Comparative Genome of GK and Wistar Rats Reveals Genetic Basis of Type 2 Diabetes

The Goto-Kakizaki (GK) rat, which has been developed by repeated inbreeding of glucose-intolerant Wistar rats, is the most widely studied rat model for Type 2 diabetes (T2D). However, the detailed genetic background of T2D phenotype in GK rats is still largely unknown. We report a survey of T2D susceptible variations based on high-quality whole genome sequencing of GK and Wistar rats, which have generated a list of GK-specific variations (228 structural variations, 2660 CNV amplification and 2834 CNV deletion, 1796 protein affecting SNVs or indels) by comparative genome analysis and identified 192 potential T2D-associated genes. The genes with variants are further refined with prior knowledge and public resource including variant polymorphism of rat strains, protein-protein interactions and differential gene expression. Finally we have identified 15 genetic mutant genes which include seven known T2D related genes (Tnfrsf1b, Scg5, Fgb, Sell, Dpp4, Icam1, and Pkd2l1) and eight high-confidence new candidate genes (Ldlr, Ccl2, Erbb3, Akr1b1, Pik3c2a, Cd5, Eef2k, and Cpd). Our result reveals that the T2D phenotype may be caused by the accumulation of multiple variations in GK rat, and that the mutated genes may affect biological functions including adipocytokine signaling, glycerolipid metabolism, PPAR signaling, T cell receptor signaling and insulin signaling pathways. We present the genomic difference between two closely related rat strains (GK and Wistar) and narrow down the scope of susceptible loci. It also requires further experimental study to understand and validate the relationship between our candidate variants and T2D phenotype. Our findings highlight the importance of sequenced-based comparative genomics for investigating disease susceptibility loci in inbreeding animal models.Goto-Kakizaki（GK）大鼠是通过对糖耐量异常的Wistar大鼠进行连续近交培育获得的，是目前研究2型糖尿病（Type 2 diabetes, T2D）最广泛使用的大鼠模型。然而，GK大鼠T2D表型的详细遗传背景仍未完全阐明。本研究基于GK大鼠与Wistar大鼠的高质量全基因组测序数据，开展了T2D易感变异的系统性调研，通过比较基因组分析鉴定出一系列GK特异性变异（包括228个结构变异、2660个拷贝数变异（Copy Number Variation, CNV）扩增事件、2834个CNV缺失事件以及1796个影响蛋白质功能的单核苷酸变异（Single Nucleotide Variant, SNV）或插入缺失变异（Insertion/Deletion, indel）），并筛选得到192个潜在的T2D相关基因。我们结合既往研究认知与公共数据库资源（包括大鼠品系变异多态性数据、蛋白质相互作用数据以及差异基因表达数据），对携带变异的基因进行了进一步筛选优化。最终，我们共鉴定出15个遗传突变基因，其中包含7个已报道的T2D相关基因（Tnfrsf1b、Scg5、Fgb、Sell、Dpp4、Icam1及Pkd2l1），以及8个高可信度的新型候选基因（Ldlr、Ccl2、Erbb3、Akr1b1、Pik3c2a、Cd5、Eef2k及Cpd）。本研究结果表明，GK大鼠的T2D表型可能由多个变异的累积效应所导致，而这些突变基因可能通过调控多种生物学通路发挥作用，包括脂肪细胞因子信号通路、甘油脂代谢通路、过氧化物酶体增殖物激活受体（Peroxisome Proliferator-Activated Receptor, PPAR）信号通路、T细胞受体信号通路以及胰岛素信号通路。本研究揭示了两个亲缘关系相近的大鼠品系（GK与Wistar）之间的基因组差异，并缩小了T2D易感基因座的研究范围。后续仍需开展进一步的实验研究，以阐明并验证本研究发现的候选变异与T2D表型之间的关联。本研究结果凸显了基于测序的比较基因组学方法在近交系动物模型疾病易感基因座研究中的重要价值。