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

遗传因素在很大程度上促进了2型糖尿病（T2D）的发生和发展。然而，许多与胰岛素抵抗和糖尿病相关的潜在遗传变异仍有待确定。近交系小鼠模型，如糖尿病易发的新西兰肥胖（NZO）和瘦，糖尿病抵抗小鼠品系C3H和129P2反映了与人类疾病相关的复杂遗传结构，因此为研究导致T2D发生和发展的机制提供了强大的实验平台。虽然我们之前的系统全基因组连锁扫描已经确定了与T2D和相关性状相关的多个新的候选基因，但大部分解释糖尿病保护或易感性的遗传变异仍然未知。由于DNA测序技术的最新发展，结构DNA变异（SV）被定义为50bp或更长时间的遗传变异，已成为遗传多样性的主要贡献者。此外，SVs已被证明会影响基因结构和功能，从而导致SVs可能导致T2D易感性的假设。为了确定SVs在T2D发展中的作用，这个跨学科项目结合了最先进的下一代基因组学技术、新的生物信息学算法和先进的实验小鼠遗传学。新的基因组组合的全基因组整合分析，定量组织特异性转录组学，以及T2D易发和耐药小鼠品系的深层代谢表型，将用于获得新的见解，以了解SV在T2D发病和发展及相关性状中的功能。

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.