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The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, e0123173Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (rho(corrected) approximate to 1:68 x 10(-6)) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (rho = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

Place, publisher, year, edition, pages
2015. Vol. 10, no 5, e0123173
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-256241DOI: 10.1371/journal.pone.0123173ISI: 000354544200009PubMedID: 25970163OAI: oai:DiVA.org:uu-256241DiVA: diva2:825786
Available from: 2015-06-24 Created: 2015-06-22 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Complex Trait Genetics: Beyond Additivity
Open this publication in new window or tab >>Complex Trait Genetics: Beyond Additivity
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The link between the genotype and the phenotype of an organism is immensely complex. Despite this it can, to a great extent, be captured using models that assume that gene variants combine their effects in an additive manner. This thesis explores aspects of genetics that cannot be fully captured using such additive models. Using experimental data from three different model organisms, I study two phenomena that fall outside of the additive paradigm: genetic interactions and genetic variance heterogeneity.

Using the model plant Arabidopsis thaliana, we show how important biological insights can be reached by exploring loci that display genetic variance heterogeneity. In the first study, this approach identified alleles in the gene CMT2 associated with the climate at sampling locations, suggesting a role in climate adaption. These alleles affected the genome wide methylation pattern, and a complete knock down of this gene increased the plants heat tolerance. In the second study, we demonstrate how the observed genetic variance heterogeneity was the result of the partial linkage of many functional alleles near the gene MOT1, all contributing to Molybdenum levels in the leaves.

Further, we explore genetic interactions using data from dogs and budding yeast (Saccharomyces cerevisiae). In the dog population, two interacting loci were associated with fructosamine levels, a biomarker used to monitor blood glucose. One of the loci displayed the pattern of a selective sweep in some of the studied breeds, suggesting that the interaction is important for the phenotypic breed-differences.

In a cross between two strains of yeast, with the advantage of large population size and nearly equal allele frequencies, we identified large epistatic networks. The networks were largely centered on a number of hub-loci and altogether involved hundreds of genetic interactions. Most network hubs had the ability to either suppress or uncover the phenotypic effects of other loci. Many multi-locus allele combinations resulted in phenotypes that deviated significantly from the expectations, had the loci acted in an additive manner.

Critically, this thesis demonstrates that non-additive genetic mechanisms often need to be considered in order to fully understand the genetics of complex traits. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1278
Keyword
genetic interactions, epistasis, additivity, GWAS, vGWAS, Genetic mapping, yeast, Arabidopsis Thaliana, dog
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-307837 (URN)978-91-554-9754-5 (ISBN)
Public defence
2017-01-13, B22, BMC, Husarg. 3, Uppsala, 10:15 (English)
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Available from: 2016-12-22 Created: 2016-11-22 Last updated: 2016-12-28

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Kierczak, MarcinCarlborg, ÖrjanLindblad-Toh, Kerstin

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