History

Dog Genetics

Key Message

WALTHAM is at the forefront of research into the genetics of the dog, partnering with world class scientists in discoveries such as:

  • Understanding the history of dog domestication.
  • Showing that a single gene is a major determinant of dog size.
  • Demonstrating that genetic variants are linked to stereotypical dog characteristics.
  • Understanding the genetic basis of canine disease.

Background

The dog is descended from the wolf (Vonholdt et al. 2010) and has since continued to evolve, successfully adapting to a wide range of environments.

Following domestication, the dog has undergone centuries of selective breeding as people strived to accentuate the traits they wanted. Some of these were behavioural (for example herding or guarding ability) and some were morphological (to enable them to assist their owner's hunting lifestyle).

Nowadays, there are hundreds of distinct dog breeds which differ markedly in phenotypic traits. As a species, the dog is unique with a mature body weight that varies over a huge range - from about 1 kg to over 100 kg (Burger 1994). The breeds also look very different and behaviourally fulfil a wide range of functions from companion to search and rescue dog.

Although selective breeding has given us breeds to suit every purpose, it has a downside. It can result in inbreeding (Calbodi et al. 2008), and the associated consequences are seen in the disease susceptibilities that breeders are working so hard to eliminate.

Why WALTHAM is Interested

Until recently, the genetic basis of the various dog breeds was unknown. Understanding what happened to the genes of the dog as it evolved, and the genetic differences between the breeds, will provide information that may enable intervention in some of the breed-specific health problems that continue to affect the welfare of many dogs.

Approach

Molecular techniques were used to examine the genetic variation patterns across dog breeds, how the patterns differ between wolf and dog breeds, the amount of diversity within dog breeds, and the DNA patterns linked to health conditions.

Discovery (Domestication)

There is rich history underlying dog domestication

Previously, mitochondrial DNA analysis suggested domestic dogs originated from East Asia (Savolainen et al. 2002).

Collaborative research between WALTHAM and scientists all over the world involved an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their ancestor, the grey wolf (Vonholdt et al. 2010). Haplotype analysis showed that the dog is descended from Middle Eastern grey wolves rather than from East Asian wolves (Vonholdt et al. 2010). Breed groupings based on phenotypic or functional similarities were generally found to share genetic characteristics, although in some cases individuals with novel phenotypes were the basis of traits (Vonholdt et al. 2010).

Discovery (Size)

A single gene is a major determinant of dog size

The genetic origin of the great range of body size in dogs was unclear.

For this study, WALTHAM collaborated with US scientists at the National Human Genome Research Institute in Bethesda, Cornell University New York, the University of Utah, the University of California, the University of Southern California, the University of Missouri, and the Nestle Research Center in St Louis. Following a genome-wide scan, a major quantitative trait locus (QTL) was identified on chromosome 15 that influences size variation within a single dog breed (Sutter et al. 2007). By examining the genetic variation surrounding the QTL in small and giant breeds, a selective sweep spanning a single gene, encoding insulin-like growth factor 1 (IGF1), was identified (Sutter et al. 2007). A single IGF1 single-nucleotide polymorphism haplotype (SNP 5 A allele) was found to be common to all small breeds and absent from almost all giant breeds (Figure 1. Sutter et al. 2007). This study suggests that this gene is a major contributor to body size in all small dogs.

Dog Genetics
From Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA. A single IGF1 allele is a major determinant of small size in dogs. Science 2007. 316(5821):112-115. Reprinted with permission from AAAS.

Figure 1: Association of body size and frequency of the SNP 5 A allele (Sutter et al. 2007).  Binomial regression of allele frequency on square root of mean breed mass. Dashed lines indicate the 95% confidence interval on the predicted equation line as estimated from nonparametric bootstrap resampling. Between 5 and 109 (median 22) dogs were genotyped for each of 143 breeds. The Portuguese water dog is highlighted in red along with three giant breeds that have larger breed average masses than is predicted by their SNP 5 allele frequency. The frequency of the SNP 5 A allele is strongly negatively correlated with breed average mass across this large sample of breeds (Spearman's rank correlation coefficient ?= ?0.773; P<2.2 x 10?16, likelihood ratio test = 2882.3, X2df-1 <2 x 10?16, logistic regression of allele frequency on body size)

Discovery (Phenotype)

Genetic variants are linked to stereotypical dog characteristics

Selective breeding has resulted in traits (or phenotypic stereotypes), such as conformation and behaviours, that are special to each breed. However, the genetics underlying these traits was not known.

