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

遗传因素在2型糖尿病(T2D)的发生和发展中起着重要作用。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，如易患糖尿病的新西兰肥胖(NZO)和瘦而耐糖尿病的小鼠品系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T2D的发生和发展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发现了与T2D和相关特征相关的多个新的候选基因，但解释糖尿病保护或易感性的很大一部分遗传变异仍然未知。由于DNA测序技术的最新发展，结构DNA变异(SV)，即50bp或更长的遗传变异，已成为遗传多样性的主要贡献者。此外，SVS已被证明影响基因结构和功能，导致假设SVS可能与T2D的易感性有关。为了确定SVS在T2D发展中的作用，这个跨学科的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。对T2D易感和耐药小鼠品系的新基因组组合、定量组织特异性转录和深层代谢表型的全基因组整合分析将被用来获得对T2D和相关性状发生和发展中的发病机制和SV功能的新见解。

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.