Investigating the role of structural variants in insulin action and type 2 diabetes

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Genetic factors substantially contribute to the onset and development of type 2 diabetes (T2D). However, many of the underlying genetic variants associated with insulin resistance and diabetes remain to be identified. Inbred mouse models such as the diabetes-prone New Zealand Obese (NZO) and the lean, diabetes-resistant mouse strains C3H and 129P2 reflect the complex genetic architecture relevant for the human disease and therefore provide a powerful experimental platform for studying the mechanisms leading to onset and development of T2D. While our previous systematic genome-wide linkage scans have identified multiple novel candidate genes associated with T2D and related traits, a large proportion of the genetic variants explaining protection or susceptibility for diabetes remains unknown. Due to recent developments in DNA sequencing technologies, structural DNA variants (SV), defined as genetic variants of 50bp or longer, have emerged as major contributors to genetic diversity. Moreover, SVs have been shown to affect gene structure and function, leading to the hypothesis that SVs may contribute to the susceptibility for T2D. In order to determine the role of SVs in the development of T2D, this interdisciplinary project combines state-of-the-art next generation genomics technologies, novel bioinformatics algorithms and advanced experimental mouse genetics. Genome-wide integrative analysis of novel genome assemblies, quantitative tissue-specific transcriptomics, and deep metabolic phenotyping of T2D-prone and -resistant mouse strains will be used to gain new insights into pathogenesis and SV function in onset and development of T2D and related traits.