In a collaboration between WALTHAM, an experienced dog trainer and judge, the University of Utah, and the National Human Genome Research Institute, Bethesda, Maryland, USA, DNA samples from dogs representing 148 breeds were used to associate single nucleotide polymorphism markers with breed stereotypes (Jones et al. 2008). Significant loci linked to the shape of dogs, their weight, coat length, tail curve, and the ratio of the head, neck or leg to body size were found (Jones et al. 2008; Chase et al. 2009). Loci were also tentatively identified that affected behavioural stereotypes such as herding, pointing, boldness, and trainability (Jones et al. 2008). Four significant loci were identified for longevity, a characteristic that is inversely correlated with breed size (Jones et al. 2008).

Discovery (Disease)

Partnering with world class scientists WALTHAM research has contributed to the understanding of the genetic basis of canine disease.

Diabetes
This research showed that canine diabetes has a similar genetic basis to human diabetes. Single nucleotide polymorphisms in the canine CTLA4 gene were found to be associated with diabetes (Short et al. 2010), as they are in human type-1 diabetes mellitus. CTLA4 promoter polymorphisms were associated with diabetes in crossbreed dogs and in five pedigree breeds, including the Samoyed, miniature schnauzer, West Highland white terrier, Border terrier and Labrador retriever (Short et al. 2010).

Major histocompatibility complex haplotypes (Kennedy et al. 2006) and cytokines (Short et al. 2009; Short et al. 2007) have also been implicated in canine diabetes.

Anal furunculosis
A genetic basis of anal furunculosis was identified. This is a chronic inflammatory disease of perianal tissues that particularly affects German shepherds. Susceptibility to anal furunculosis was found to be primarily associated with the major histocompatibility complex allele DLA-DRB1*00101 (Barnes et al. 2009; Kennedy et al. 2008).

Copper accumulation

The mutation responsible for copper toxicosis, an autosomal recessive disorder affecting Bedlington terriers, was characterised (Forman et al. 2005). Subsequently, a genomic diagnostic test for the disease was developed (Forman et al. 2005). The heritability of copper accumulating traits in Labrador retrievers was also investigated (Hoffman et al. 2008).

Musculoskeletal health

A genetic link between dog size and hip dysplasia was identified. A major determinant of size in dogs is a single insulin-like growth factor 1 (IGF1) haplotype (Sutter et al. 2007). This was found to be significantly associated with hip dysplasia (known to be more prevalent in larger dogs) as well as patella luxation and pancreatitis (Chase et al. 2009). Subsequently, it was shown that it may be possible to predict hip dysplasia from genome data (Guo et al. 2011).

A genetic basis for chondrodysplasia was identified. This is a short-legged phenotype that defines breeds including the dachshund, corgi, and Basset hound. It is strongly associated with a recently acquired retrogene encoding fibroblast growth factor 4 (fgf4) (Parker et al. 2009).

Atopic dermatitis

This research identified the genes potentially involved in the pathology of atopic dermatosis. The expression of 54 genes was found to be significantly associated with the disease, of which 12 genes were expressed only in skin lesions (Merryman-Simpson et al. 2008). The genes were associated with innate immune and inflammatory responses, cell cycle, apoptosis, barrier formation, and transcriptional regulation (Merryman-Simpson et al. 2008). Understanding which genes are activated during atopic dermatosis aids understanding of the disease and ultimately its treatment.

References

Barnes A, O'Neill T, Kennedy LJ, Short AD, Catchpole B, House A, Binns M, Fretwell N, Day MJ, Ollier WE. Association of canine anal furunculosis with TNFA is secondary to linkage disequilibrium with DLA-DRB1*. Tissue Antigens. 2009 Mar;73(3):218-24.


Burger IH. Energy needs of companion animals: matching food intakes to requirements throughout the life cycle. J Nutr. 1994 Dec;124(12 Suppl):2584S-2593S.


Calboli FC, Sampson J, Fretwell N, Balding DJ. Population structure and inbreeding from pedigree analysis of purebred dogs. Genetics. 2008 May;179(1):593-601.


