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. Author manuscript; available in PMC: 2015 Jun 25.
Published in final edited form as: Dobutsu Iden Ikushu Kenkyu. 2014;42(2):79–89. doi: 10.5924/abgri.42.79

Inherited retinal diseases in dogs: advances in gene/mutation discovery

Keiko Miyadera 1
PMCID: PMC4480793  NIHMSID: NIHMS700467  PMID: 26120276

Abstract

1. Inherited retinal diseases (RDs) are vision-threatening conditions affecting humans as well as many domestic animals. Through many years of clinical studies of the domestic dog population, a wide array of RDs has been phenotypically characterized. Extensive effort to map the causative gene and to identify the underlying mutation followed. Through candidate gene, linkage analysis, genome-wide association studies, and more recently, by means of next-generation sequencing, as many as 31 mutations in 24 genes have been identified as the underlying cause for canine RDs. Most of these genes have been associated with human RDs providing opportunities to study their roles in the disease pathogenesis and in normal visual function. The canine model has also contributed in developing new treatments such as gene therapy which has been clinically applied to human patients. Meanwhile, with increasing knowledge of the molecular architecture of RDs in different subpopulations of dogs, the conventional understanding of RDs as a simple monogenic disease is beginning to change. Emerging evidence of modifiers that alters the disease outcome is complicating the interpretation of DNA tests. In this review, advances in the gene/mutation discovery approaches and the emerging genetic complexity of canine RDs are discussed.

1. Introduction

Inherited retinal diseases (RDs) in humans comprise a spectrum of clinically heterogeneous vision-threatening conditions such as retinitis pigmentosa (RP), cone-rod dystrophy (CRD) and Leber’s congenital amaurosis (LCA). Since the mapping of the RHO (rhodopsin) gene in a form of RP (Farrar et al. 1990), 221 genes have been associated with human RDs (RetNet; www.sph.uth.tmc.edu/RetNet/), and the number of genes continues to grow. Animal models have been indispensable in validating the physiologic and pathologic mechanisms of these genes, most extensively, as genetically modified mice. To a lesser degree but with no less significance, dogs also have received much attention over the years as a unique, naturally-occurring model of RDs. In this review, I will discuss the current knowledge of the molecular basis of canine RDs and advances in the gene/mutation discovery approach.

2. Phenotypic characteristics of canine RDs

The most commonly diagnosed canine RD is progressive retinal atrophy (PRA) which is considered homologous to RP in humans. Dogs affected with PRA initially present night blindness, eventually progressing into total vision loss. While PRA has been documented in numerous canine breeds, it was once thought to be a single disease caused by the same mutation across breeds. However, breed-specific clinical phenotype (e.g. age of onset, rate of progression) together with the evidence from diligent mating trials indicated that multiple independent forms of PRAs exist, and that each form is specific to certain breed(s). Inherited canine RDs may be classified as “progressive” that undergo programmed degenerative changes during life, “stationary” that are congenital functional abnormalities where the functional defect of the retina, often caused by a total absence of a functional retina protein is present at birth and do not change throughout life, or “developmental” that are (Table 1). Most canine RDs are autosomal recessive, while autosomal dominant (Kijas et al. 2002) and X-linked PRAs have been identified (Acland et al. 1994; Zhang et al. 2002). Notably, all canine RDs molecularly characterized to date have been reported as a monogenic trait (i.e. caused by a mutation in a single gene), following a Mendelian inheritance.

Table 1.

