I am Principal Investigator of the Canine Genetics Centre and lead a team of researchers dedicated to understanding the genetic basis of inherited canine diseases. We study diseases that are painful, blinding, require surgical or medical intervention or otherwise reduce the quality of life of affected dogs. We use next-generation sequencing methods, including whole genome sequencing, to identify variants that are causal for, or associated with the diseases we investigate. An immediate-term objective of my research is the development of selective breeding tools that dog breeders can use to reduce the incidence of disease pure bred populations of dogs and that veterinary surgeons can use to help diagnose disease. A longer-term aim is to improve our understanding of disease aetiology in dogs and other species.
We investigate the genetics of a wide variety of inherited disorders but have a particular interest in occular and neurological disorders.
Our research involves close collaboration with many canine stakeholder groups, including fellow canine geneticists, veterinary surgeons, the Kennel Club, dog Breed Clubs and the dog-owning public.
Research
We use next-generation sequencing methods, including whole genome sequencing, to identify variants that are causal for, or associated with inherited diseases that affect the domestic dog. An immediate-term objective of my research is the development of selective breeding tools that dog breeders can use to reduce the incidence of disease pure bred populations of dogs and that veterinary surgeons can use to help diagnose disease. A longer-term aim is to improve our understanding of disease aetiology in dogs and other species.
We investigate the genetics of a wide variety of inherited disorders but have a particular interest in occular and neurological disorders.
Consortium to Research Inherited Eye Diseases in Dogs (CRIEDD)
Inherited eye diseases (IEDs) cause pain and blindness in thousands of purebred and crossbred dogs every year. Funded by Dogs Trust, an interdisciplinary consortium comprised of veterinary ophthalmologists and canine geneticists from the Kennel Club Genetics Centre was established in 2019 specifically to research inherited eye diseases in dogs.
To date, over 86 eye disease mutations and 9 risk alleles believed to be associated with disease, located within 61 different genes, have been identified in hundreds of different dog breeds. Many of these ocular diseases are genetically heterogeneous, meaning that clinically similar diseases can be caused by different mutations. By identifying the causal mutations for specific diseases, DNA tests can be developed and made available to breeders and veterinary ophthalmologists, to prevent the spread of disease in future generations of dogs and to aide definitive diagnosis of patients.
The consortium to research inherited eye diseases in dogs – known as CRIEDD– aims to identify novel mutations responsible for inherited eye diseases in dogs and develop DNA screening tools for these mutations.
The Research Process
We have developed a multi-step laboratory work flow that we use to investigate both known and novel inherited eye diseases in all breeds of dog. DNA from multiple confirmed or suspected IED cases are screened simultaneously for all published mutations. By screening dogs of ALL breeds for ALL mutations the outcomes are three-fold:
• We are developing a better understanding of the frequency of specific mutations within different breeds
• We are identifying breeds that are segregating mutations previously found in other breeds
• We are identifying dogs that are clinically affected but that do not carry the mutation(s) associated with their specific breed
Cases that remain without a molecular diagnosis at the end of step 1 are investigated further, typically by whole genome sequencing. We compare the whole genome sequences of the IED cases with the sequences of unaffected dogs and use stringent filtering criteria to identify candidate variants, which are variants that could be associated or cause the IED under investigation.
Once candidate mutations have been identified we validate the mutation(s) by genotyping large cohorts of the relevant breed, comprising robust cases and controls to confirm the disease association. Once confirmed the ‘novel’ mutation will be added to the DNA screening panel in step 1.
We develop DNA tests for all novel mutations we identify. These DNA tests will be offered commercially by the Canine Genetic Testing service at the University of Cambridge once it officially opens for business in the Autumn of 2021 and all our findings are subject to appropriate peer-review.
Samples
We invite the submission of DNA from ANY dog of ANY breed that has been diagnosed with clinical signs of inherited eye disease. The DNA can be collected as buccal (cheek) swabs that can be taken by the dog’s veterinary ophthalmologist, veterinary nurse or owner. To help facilitate the research process we ask for detailed information about the dog and his/her diagnosis. We can provide DNA buccal swab kits free of charge.
