NEWS FEATURE
Biomedical research gone to the dogs
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© 2014 Nature America, Inc. All rights reserved.
Much of biomedical research is aimed at understanding and treating diseases that affect humans. But sometimes the l essons learned from animal studies b enefit the a nimals too, especially when veterinary medicine and research intersect. Holger Volk (Royal Veterinary College, London, UK), who studies epilepsy in dogs, r ecognizes the interplay between veterinary and biomedical research. In an interview with BBC TV in March 2013 (video a vailable online at http://www.bbc. com/news/health-26573242), he said, “My research is driven to improve animal health, and by doing that, I can also help the human counterpart, and it’s a win/win situation for both species.” Humanity’s best friend Dogs are often considered humanity’s best friends, a role that may also make them its best models of disease. Canines share people’s environment and lifestyle in ways that other animals do not. Dogs are s ubjected to the same environmental conditions in which their owners live, including potential exposure to secondhand smoke and other allergens; they might even share their owners’ dietary habits. They often live well into their old age, and generally receive high-quality h ealthcare. Their r eflection of human lifestyles p rovides insight into the epidemiology and risk factors, including environmental contributions and aging, associated with diseases1. In addition, dogs are susceptible to many naturally occurring diseases, whereas d isease frequently must be induced in other species. Cathryn Mellersh and David Sargan, members of the Editorial Board of Canine Genetics and Epidemiology, which began publishing in April 2014, addressed this advantage of dogs as m odels of human disease in a recent i nterview with Biome2. Mellersh explained, “[I]n the dog (as in man) the conditions are naturally o ccurring, and are similar LAB ANIMAL
Lilun_Li/iStock/Thinkstock
by Monica Harrington
iologically, histologically, and in clinical b course. The dog also exhibits a physiology more s uited to gross comparison with the human than many traditional model organisms.” Sargan added that more than 500 naturally o ccurring diseases have been described in dogs, more than in any other mammal except humans. “These diseases, o ccurring in a large natural p opulation under r easonably close veterinary m edical s urveillance, represent an enormous p otential resource for the modelling of pathogenesis and testing of therapy for autologous human diseases,” he stated.
disease is simpler than that of the same clinical condition in humans2,6. Genetic association studies like these are possible thanks to the Canine Genome Sequencing Project, which produced a high-quality draft sequence of the dog genome from a female boxer named Tasha in 2005 (ref. 3). Tasha’s genetic sequence was then compared with those of dogs of many other breeds to map an array of more than 25,000 single-nucleotide p olymorphisms found in the canine genome, which serve as landmarks for disease-associated gene regions or loci.
Familiarity breeds genetic tractability The domestication of dogs has also contributed to their amenability as research models. Dogs have been bred selectively for centuries; more than 400 canine breeds are recognized today, and each descends from only a few founders. This means that dogs of a single breed have a very high degree of genetic similarity, making it easy to spot genetic differences among them. By comparing genetic sequences in dogs that have a specific disease (cases) and in breedmates that do not (controls), researchers can identify differences associated with that disease2–4. And because of dogs’ unique genetic similarity, disease-associated gene regions can be identified using relatively small sample sizes, with far fewer cases than would be needed in equivalent studies with humans2,5. Researchers showed that genetic changes associated with specific inherited conditions could be identified by c omparing samples from as few as 20 dogs (10 cases and 10 controls)4. Dogs’ genetic similarity may also mean that the genetic basis for a canine
Clinical companions For many diseases that occur naturally both in humans and in dogs of certain breeds, research done in one species can improve mechanistic understanding and clinical treatment of the condition in both species, as shown in the following four examples. Systemic lupus erythematosus (SLE). Nova Scotia duck tolling retrievers (sometimes called ‘tollers’) are strongly predisposed to developing an autoimmune disease complex that shares some c haracteristics with SLE in humans. The disease in tollers is multigenic, like most autoimmune disorders in humans. A genetic mapping study identified five loci associated with the SLE-like disorder in t ollers5. The specific mutations associated with the disease have not yet been reported, but researchers hope that understanding the underlying genetics could enable them to develop treatment plans based on an a ffected dog’s particular risk genotype. Studies of targeted therapies could also potentially lead to better treatment options for SLE in humans5.