Canine retinal diseases and associated genes

Disease Name Disease
Symbol		 Breed Gene Gene Function Approach References
Progressive Disorders
Progressive Retinal Atrophy (PRA)
 Rod-cone dysplasia 1 rcd1 Irish Setter PDE6B Phototransduction Candidate gene (Clements et al. 1993; Suber et al. 1993)
 Rod-cone dysplasia 1a rcd1a Sloughi PDE6B Phototransduction Candidate gene (Dekomien et al. 2000)
 Rod-cone dysplasia 2 rcd2 Collie RD3 Phototransduction LA (Kukekova et al. 2009)
 Rod-cone dysplasia 3 rcd3 Cardigan Welsh Corgi PDE6A Phototransduction Candidate gene (Petersen-Jones et al. 1999)
 Rod-cone dysplasia 4 rcd4 Setters and othersa C2orf71 N.D. GWAS (Downs et al. 2013)
 Early retinal degeneration erd Norwegian Elkhound STK38L N.D. LA (Goldstein et al. 2010b)
 Progressive rod-cone degeneration PRCD Multiple breedsb PRCD N.D. LA (Zangerl et al. 2006)
 Golden Retriever PRA 1 GR_PRA1 Golden Retriever SLC4A3 Anion exchange GWAS (Downs et al. 2011)
 Golden Retriever PRA 2 GR_PRA2 Golden Retriever TTC8 Cilia formation GWAS, targeted-NGS (Downs et al. 2014)
 X-linked PRA 1 XLPRA1 Samoyed, Siberian Husky RPGR Cilia trafficking LA (Zhang et al. 2002)
 X-linked PRA 2 XLPRA2 Mongrel RPGR Cilia trafficking LA (Zhang et al. 2002)
 Autosomal dominant PRA ADPRA Bullmastiff, English Mastiff RHO Phototransduction Candidate gene (Kijas et al. 2002)
 Generalized PRA gPRACCDC66 Schapendoes CCDC66 N.D. LA (Dekomien et al. 2010)
 Italian Greyhound PRA IG_PRA1 Italian Greyhound - - - (Goldstein, personal communication)
 Papillon PRA Pap_PRA1 Papillon CNGB1 Phototransduction (Ahonen et al. 2013; Winkler et al. 2013)
 Basenji PRA Bas_PRA1 Basenji SAG Phototransduction GWAS (Goldstein et al. 2013a)
 PRA3 PRA3 Tibetan Spaniel/Terrier FAM161A Cilia trafficking GWAS, targeted-NGS (Downs and Mellersh. 2014)
Cone-Rod Dystrophy (CRD)
 Cone-rod dystrophy crd1 American Staffordshire Terrier PDE6B Phototransduction GWAS (Goldstein et al. 2013b)
 Cone-rod dystrophy crd2 American Pit Bull/Staffordshire Terrier IQCB1 Cilia trafficking GWAS (Goldstein et al. 2013b)
 Cone-rod dystrophy crd3 Glen of Imaal Terrier ADAM9 N.D. GWAS (pet, colony) (Goldstein et al. 2010c)
 Cone-rod dystrophy cord1 Miniature Longhaired/Smooth/Wirehaired Dachshunds RPGRIP1 Cilia trafficking LA
GWAS (modifier)		 (Mellersh et al. 2006; Miyadera et al. 2012)
 Cone-rod dystrophy CRDNPHP4 Standard Wirehaired Dachshund NPHP4 Cilia trafficking GWAS (Wiik et al. 2008)
Stationary Disorders
 Cone degeneration (achromatopsia, day blindness) CD Alaskan Malamute, Miniature
Australian shepherd, Siberian Husky		 CNGB3 Phototransduction LA (Sidjanin et al. 2002)
 Cone degeneration (achromatopsia, day blindness) CD German Shorthaired Pointer CNGB3 Phototransduction LA (Sidjanin et al. 2002)
 Canine LCA cLCA Briard RPE65 Visual cycle Candidate gene (Aguirre et al. 1998; Veske et al. 1999)
Developmental Disorders
 Retinal dysplasia/Oculo-skeletal dysplasia 1 RD/OSD1 Labrador Retriever COL9A3 Collagen formation LA (Goldstein et al. 2010a)
 Retinal dysplasia/Oculo-skeletal dysplasia 2 RD/OSD2 Samoyed COL9A2 Collagen formation LA (Goldstein et al. 2010a)
 Collie eye anomaly CEA Collies and other breedsc NHEJ1 N.D. LA (Parker et al. 2007)
Others
 Canine multifocal retinopathy 1 CMR1 Multiple breedsd BEST1 Epithelial transport Candidate gene (Guziewicz et al. 2007)
 Canine multifocal retinopathy 2 CMR2 Coton de Tulear BEST1 Epithelial transport Candidate gene (Guziewicz et al. 2007)
 Canine multifocal retinopathy 3 CMR3 Lapponian Herder BEST1 Epithelial transport Candidate gene (Zangerl et al. 2010)
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Modified from Miyadera et al. (2012a). The Approach column shows the method used to identify the chromosomal location and/or the gene, and the type of sample population used. LA, linkage analysis; N.D., not determined; GWAS, genome-wide association study.

