Abstract
Large efforts have been taken to search for genes responsible for type 2 diabetes (T2D), but have resulted in only about 20 in humans due to its complexity and heterogeneity. The GK rat, a spontanous T2D model, offers us a superior opportunity to search for more diabetic genes. Utilizing array comparative genome hybridization (aCGH) technology, we identifed 137 non-redundant copy number variation (CNV) regions from the GK rats when using normal Wistar rats as control. These CNV regions (CNVRs) covered approximately 36 Mb nucleotides, accounting for about 1% of the whole genome. By integrating information from gene annotations and disease knowledge, we investigated the CNVRs comprehensively for mining new T2D genes. As a result, we prioritized 16 putative protein-coding genes and two microRNA genes (rno-mir-30b and rno-mir-30d) as good candidates. The catalogue of CNVRs between GK and Wistar rats identified in this work served as a repository for mining genes that might play roles in the pathogenesis of T2D. Moreover, our efforts in utilizing bioinformatics methods to prioritize good candidate genes provided a more specific set of putative candidates. These findings would contribute to the research into the genetic basis of T2D, and thus shed light on its pathogenesis.
Highlights
Type 2 diabetes (T2D), formally known as non-insulindependent diabetes, accounts for about 90% of the 180 million diabetic cases around the world [1]
We identified a catalogue of copy number variations (CNVs) regions (CNVRs) between GK and Wistar rats using tiling array CGH
Given the hypothesis that the phenotypic difference between GK and Wistar ought to be attributed in a large part to their genomic variations, we carried out a series of bioinformatics functional analysis on these GK/Wistar CNVRs to narrow down the scope for further exploration of T2D candidate genes
Summary
Type 2 diabetes (T2D), formally known as non-insulindependent diabetes, accounts for about 90% of the 180 million diabetic cases around the world [1]. Characterized by defects in both insulin secretion from pancreatic islet beta-cells and insulin action in peripheral tissues, this chronic and complex disorder is supposed to be predisposed by the combined action of multiple genetic factors [2,3]. The Goto-Kakizaki (GK) rat, a nonobese animal model of T2D, was developed by repeated inbreeding of glucose-intolerant Wistar rats [11]. During their development, GK rats suffer from reduced beta-cell mass and insulin resistance spontaneously, and provide a feasible opportunity to search for susceptible loci, investigate pathogenesis and develop therapeutic strategies [12,13]. Several quantitative trait locus (QTL) analyses on this model have already identified a number of genomic loci harboring susceptible variants [14,15,16]
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