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David Sargan

Comparative genetics of inherited disease specialising in BOAS, breed predisposition to cancer and eye diseases

My lab is interested in comparative genetics of disease and in particular in genetic diseases of dogs. We believe that understanding canine models will throw light on human disease, whilst also allowing us to develop veterinary insights and better advice for breeders.

  •  Pathogenesis of retinal and other ocular inherited disease.
  •  Canine breed predispostion to “complex” genetic diseases, especially brachycephalic obstructive airway syndrome (BOAS) and cancer.
  • Secondary epigenetic and somatic genetic change in complex inherited diseases.
  • Comparative genomic mapping in companion and exotic animal species.
  • Technical development of mapping and genetic analysis methods.
  • Genetic aspects of welfare issues for the breed.

One major current study is centred on uncovering the genetics of BOAS. This is a complex disease of the upper airway in short-faced dogs, which, if left untreated, can give complications ranging from exercise intolerance to food regurgitation, inability to sleep normally, heat stroke, and death. In the past, a major problem in understanding the disease has been that diagnosis is complex because there has been no absolute agreement as to how respiratory noises (snoring and snorting) in affected breeds correlate with functional respiratory disease.

A close collaboration with Dr Jane Ladlow and Dr Nai-chieh Liu, has developed objective tools to measure effectiveness of respiratory cycles in pugs, French bulldogs and bulldogs using whole body barometric plethysmography. At the same time the group has measured conformation of the head and of parts of the airway in these same dogs.

To look at genetic changes associated with the differences we measure between BOAS affected and normal animals, we are carrying out genome wide association studies (GWAS) in each breed to locate genes important to the disease within the genome, led by Dr Lajos Kalmar.

We are now comparing those regions of the genome implicated in this study in greater detail, in order to identify the particular genes and mutations that are associated with the disease. The frequency of each mutation in the population at risk, as well as the additional relative risk from each mutation will then be assessed. This will allow the development of advice to breeders based on estimating genetic breeding values associated with DNA profiles containing combinations of different mutations.

In addition, by analysing biopsy material from affected dogs and relating our findings to the GWAS results, we hope to develop a biological understanding of changes occurring in cartilage and soft tissues of the airway, which will feed through to wider and more appropriate options for therapy.

Additional studies are looking at miRNA signatures of canine tumours, and at genetics of the blinding inherited disease of dogs and cats, progressive retinal atrophy: an equivalent of human retinitis pigmentosa. I also collaborate with Prof Wood and others in studies of distribution of bat species that may act as viral disease vectors in tropical Africa using population genetic techniques. I curate a website aiming to collate the genetic basis of inherited disease traits in dogs

Key Publications

Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1 associated canine retinal degeneration Forman OP, Hitti R, Boursnell M, Miyadera K, Sargan DR, Mellersh C. (2016) . Mammalian Genome, 2016 Mar 26. [Epub ahead of print]

Whole-body barometric plethysmography characterises upper airway obstructions in 3 brachycephalic breeds of dog. Liu NC Adams VJ, Kalmar L, Ladlow JF1, Sargan DR1*. J Vet Internal Medicine, 2016 May; 30(3):853-65. doi: 10.1111/jvim.13933. 1Both authors contributed equally. *Corresponding author

Continent-wide panmixia of an African fruit bat facilitates transmission of potentially-zoonotic viruses. Peel AJ, Sargan DR, Baker KS, Hayman DTS, Barr JA, Crameri G, Suu-Ire R, Broder CC, Wang L-F, Fooks AR, Rossiter SJ, Wood JLN & Cunningham AA. (2013)  Nature Commun. 4: 2770. doi: 10.1038/ncomms3770.

Multiple Mechanisms Contribute to Leakiness of a Frameshift Mutation in Canine Cone-Rod Dystrophy. Miyadera K, Brierley I, Aguirre-Hernández J, Mellersh CS and Sargan DR. (2012) PLoS One 7(12): e51598

Internet resources cataloguing inherited disorders in dogs (Review) Nicholas FW, Crook A, Sargan DR (2011) Veterinary J. 189(2):132-5

 

 

Dr David Sargan

Senior Lecturer

drs20@cam.ac.uk

Group members: Dr Lajos Kalmar, Harriet Wright. We work closely with Jane Ladlow, Nai-chieh Liu and Eileen Troconis

Inherited diseases in dogs website

BOAS research group website

    Plain English

    We work on genetic disease problems in veterinary species, and particularly on those inherited diseases which may also give insight into human diseases. Currently much of our work focuses on a severe respiratory disease of short-faced dogs, called BOAS. As well as causing exercise intolerance and additional (sometimes very severe) problems for many pugs, French bulldogs, and bulldogs, BOAS has similarities to human sleep apnoea - which deprives up to 1.5 million people in the UK of comfortable sleep, and causes up to 40,000 traffic accidents per year. By finding genetic mutations that are associated with this disease, we expect to:

    • develop DNA based tests allowing breeders to estimate the likelihood that particular dogs will suffer from the disease.
    • develop a biological understanding of the disease that may lead to future improvements in treatment.
    • offer insights into the biology and perhaps the treatment of human sleep apnoea.