a

rcd4-affected breeds: English/Gordon/Irish/Llwellyn Setters, Polish Lowland Sheepdog, Tibetan Terrier.

b

PRCD-affected breeds: American Cocker Spaniel, American Eskimo Dog, Australian Cattle Dog, Australian Shepherd, Australian Stumpy Tail Cattle Dog, Bolonka Zwetna, Chesapeake Bay Retriever, Chinese Crested, English Cocker Spaniel, English Shepherd, Entlebucher Mountain Dog, Finnish Lapphund, Giant Schnauzer, Golden Retriever, Karelian Bear Dog, Kuvasz, Labrador Retriever, Lapponian Herder, Norwegian Elkhound, Poodle (Miniature/Toy/Standard), Nova Scotia Duck Tolling Retriever, Portuguese Water Dog, Spanish Water Dog, Swedish Lapphund, Yorkshire Terrier.

c

CEA-affected breeds: Australian Shepherd, Bearded Collie, Boykin Spaniel, Border Collie, Hokkaido Dog, Lancashire Heeler, Nova Scotia Duck Tolling Retriever, Rough/Smooth Collie, Shetland Sheepdog, Silken Windhound, Longhaired Whippet.

d

CMR1-affected breeds: American Bulldog, Australian Shepherd, Boerboel, Bullmastiff, Cane Corso, Dogue de Bordeaux, Great Pyrenees, Old English Mastiff, Perro de Presa Canario, English/American Bulldog.

2.1. Progressive disorders

PRA and CRD are progressive RDs, primarily affecting the photoreceptors. PRA is characterized by initial degeneration of rod photoreceptors causing night blindness, progressing to total blindness. Affected dogs with visual deficits have characteristic fundus changes starting from tapetal hyperreflectivity, attenuation of retinal blood vessels, then pale optic disc. CRD is less common, and predominantly affects cone photoreceptors while rods are affected later or to a lesser degree. Early clinical signs therefore can be day vision problems. However, diagnosis is often made when there is already extensive day and light visual deficit with end-stage fundic changes similar to PRA. As such, CRD may be indistinguishable from PRA at the clinical level, thus often being referred to as PRA.

While dogs affected with PRA/CRD show similar fundic changes at the end-stage of the disease, the age of onset and the rate of progression may vary, depending on the underlying gene/mutation, thereby depending on the breed. Early-onset PRA/CRD results from abnormal retinal development or progressive degeneration starting during or soon after retinogenesis. This is followed by a rapid progression toward end-stage retinal degeneration, and can be clinically evident in young adult dogs. Late-onset PRA/CRD is characterized by pathological changes after normal development of the retina. As such, they tend to represent defects in pathways critical for the long-term maintenance of normal photoreceptors. Visual deficits may not become apparent until well after reproductive maturity, and further progression is typically much slower than in early-onset PRA/CRD, and may not become clinically evident until later in life.

2.2. Stationary disorders

Certain forms of RD show no or very limited progression. Examples of such stationary disorders are achromatopsia (cone degeneration) (Sidjanin et al. 2002) and canine LCA (cLCA), previously known as congenital stationary night blindness (CSNB) (Narfström et al. 1989).

2.3. Developmental disorders

Retinal dysplasia is a developmental disorder characterized by a defect in retinal differentiation. Syndromic retinal dysplasia in Labrador Retrievers and Samoyeds are oculoskeletal disorders that model autosomal recessive Stickler syndrome in humans (Goldstein et al. 2010a). Another developmental disorder is Collie eye anomaly (CEA) variably affecting the retina-choroid-scleral complex ranging from choroidal hypoplasia, scleral coloboma to retinal detachment. CEA are considered homologous to macular coloboma in humans. Due to high worldwide prevalence of CEA in Collies (70–90%), it is the most common inherited canine RDs, yet impairment of vision is uncommon (Barnett and Stades 1979; Roberts 1969).

3. Genes associated with RDs in humans and dogs

The phototransduction cascade and the retinoid cycle are the two critical functional pathways involved in vision. Mutations in genes participating in these pathways may be associated with RDs, and many of the protein products are localized to the outer retina where these pathways take place. More recently, genes associated with the morphology and function of the photoreceptor connecting cilia have been associated with RDs, and their roles in normal and diseased retina have been a major focus of study (Estrada-Cuzcano et al. 2012). Of the ~23 genes associated with canine RDs to date, at least 6 genes have implications of a primary role in cilia trafficking. The complex gene-gene interaction associated with cilia trafficking remains to be fully unraveled.

