<p> Comprehensive mastery of modern genetics involves a myriad of data processing and analytic techniques; these approaches vary because some genetic conditions are the result of single gene mutations that alter protein function, while other more complex diseases and traits are influenced by many genes. This dissertation will undertake investigation of the heritability and genetic risk of cranial cruciate ligament rupture in Labrador Retrievers, a congenital hypomyelinating polyneuropathy in four Golden Retrievers, and the potential usage of telomere length as a biomarker of welfare in dogs housed in commercial breeding facilities. </p>
<p>In the first disease studied, 333 Labrador Retrievers with known torn or healthy cranial cruciate ligament(s) were genotyped via SNP array. Heritability of this polygenic trait was calculated using a variety of programs and including different fixed effects. Overall, heritability was high, ranging from 0.550 to 0.893, with sex and sterilization at a young age (≤12 months) strongly influencing risk of cranial cruciate ligament rupture. Neither genome-wide association analyses using this novel dataset of 333 Labrador Retrievers, nor additional analyses combining this data with publicly-available data, identified any significantly associated SNPs. However, the most associated SNPs were located near biologically relevant genes, such as <em>COL1A2</em> (a collagen gene) and <em>ITGA11</em> (a protein that binds to collagen), as well as genes encoding sex hormone receptors, such as <em>FSHR </em>and <em>LHCCGR</em>. Splitting the data in an attempt to predict phenotypes based on genotype was unsuccessful. Future work focused on parsing out genetic influencers of cranial cruciate ligament rupture risk should continue to collect sex, sterilization status, and age at sterilization data, and larger collaborations and use of publicly-available data will be required to increase the data robustness.</p>
<p>For the second study, DNA from four unrelated Golden Retrievers diagnosed with congenital hypomyelinating polyneuropathy via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology were explored for genetic causes. Whole-genome sequencing was performed on all four dogs to identify potential causative variants. When compared to WGS from >1,000 other dogs who were presumably unaffected by this rare disease, likely causative variants were identified in all four dogs. Two cases shared a homozygous <em>MTMR2 </em>splice donor site variant, with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous <em>MPZ</em> missense mutation leading to an isoleucine to threonine substitution. The last case had a homozygous <em>SH3TC2</em> nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analyses using 524 Golden Retrievers indicated that these variants emerged recently. Each of these variants occurred in genes that are associated with the human Charcot-Marie-Tooth group of heterogeneous peripheral nervous system diseases. Testing a population of unrelated Golden Retrievers (n > 200) did not identify any other dogs with these variants, though breeders should be cautious to avoid propagating these alleles.</p>
<p>Finally, the last study within this dissertation investigates the relationship between telomere length and metrics such as age, breed, environment, average breed lifespan, parity, and response to a mild social stressor in a population of dogs housed at commercial breeding facilities. FIDO scores (behavioral phenotypes) were collected for all dogs as a measurement of response to a social stressor. This study is not yet complete; many more dogs remain to be recruited in the near future. Telomere lengths were measured using qPCR and compared to a single-copy gene, <em>36B4</em>, for 309 dogs representing 37 breeds or breed crosses. Age was not significantly associated with telomere length after making appropriate corrections (p-value = 0.077). Breed and facility were significantly associated with telomere length after corrections (p-value = 0.010 and <2.2E-16, respectively). Neither parity nor average breed lifespan were associated with telomere length, however, response to a mild social stressor was, with dogs who responded positively having significantly longer telomeres than dogs who responded negatively across all analyses. This preliminary data indicates that, within this population, breed, environment, and response to stress have strong influences on telomere length, while parity and average breed lifespan did not. As this work continues, increased sample sizes will lead to increased power for detecting associations. Future work should examine these identified relationships in other populations of dogs.</p>
<p>Taken together, these studies encompass phenotypes of various complexity, and each study encompassed different methodologies utilized in modern canine genetics. The overall goal for this work was to improve canine health, with the potential for translational implications to human health. The identification of genetic markers associated with or causative of disease, or indicative of health and welfare traits, is necessary for reducing the prevalence of disease and increasing the knowledge of welfare metrics in canines, respectively.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/22696648 |
| Date | 27 April 2023 |
| Creators | Shawna R Cook (12871985) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/GENETIC_MARKERS_IN_DOGS_INFLUENCING_CRANIAL_CRUCIATE_LIGAMENT_RUPTURE_ASSOCIATED_WITH_HYPOMYELINATING_POLYNEUROPATHY_AND_INDICATING_WELFARE/22696648 |
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