, in agreement with previous studies, but that this effect is stronger in male dogs. We also found evidence for positive crossover interference influencing the spacing between recombination events in dogs, as has been observed in other species including humans and mice. Overall our data suggests that dogs have similar broad scale properties of recombination to humans, while fine scale recombination is similar to other species lacking PRDM9.

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Complex disease and phenotype mapping in the domestic dog

Cited by 228 publications

References 70 publications

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

Multiple morbidities in companion dogs: a novel model for investigating age-related disease

A Pedigree-Based Map of Recombination in the Domestic Dog Genome

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