4. Advances in canine RD gene/mutation discovery

The gene/mutation discovery approaches for inherited canine traits have seen considerable development over the past 20 years. Initial attempts were focused on candidate genes, followed by the introduction of linkage mapping, positional cloning strategies, and microarray-based genome-wide association study (GWAS). More recently, next-generation sequencing (NGS) has been implemented with increasing availability and affordability. In dogs, due to the “breed barrier” which prevents admixture of different breeds to establish and maintain distinct breeds, the genetic makeup within the same breed is typically uniform where many sequence variants are ‘fixed’. Such within-breed genetic uniformity has been both an advantage and a disadvantage in investigating canine genetic traits (Miyadera et al. 2012a).

4.1. Candidate gene analysis

Candidate genes are selected based on existing knowledge of the biochemistry or associated diseases, or on information from other species such as humans and mice. Early studies have largely relied on a candidate gene approach largely because of the lack of alternative canine genomic tools.

The first canine RD mutation was found by screening a candidate gene PDE6B for rcd1 in Irish Setters (Clements et al. 1993; Suber et al. 1993), based on phenotypic and biochemical similarity to the rd mice with a PDE6B mutation (Bowes et al. 1990; Farber and Lolley 1974). Candidate gene approaches have since identified mutations for rcd1a in Sloughi dogs (PDE6B) (Dekomien et al. 2000), for rcd3 in Cardigan Welsh Corgis (PDE6A) (Petersen-Jones et al. 1999), and ADPRA in Bullmastiffs and English Mastiffs (RHO) (Kijas et al. 2002). However, while successes are often highlighted, there have been too many failed candidate gene screening attempts mostly unpublished, questioning its efficacy as the primary approach for mutation discovery in canine RDs (Aguirre-Hernandez and Sargan 2005). Further, while there are hundreds of genes so far associated with human RDs, screening for all the candidate genes has become unrealistic. Still, phenotype-based selection of BEST1 in CMR1, CMR2, and CMR3 has proven to be a success (Guziewicz et al. 2007; Zangerl et al. 2010) guided by the high clinical and pathologic resemblances to Best macular dystrophy in humans.

4.2. Whole-genome scan

Unlike candidate gene studies which limit the inspection to certain genes of interest, a whole genome scan interrogates the entire genome necessitating no prior assumption or knowledge of the target locus. The current tools of gene/mutation discovery are based on the 7.5X sequence of the Boxer dog (Lindblad-Toh et al. 2005), the earlier 1.5X Poodle genome sequence (Kirkness et al. 2003), as well as single nucleotide polymorphisms (SNPs) information across multiple breeds.

Linkage mapping and positional cloning strategies

A linkage analysis (LA) mapping utilizes informative families containing affected and non-affected dogs. Co-segregation of genetic markers with the phenotype is analyzed to identify recombination, or lack thereof. Subsequently, the region of interest may be further narrowed by fine-mapping, followed by positional candidate gene analysis.

Genome-wide association studies (GWAS)

With the development of microarray-based DNA chips, high-throughput SNP analysis has become feasible in both humans and domestic animals (Andersson 2009). In a GWAS approach, SNP markers pre-determined across the genome are used to assess association with the disease. For canine traits, the 170K canine SNP chip (Illumina) is the currently most commonly used platform. It has been postulated that 20 cases and 20 controls, and 50 cases and 50 controls should be sufficient for mapping autosomal recessive and dominant traits, respectively using 10,000–30,000 SNPs chips (Lindblad-Toh et al. 2005), due to the conveniently long linkage disequilibrium within a given breed (0.5–5Mb) (Gray et al. 2009; Sutter et al. 2004). Since the first report of CRD in Standard Wirehaired Dachshunds (Wiik et al. 2008), at least 10 forms of canine RDs have been mapped by GWAS (Table 1). These studies typically map a relatively large chromosomal region, followed by positional candidate gene screening with/without fine mapping.

