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Analysis of inherited and somatic variants to decipher canine complex traits
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents several investigations of the dog as a model for complex diseases, focusing on cancers and the effect of genetic risk factors on clinical presentation.

In Papers I and II, we performed genome-wide association studies (GWAS) to identify germline risk factors predisposing US golden retrievers to hemangiosarcoma (HSA) and B-cell lymphoma (BLSA). Paper I identified two loci predisposing to both HSA and BLSA, approximately 4 megabases (Mb) apart on chromosome 5. Carrying the risk haplotype at these loci was associated with separate changes in gene expression, both relating to T-cell activation and proliferation.

Paper II followed up on the HSA GWAS by performing a meta-analysis with additional cases and controls. This confirmed three previously reported GWAS loci for HSA and revealed three new loci, the most significant on chromosome 18. This locus contains several candidate genes with a clear role in carcinogenesis, including KMT5B and LRP5. Overall, carriers of the risk alleles at the top six loci are diagnosed with HSA earlier in life.

In Paper III we investigated the somatic mutations which occur in HSA tumor tissue by performing tumor-normal exome sequencing of 47 golden retrievers. We identified 7 recurrently mutated genes, including the tumor suppressor TP53 (mutated in 59.6% of tumors) and oncogene PIK3CA (mutated in 29.8% of tumors). Additional somatically mutated genes overlap those found in human angiosarcomas, suggesting that angiosarcomas in dogs and humans are genetically very similar.

In Paper IV, we investigated the variable penetrance of a SOD1 mutation in Pembroke Welsh corgis causing degenerative myelopathy (DM), a model of the human motor neuron disease amyotrophic lateral sclerosis (ALS). We discovered that regulatory variants near the SP110 gene were associated with an increased risk of DM and an earlier age at diagnosis, suggesting a role for immune response in the pathogenesis of the disease.

Taken together, these findings provide new insight into the pathophysiology of both hemangiosarcoma and degenerative myelopathy, which could guide future diagnostics and therapeutic strategies both in humans and veterinary patients. In addition, they demonstrate the power of the dog as a biomedical model for human complex diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1454
Keyword [en]
dog, genetics, GWAS, exome, cancer, DM
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-347165ISBN: 978-91-513-0310-9 (print)OAI: oai:DiVA.org:uu-347165DiVA, id: diva2:1193429
Public defence
2018-05-21, A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-04-26
List of papers
1. Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers
Open this publication in new window or tab >>Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers
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2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 2, article id e1004922Article in journal (Refereed) Published
Abstract [en]

Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute similar to 20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6x10(-7) and 2.7x10(-6), respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangio-sarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-252254 (URN)10.1371/journal.pgen.1004922 (DOI)000352081800010 ()
Available from: 2015-05-05 Created: 2015-05-04 Last updated: 2018-03-27Bibliographically approved
2. Genome-wide meta-analysis identifies inherited variation contributing to overall risk and age of onset in canine angiosarcoma
Open this publication in new window or tab >>Genome-wide meta-analysis identifies inherited variation contributing to overall risk and age of onset in canine angiosarcoma
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(English)Manuscript (preprint) (Other academic)
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-347163 (URN)
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27
3. Exome sequencing of hemangiosarcomas in the golden retriever reveals frequent mutation of TP53 tumor suppressor and PIK3CA oncogene
Open this publication in new window or tab >>Exome sequencing of hemangiosarcomas in the golden retriever reveals frequent mutation of TP53 tumor suppressor and PIK3CA oncogene
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(English)Manuscript (preprint) (Other academic)
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-347164 (URN)
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27
4. Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy
Open this publication in new window or tab >>Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 22, p. E3091-E3100Article in journal (Refereed) Published
Abstract [en]

Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 x 10(-5)), and was associated with increased probability of developing DM (P = 4.8 x 10(-6)) and earlier onset of disease (P = 1.7 x 10(-5)). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.

Keyword
degenerative myelopathy, amyotrophic lateral sclerosis, ALS, SOD1, SP110
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-298872 (URN)10.1073/pnas.1600084113 (DOI)000376784600009 ()27185954 (PubMedID)
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2018-03-27Bibliographically approved

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