Volume 43, No. 10 | OCTOBER 2014 339
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© 2014 Nature America, Inc. All rights reserved.
Leukocyte adhesion deficiency (LAD). Individuals affected with this rare but d evastating immunodeficiency d isease t ypically die from recurrent bacterial infections. LAD occurs in Irish setter dogs as well as humans and cows and has similar characteristics in the three s pecies. Previous omozygous m utations research showed that h in the gene encoding beta-2 i ntegrin (ITGB2) were responsible for human and bovine LAD, and sequence analysis of samples from Irish setters with canine LAD confirmed that the same gene was mutated in these cases7. This d iscovery enabled the development of a diagnostic test to identify dogs that carry the mutation associated with canine LAD, such that breeding schemes could be designed to avoid producing puppies with the d isease. The findings also suggest that affected dogs might serve as models for the development and evaluation of treatments for human LAD. Leber congenital amaurosis. Large sheep dogs known as briards can inherit an eye disorder called congenital stationary night blindness. The genetic basis for this disease, and for related forms of retinal d egeneration, is the mutation of a gene called RPE65 (ref. 8). As with the ITGB2 mutation in Irish setters, diagnostic tests were developed to identify briards c arrying the RPE65 m utation in order to guide breeding practices. In addition, gene therapy was used to deliver normal RPE65 transcripts into the retinas of affected dogs, restoring their vision (http://www. akcchf.org/research/success-stories/giving- eyesight-to-the-blind.html). This success led to the application of gene t herapy in people isease called affected with a s imilar r etinal d Leber congenital amaurosis, where it has had some success in improving visual function and acuity9.
340 Volume 43, No. 10 | OCTOBER 2014
Wavetop/iStock/Thinkstock
NEWS FEATURE
Amyotrophic lateral sclerosis (ALS). Canine degenerative myelopathy (CDM) is a fatal neurodegenerative disease prevalent in several dog breeds including the Pembroke Welsh corgi. Genome-wide association m apping identified a region in which the genetic sequence differed in corgi cases c ompared with controls10. This region included the gene SOD1, which is mutated in a small fraction of people with ALS, an adult-onset, fatal, paralytic, p rogressive n eurodegeneration that is s imilar in presentation to CDM. When r esearchers sequenced SOD1 in dogs, they found a homozygous mutation in those with CDM that was not present in controls of five dog breeds: corgi, boxer, Rhodesian ridgeback, German Shepherd dog and Chesapeake Bay retriever. A closer look at the spinal cords from affected dogs showed some s imilarities with spinal cord sections from people with ALS linked to SOD1 mutations, leading to the proposal of CDM as a spontaneously occurring animal model for inherited ALS10. Development of a d iagnostic test to identify carriers has been recommended to help prevent the breeding of dogs at risk for developing CDM in the future. Many other studies of conditions shared by humans and dogs have yielded valuable information about the genetics,
athology, epidemiology and other aspects p of disease11. The close relationship between the two species suggests that such research will continue to advance both veterinary and medical care, improving therapeutic options for both people and dogs.
1. Tsai, K.L., Clark, L.A. & Murphy, K.E. Understanding hereditary diseases using the dog and human as companion model systems. Mamm. Genome 18, 444–451 (2007). 2. From canine genetics to human disease: a Q&A with Cathryn Mellersh and David Sargan. Biome (18 April 2014). 3. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005). 4. Karlsson, E.K. et al. Efficient mapping of mendelian traits in dogs through genome-wide association. Nat. Genet. 39, 1321–1328 (2007). 5. Wilbe, M. et al. Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat. Genet. 42, 250–254 (2010). 6. Shearin, A.L. & Ostrander, E.A. Leading the way: canine models of genomics and disease. Dis. Model. Mech. 3, 27–34 (2010). 7. Kijas, J.M. et al. A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics 61, 101–107 (1999). 8. Aguirre, G.D. et al. Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol. Vis. 4, 23 (1998). 9. Jacobson, S.G. et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch. Ophthalmol. 130, 9–24 (2012). 10. Awano, T. et al. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 106, 2794–2799 (2009). 11. Karlsson, E.K. & Lindblad-Toh, K. Leader of the pack: gene mapping in dogs and other model organisms. Nat. Rev. Genet. 9, 713–725 (2008).
www.labanimal.com
Biomedical research gone to the dogs
npg
© 2014 Nature America, Inc. All rights reserved.