4.3. Next-generation sequencing

More recently, the next-generation sequencing (NGS) technique has been applied to canine RD studies aiding in mapping, fine mapping and functional analysis. NGS is based on a massively-parallel, high-throughput sequencing which produces millions of short sequences to be analyzed by extensive bioinformatics. A targeted-NGS approach is used where a genetic locus has been mapped by a whole genome scan. The genomic area of interest is then captured using custom-designed probes, and the enriched DNA is subjected to NGS. GWAS-guided fine mapping by targeted-NGS has so far identified mutations associated with GR_PRA2 in Golden Retrievers (Downs et al. 2014) and PRA3 in Tibetan Spaniels/Terriers (Downs & Mellersh 2014). Exome-sequencing is a form of targeted-NGS which captures only the predetermined known canine exon regions for NGS. Ahonen et al. (2013) used exome-sequencing as a parallel approach to identify the CNGB1 mutation associated with Papillon PRA. Other NGS applications include RNA-seq and whole-genome sequencing, each of which has already proven useful in mapping and mutation screening of non-ocular diseases in dogs (Forman et al. 2012; Drogemuller et al. 2013; Guo et al. 2014). RNA-seq uses tissue-specific RNA as the template and provides a complete snapshot of transcripts expressed in the tissue of interest, allowing assessment of the level of expression (quantitative) as well as structural and sequence changes (qualitative).

5. Emerging complexity of canine RDs

5.1. Multiple forms of RD per breed

After a DNA test for certain RD has become available, some of the target breed populations have been found to contain dogs that are tested as genetically tested “clear” but are in fact clinically affected with RD (Table 2). This indicates the presence of alternative form(s) of RD independent of the already known RD. Such genetic heterogeneity has been a dilemma for the DNA test providers as well as the users alike, and those dogs with discordant DNA test results become subjects for further investigation to identify the missing RD gene/mutation for the breed.

Table 2.

Examples of breeds affected with more than one confirmed RDs

Breed Disease 1 Disease 2 Disease 3 Disease 4
Australian Shepherd prcd-PRA CEA CMR1 CD
Golden Retriever prcd-PRA GR_PRA1 GR_PRA2 -
Golden Doodle prcd-PRA GR_PRA1 GR_PRA2 -
Norwegian Elkhound prcd-PRA rd erd -
Lapponian Herder prcd-PRA CMR3 - -
Irish Setter rcd1-PRA rcd4-PRA - -
Labrador Retriever prcd-PRA RD/OSD1 - -
Nova Scotia Duck Tolling Retriever prcd-PRA CEA - -
Miniature Wirehaired Dachshund CRDNPHP4 cord1 - -
Bullmastiff/English Mastiff ADPRA CMR1 - -
Samoyed XLPRA1 RD/OSD2 - -
Tibetan Terrier rcd4-PRA PRA3 - -
Collie rcd2-PRA CEA - -
Portuguese Water Dog prcd-PRA early-onset PRA - -
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Early-onset PRA in Portuguese Water Dogs (PWD)

PWDs are one of many breeds affected with PRCD-PRA. PRCD in this breed is a late-onset form of PRA typically presenting with night blindness at mid age gradually progressing into total blindness. The author and colleagues have recently identified a new form of PRA in PWDs that are not associated with PRCD. It presents as an early-onset PRA where night blindness is recognized at 1–2 years of age followed by rapid progression to total blindness. Affected cases and controls have been identified for a GWAS.

5.3. Modifiers

While RDs have largely been considered as simple monogenic traits, there is increasing evidence to suggest that more than one gene mutation could be affecting the phenotypic outcome. This is not surprising considering the number of genes (>220) associated with human RDs to date. Genetic polymorphisms in any of these genes albeit non-pathogenic on their own, could potentially function as modifiers altering the effect of a primary mutation. PRCD-PRA affecting a variety of dog breeds show variable yet breed-specific ages of onset. This is thought to be largely attributed to breed-specific genetic backgrounds that are collections of genetic polymorphisms across the genome. Modifier genes may or may not be retina-specific, and could be genes interacting with any retinal gene, further inflating the number of potential modifier genes.

