Sammanfattning

This thesis addresses the genetic background of five spontaneous canine models of rare human disease. By utilizing genome-wide mapping methods, next-generation sequencing analyses and variant validation combined with detailed clinical and post-mortem examinations, we characterized new canine models, identified novel disease-associated variants and dissected their effects on health and morphology. In Study I, next-generation sequencing analysis in a Central Asian Shepherd dog affected by epidermolysis bullosa revealed a nonsense variant in COL7A1. Validation of the variant in 190 dogs confirmed the disease type as recessive dystrophic epidermolysis bullosa. Immunohistochemical stainings in skin samples illustrated the lack of full-length type VII collagen protein in the affected dog. In Study II, genome-wide association analysis combined with next-generation sequence analysis identified a locus and candidate variant associated with recessive pituitary dwarfism in Karelian Bear Dogs. A splice site variant in POU1F1 was confirmed with validation in over 8000 dogs. Computational predictions indicated weakening of the splice acceptor site at the affected intron-exon junction. In Study III, homozygosity mapping combined with next-generation sequence analysis identified candidate regions and variants associated with recessive congenital hearing loss in Rottweilers. A missense variant in LOXHD1 was confirmed with validation in over 800 000 dogs, revealing a link between the variant and Rottweiler breed background. In Study IV, variant screening combined with clinical examinations and statistical analyses revealed novel morphological consequences of a previously described variant in DVL2. The findings showed that the variant is involved in variable caudal vertebral anomalies and contributes to a brachycephalic phenotype. Varying allele frequencies were identified across populations, indicating the differential impact of the variant on the genetic health of dog breeds. In Study V, clinical and post-mortem examinations revealed malignant polymorphic ventricular arrhythmia and sudden cardiac death in young Leonberger dogs. The high prevalence of the disorder in litters and families strongly indicated a genetic aetiology. However, genome-wide association analyses failed to reveal associated loci, likely due to genetic or phenotypic heterogeneity. Future studies aim to overcome these obstacles with expanded cohorts and improved clinical and molecular phenotypes. Our findings have multiple scientific and practical implications. The discoveries facilitate diagnostics and treatment by revealing the molecular and pathophysiological mechanisms of the disorders. Affected dogs also provide novel large animal models for preclinical studies, benefitting both human and veterinary medicine. Finally, the development of gene tests support dog owners and breeders in revising breeding programmes to improve the health of dog breeds.
Originalspråkengelska
Handledare
  • Lohi, Hannes, Handledare
  • Hytönen, Marjo, Handledare
  • Wiberg, Maria, Handledare
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-8224-1
Elektroniska ISBN978-951-51-8225-8
StatusPublicerad - 2022
MoE-publikationstypG5 Doktorsavhandling (artikel)

Bibliografisk information

M1 - 86 s. + liitteet

Vetenskapsgrenar

  • 413 Veterinärvetenskap
  • 1184 Genetik, utvecklingsbiologi, fysiologi

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