Much of biomedical research is aimed at understanding and treating diseases that affect humans. But sometimes the l essons learned from animal studies b enefit the a nimals too, especially when veterinary medicine and research intersect. Holger Volk (Royal Veterinary College, London, UK), who studies epilepsy in dogs, r ecognizes the interplay between veterinary and biomedical research. In an interview with BBC TV in March 2013 (video a vailable online at http://www.bbc. com/news/health-26573242), he said, “My research is driven to improve animal health, and by doing that, I can also help the human counterpart, and it’s a win/win situation for both species.” Humanity’s best friend Dogs are often considered humanity’s best friends, a role that may also make them its best models of disease. Canines share people’s environment and lifestyle in ways that other animals do not. Dogs are s ubjected to the same environmental conditions in which their owners live, including potential exposure to secondhand smoke and other allergens; they might even share their owners’ dietary habits. They often live well into their old age, and generally receive high-quality h ealthcare. Their r eflection of human lifestyles p rovides insight into the epidemiology and risk factors, including environmental contributions and aging, associated with diseases1. In addition, dogs are susceptible to many naturally occurring diseases, whereas d isease frequently must be induced in other species. Cathryn Mellersh and David Sargan, members of the Editorial Board of Canine Genetics and Epidemiology, which began publishing in April 2014, addressed this advantage of dogs as m odels of human disease in a recent i nterview with Biome2. Mellersh explained, “[I]n the dog (as in man) the conditions are naturally o ccurring, and are similar LAB ANIMAL
Lilun_Li/iStock/Thinkstock
by Monica Harrington
iologically, histologically, and in clinical b course. The dog also exhibits a physiology more s uited to gross comparison with the human than many traditional model organisms.” Sargan added that more than 500 naturally o ccurring diseases have been described in dogs, more than in any other mammal except humans. “These diseases, o ccurring in a large natural p opulation under r easonably close veterinary m edical s urveillance, represent an enormous p otential resource for the modelling of pathogenesis and testing of therapy for autologous human diseases,” he stated.
disease is simpler than that of the same clinical condition in humans2,6. Genetic association studies like these are possible thanks to the Canine Genome Sequencing Project, which produced a high-quality draft sequence of the dog genome from a female boxer named Tasha in 2005 (ref. 3). Tasha’s genetic sequence was then compared with those of dogs of many other breeds to map an array of more than 25,000 single-nucleotide p olymorphisms found in the canine genome, which serve as landmarks for disease-associated gene regions or loci.
Familiarity breeds genetic tractability The domestication of dogs has also contributed to their amenability as research models. Dogs have been bred selectively for centuries; more than 400 canine breeds are recognized today, and each descends from only a few founders. This means that dogs of a single breed have a very high degree of genetic similarity, making it easy to spot genetic differences among them. By comparing genetic sequences in dogs that have a specific disease (cases) and in breedmates that do not (controls), researchers can identify differences associated with that disease2–4. And because of dogs’ unique genetic similarity, disease-associated gene regions can be identified using relatively small sample sizes, with far fewer cases than would be needed in equivalent studies with humans2,5. Researchers showed that genetic changes associated with specific inherited conditions could be identified by c omparing samples from as few as 20 dogs (10 cases and 10 controls)4. Dogs’ genetic similarity may also mean that the genetic basis for a canine
Clinical companions For many diseases that occur naturally both in humans and in dogs of certain breeds, research done in one species can improve mechanistic understanding and clinical treatment of the condition in both species, as shown in the following four examples. Systemic lupus erythematosus (SLE). Nova Scotia duck tolling retrievers (sometimes called ‘tollers’) are strongly predisposed to developing an autoimmune disease complex that shares some c haracteristics with SLE in humans. The disease in tollers is multigenic, like most autoimmune disorders in humans. A genetic mapping study identified five loci associated with the SLE-like disorder in t ollers5. The specific mutations associated with the disease have not yet been reported, but researchers hope that understanding the underlying genetics could enable them to develop treatment plans based on an a ffected dog’s particular risk genotype. Studies of targeted therapies could also potentially lead to better treatment options for SLE in humans5.