The author has previously demonstrated the presence of a genetic modifier in cone-rod dystrophy 1 (cord1) in Miniature Longhaired Dachshunds (MLHDs). The condition was first described as an autosomal recessive CRD with an early-onset (age <1 year) in a MLHD research colony in the UK (Curtis & Barnett 1993). This disease was found to segregate completely with a mutation in RPGRIP1, at least within this closed research colony (Mellersh et al. 2006). However, when Japanese pet MLHDs were screened, the age of onset was much broader (4 months - 15 years, mean ± SD: 4.6 ± 3.4 years) compared to the UK colony (Miyadera et al. 2009). Furthermore, the Japanese pet MLHDs showed significant phenotype-genotype discordance; 20% of blind cases were not homozygous for the mutation, while 16% of the apparently normal dogs were homozygous affected genetically. To account for this disparity, a GWAS was carried out using 80 RPGRIP1−/− (homozygous mutant) dogs differing by the clinical phenotypes; this led to the identification of an independently segregating homozygous modifier locus on chromosome 15 (Miyadera et al. 2012b). The UK research colony turned out to be ‘fixed’ for this modifier locus, thus being masked in the initial mapping study by Mellersh et al. (2006). The gene/mutation underlying this modifier and its interaction with RPGRIP1 is current our focus of study.

7. DNA tests

DNA tests for most canine RDs whose underlying mutation is known are available commercially (Mellersh 2012). Unlike in the human population with a huge amount of genetic heterogeneity requiring screening of an extensive panel of genes and mutations (Stone 2007; Zernant et al. 2005), in dogs, testing of only the known mutation(s) associated with the respective breed is often sufficient. Notably, a mix dog produced from different canine breeds which happen to harbor the same RD mutation can be affected with that RD such as PRCD-PRA seen among the increasingly popular ‘designer dogs’ (e.g. Labradoodles, Goldendoodles). Meanwhile, new breeds affected with the existing forms of RDs are found each year and added to the list.

The advantage of DNA tests is its ability to detect unaffected carriers and subclinical cases prior to disease onset. It is important to note that other unidentified forms of RDs will not be screened with the existing DNA tests. In many situations, following identification of a mutation, coordinated effort is implemented by the breeding community leading to a substantial decrease in the disease and mutant allele frequencies in the breed. Meanwhile, other non-RD diseases/traits should also be taken into account when considering breeding strategies to assure the overall health of the breed while nurturing desirable traits. This is important as the selective pressure by DNA tests can significantly reduce the genetic diversity when the mutation frequency is high in the breed. In the author’s opinion, the aim of DNA tests are not to eliminate certain dogs from breeding, but to safely include them by identifying genetically ‘clear’ dogs that can be bred to. Where maintaining the genetic diversity of the breed population is a concern, otherwise desirable dogs may potentially be used for breeding as long as a DNA-test is performed and breeding is planned accordingly.

8. Prospects

While many successful mapping studies have benefited from purpose-bred research colonies, cases and controls recruited from the general pet population have contributed significantly to the effort. Still, research colonies remain essential in providing adequate resources for functional studies and developing new therapies. Identification of genes/mutations underlying canine RDs have provided excellent testing grounds for gene replacement therapy, one of the approaches under active development to prevent, stabilize, or reverse the retinal degenerative process in humans and animals.

cLCA in Briards with an RPE65 mutation has been treated successfully with subretinal injection of a recombinant adeno-associated virus 2 carrying wild-type RPE65 (Acland et al. 2001; Narfström et al. 2003). The single injection was safe, effective and stable with functional improvement up to four years (Acland et al. 2005; Narfstrom et al. 2008). The treatment was subsequently applied to human LCA patients carrying RPE65 mutations leading to significant restorations of vision (Bainbridge et al. 2008; Hauswirth et al. 2008; Maguire et al. 2008). Successful gene therapy using the dog model has also been achieved in achromatopsia (Komaromy et al. 2010) and CMR (Guziewicz, personal communication).

9. Conclusion

Since the first identification of the PDE6B mutation in 1993, significant progress has been made in the molecular study of canine RDs thanks to the development of genetic resources and tools. Phenotypic and genetic similarities between canine and human RDs have provided an excellent opportunity to study the molecular mechanisms across species. Molecular characterization of canine RDs is likely to become even faster and affordable over the coming years, with increasing feasibility of the NGS approach. Due to the history of breed development, the genomic background within each dog breed is relatively uniform compared to the extremely heterogeneous human population as a whole. Identification of primary mutations and manageable number of minor alleles or modifiers should therefore be more advantageous using the canine population, and will continue to contribute in the understanding of RDs in dogs and in humans.

Acknowledgments

I wish to thank Dr. Gustavo Aguirre, University of Pennsylvania for valuable discussions. The author is supported by the Career Development Award for Veterinary Residents from the Foundation Fighting Blindness.

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