The genetic background of five canine models of rare human disease

• Main Author: Niskanen, Julia
• Other Authors: Schleutker, Johanna, University of Helsinki, Faculty of Medicine, Doctoral Programme in Integrative Life Science, Folkhälsan Research Center, Helsingin yliopisto, lääketieteellinen tiedekunta, Integroivien biotieteiden tohtoriohjelma, Helsingfors universitet, medicinska fakulteten, Doktorandprogrammet i integrerande biovetenskap, Lohi, Hannes, Hytönen, Marjo, Wiberg, Maria
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Helsingin yliopisto 2022
• Subjects: lääketieteellinen genetiikka; karelian
• Online Access: http://hdl.handle.net/10138/346442

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 ...