Volume 43, No. 10 | OCTOBER 2014 339
npg
© 2014 Nature America, Inc. All rights reserved.
Leukocyte adhesion deficiency (LAD). Individuals affected with this rare but d evastating immunodeficiency d isease t ypically die from recurrent bacterial infections. LAD occurs in Irish setter dogs as well as humans and cows and has similar characteristics in the three s pecies. Previous omozygous m utations research showed that h in the gene encoding beta-2 i ntegrin (ITGB2) were responsible for human and bovine LAD, and sequence analysis of samples from Irish setters with canine LAD confirmed that the same gene was mutated in these cases7. This d iscovery enabled the development of a diagnostic test to identify dogs that carry the mutation associated with canine LAD, such that breeding schemes could be designed to avoid producing puppies with the d isease. The findings also suggest that affected dogs might serve as models for the development and evaluation of treatments for human LAD. Leber congenital amaurosis. Large sheep dogs known as briards can inherit an eye disorder called congenital stationary night blindness. The genetic basis for this disease, and for related forms of retinal d egeneration, is the mutation of a gene called RPE65 (ref. 8). As with the ITGB2 mutation in Irish setters, diagnostic tests were developed to identify briards c arrying the RPE65 m utation in order to guide breeding practices. In addition, gene therapy was used to deliver normal RPE65 transcripts into the retinas of affected dogs, restoring their vision (http://www. akcchf.org/research/success-stories/giving- eyesight-to-the-blind.html). This success led to the application of gene t herapy in people isease called affected with a s imilar r etinal d Leber congenital amaurosis, where it has had some success in improving visual function and acuity9.
340 Volume 43, No. 10 | OCTOBER 2014
Wavetop/iStock/Thinkstock
NEWS FEATURE
Amyotrophic lateral sclerosis (ALS). Canine degenerative myelopathy (CDM) is a fatal neurodegenerative disease prevalent in several dog breeds including the Pembroke Welsh corgi. Genome-wide association m apping identified a region in which the genetic sequence differed in corgi cases c ompared with controls10. This region included the gene SOD1, which is mutated in a small fraction of people with ALS, an adult-onset, fatal, paralytic, p rogressive n eurodegeneration that is s imilar in presentation to CDM. When r esearchers sequenced SOD1 in dogs, they found a homozygous mutation in those with CDM that was not present in controls of five dog breeds: corgi, boxer, Rhodesian ridgeback, German Shepherd dog and Chesapeake Bay retriever. A closer look at the spinal cords from affected dogs showed some s imilarities with spinal cord sections from people with ALS linked to SOD1 mutations, leading to the proposal of CDM as a spontaneously occurring animal model for inherited ALS10. Development of a d iagnostic test to identify carriers has been recommended to help prevent the breeding of dogs at risk for developing CDM in the future. Many other studies of conditions shared by humans and dogs have yielded valuable information about the genetics,
athology, epidemiology and other aspects p of disease11. The close relationship between the two species suggests that such research will continue to advance both veterinary and medical care, improving therapeutic options for both people and dogs.
1. Tsai, K.L., Clark, L.A. & Murphy, K.E. Understanding hereditary diseases using the dog and human as companion model systems. Mamm. Genome 18, 444–451 (2007). 2. From canine genetics to human disease: a Q&A with Cathryn Mellersh and David Sargan. Biome (18 April 2014). 3. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005). 4. Karlsson, E.K. et al. Efficient mapping of mendelian traits in dogs through genome-wide association. Nat. Genet. 39, 1321–1328 (2007). 5. Wilbe, M. et al. Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat. Genet. 42, 250–254 (2010). 6. Shearin, A.L. & Ostrander, E.A. Leading the way: canine models of genomics and disease. Dis. Model. Mech. 3, 27–34 (2010). 7. Kijas, J.M. et al. A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics 61, 101–107 (1999). 8. Aguirre, G.D. et al. Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol. Vis. 4, 23 (1998). 9. Jacobson, S.G. et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch. Ophthalmol. 130, 9–24 (2012). 10. Awano, T. et al. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 106, 2794–2799 (2009). 11. Karlsson, E.K. & Lindblad-Toh, K. Leader of the pack: gene mapping in dogs and other model organisms. Nat. Rev. Genet. 9, 713–725 (2008).
www.labanimal.com