For more information about the CRIEDD project and/or to request a free DNA collection kit please contact Katherine Stanbury: ks2017@cam.ac.uk.
CRIEDD Database
In addition to our research to identify novel IED mutations we have also developed a database that details all (currently 95) mutations known to cause inherited eye diseases (IED) in dogs; this database represents a much-needed resource for veterinary ophthalmologists attempting to keep abreast of developments in the field. The database is not currently available to the public (we hope it will be soon) but if you would like a copy of the database report please contact Katherine Stanbury: ks2017@cam.ac.uk.
Publications
- Hitti-Malin RJ, Burmeister LM, Ricketts SL, Lewis TW, Pettitt L, Boursnell M, Schofield EC, Sargan D and C.S. Mellersh, (2020). A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs. BMC Genet. Sep 7;21(1):100. doi: 10.1186/s12863-020-00911-w.
- Jenkins, C.A., C. Dog Biomedical Variant Database, E.C. Schofield, C.S. Mellersh, L. De Risio, and S.L. Ricketts, Improving the resolution of canine genome-wide association studies using genotype imputation: A study of two breeds. Anim Genet, 2021. 52(5): p. 703-713.
- Mäkeläinen S, Hellsand M, van der Heiden AD, Andersson E, Thorsson E, S Holst B, Häggström J, Ljungvall I, Mellersh C, Hallböök F, Andersson G, Ekesten B and T.F. Bergström, (2020) Deletion in the Bardet-Biedl Syndrome Gene TTC8 Results in a Syndromic Retinal Degeneration in Dogs. Genes (Basel). Sep 18;11(9):E1090. doi: 10.3390/genes11091090.
- Jenkins, C. A., L. Kalmar, K. Matiasek, L. Mari, K. Kyostila, H. Lohi, E. C. Schofield, C. S. Mellersh, L. De Risio and S. L. Ricketts, (2020) Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs. PLoS Genet, 16, e1008527.
- Oliver, J. A. C., H. Wright, P. A. Massidda, L. M. Burmeister and C. S. Mellersh, (2020) A variant in OLFML3 is associated with pectinate ligament abnormality and primary closed-angle glaucoma in Border Collies from the United Kingdom. Vet Ophthalmol, 23, 25-36.
- Hitti, R. J., J. A. C. Oliver, E. C. Schofield, A. Bauer, M. Kaukonen, O. P. Forman, T. Leeb, H. Lohi, L. M. Burmeister, D. Sargan and C. S. Mellersh, (2019) Whole Genome Sequencing of Giant Schnauzer Dogs with Progressive Retinal Atrophy Establishes NECAP1 as a Novel Candidate Gene for Retinal Degeneration. Genes (Basel), 10,
- Jeanes, E. C., J. A. C. Oliver, S. L. Ricketts, D. J. Gould and C. S. Mellersh, (2019) Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma. Canine Genet Epidemiol, 6, 5.
- Lewis, T. W. and C. S. Mellersh, (2019) Changes in mutation frequency of eight Mendelian inherited disorders in eight pedigree dog populations following introduction of a commercial DNA test. PLoS One, 14, e0209864.
- Makelainen, S., M. Godia, M. Hellsand, A. Viluma, D. Hahn, K. Makdoumi, C. J. Zeiss, C. Mellersh, S. L. Ricketts, K. Narfstrom, F. Hallbook, B. Ekesten, G. Andersson and T. F. Bergstrom, (2019) An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease. PLoS Genet, 15, e1007873.
- Oliver, J. A. C., S. L. Ricketts, M. H. Kuehn and C. S. Mellersh, (2019) Primary closed angle glaucoma in the Basset Hound: Genetic investigations using genome-wide association and RNA sequencing strategies. Mol Vis, 25, 93-105.
- Stavinohova, R., C. Hartley, L. M. Burmeister, S. L. Ricketts, L. Pettitt, R. Tetas Pont, R. J. Hitti, E. Schofield, J. A. C. Oliver and C. S. Mellersh, (2019) Clinical, histopathological and genetic characterisation of oculoskeletal dysplasia in the Northern Inuit Dog. PLoS One, 14, e0220761.