Chase K, Jones P, Martin A, Ostrander EA, Lark KG. Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic. J Hered. 2009 Jul-Aug;100 Suppl 1:S37-41.


Forman OP, Boursnell ME, Dunmore BJ, Stendall N, van den Sluis B, Fretwell N, Jones C, Wijmenga C, Rothuizen J, van Oost BA, Holmes NG, Binns MM, Jones P. Characterization of the COMMD1 (MURR1) mutation causing copper toxicosis in Bedlington terriers. Anim Genet. 2005 Dec;36(6):497-501.


Guo G, Zhou Z, Wang Y, Zhao K, Zhu L, Lust G, Hunter L, Friedenberg S, Li J, Zhang Y, Harris S, Jones P, Sandler J, Krotscheck U, Todhunter R, Zhang Z. Canine hip dysplasia is predictable by genotyping. Osteoarthritis Cartilage. 2011 Apr;19(4):420-9.


Hoffmann G, Heuven HC, Leegwater PA, Jones PG, van den Ingh TS, Bode P, Rothuizen J. Heritabilities of copper-accumulating traits in Labrador retrievers. Anim Genet. 2008 Aug;39(4):454.


Jones P, Chase K, Martin A, Davern P, Ostrander EA, Lark KG. Single-nucleotide-polymorphism-based association mapping of dog stereotypes. Genetics. 2008 Jun;179(2):1033-44.


Kennedy LJ, O'Neill T, House A, Barnes A, Kyöstilä K, Innes J, Fretwell N, Day MJ, Catchpole B, Lohi H, Ollier WE. Risk of anal furunculosis in German shepherd dogs is associated with the major histocompatibility complex. Tissue Antigens. 2008 Jan;71(1):51-6


Kennedy LJ, Davison LJ, Barnes A, Short AD, Fretwell N, Jones CA, Lee AC, Ollier WE, Catchpole B. Identification of susceptibility and protective major histocompatibility complex haplotypes in canine diabetes mellitus. Tissue Antigens. 2006 Dec;68(6):467-76.


Merryman-Simpson AE, Wood SH, Fretwell N, Jones PG, McLaren WM, McEwan NA, Clements DN, Carter SD, Ollier WE, Nuttall T. Gene (mRNA) expression in canine atopic dermatitis: microarray analysis. Vet Dermatol. 2008 Apr;19(2):59-66.


Parker HG, VonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA. An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science. 2009 Aug 21;325(5943):995-8.


Savolainen P, Zhang YP, Luo J, Lundeberg J, Leitner T. Genetic evidence for an East Asian origin of domestic dogs. Science. 2002 Nov 22;298(5598):1610-3.


Short AD, Saleh NM, Catchpole B, Kennedy LJ, Barnes A, Jones CA, Fretwell N, Ollier WE. CTLA4 promoter polymorphisms are associated with canine diabetes mellitus. Tissue Antigens. 2010 Mar;75(3):242-52.


Short AD, Catchpole B, Kennedy LJ, Barnes A, Lee AC, Jones CA, Fretwell N, Ollier WE. T cell cytokine gene polymorphisms in canine diabetes mellitus. Vet Immunol Immunopathol. 2009 Mar 15;128(1-3):137-46.


Short AD, Catchpole B, Kennedy LJ, Barnes A, Fretwell N, Jones C, Thomson W, Ollier WE. Analysis of candidate susceptibility genes in canine diabetes. J Hered. 2007;98(5):518-25.


Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA. A single IGF1 allele is a major determinant of small size in dogs. Science. 2007 Apr 6;316(5821):112-5.


Vonholdt BM, Pollinger JP, Lohmueller KE, Han E, Parker HG, Quignon P, Degenhardt JD, Boyko AR, Earl DA, Auton A, Reynolds A, Bryc K, Brisbin A, Knowles JC, Mosher DS, Spady TC, Elkahloun A, Geffen E, Pilot M, Jedrzejewski W, Greco C, Randi E, Bannasch D, Wilton A, Shearman J, Musiani M, Cargill M, Jones PG, Qian Z, Huang W, Ding ZL, Zhang YP, Bustamante CD, Ostrander EA, Novembre J, Wayne RK. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication. Nature. 2010

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