A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes

Abstract

To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the outcross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes.

Decreased Expression of Cilia Genes in Pancreatic Islets as a Risk Factor for Type 2 Diabetes in Mice and Humans

“…The New Zealand Obese (NZO) mouse represents a model for polygenic T2D and obesity that closely resembles the human disease (Joost and Sch€ urmann, 2014). Recently, we discovered a number of quantitative trait loci (QTL) that participate in obesity and insulin resistance in NZO mice (Chadt et al, 2008;Schallschmidt et al, 2018;Scherneck et al, 2009;Vogel et al, 2009Vogel et al, , 2018 and, furthermore, identified some of the causal disease genes and their specific metabolic effects (e.g., Zfp69 and Ifi202b) (Chung et al, 2015;Stadion et al, 2018). In contrast, the C57BL/6 mouse, which lacks leptin, the B6.V-Lep ob/ob (B6-ob/ob) mouse develops severe obesity but is protected from diabetes by an adaptive beta-cell proliferation (Kleinert et al, 2018).…”

Two Novel Candidate Genes for Insulin Secretion Identified by Comparative Genomics of Multiple Backcross Mouse Populations

“…However, the genetic comparison of only two strains usually results in a high nomination of candidate genes. The use of more than one inbred cross may substantially improve the mapping resolution of candidates and thus can facilitate gene discovery (Li et al 2005;Vogel et al 2018). In our study, we combined linkage data from two different backcross populations generated from the breeding of obese and T2D-prone NZO mice with two widely used lean strains, C3H and 129P2, thereby allowing the identification of strain-specific linkage signals.…”

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

“…Female NZO mice from our own colony (NZO/HIBomDife: German Institute of Human Nutrition, Nuthetal, Germany) and male DBA (DBA/2J: maintained in-house with breeders originating from Jackson Lab, Maine, United States) were crossed. Generation and phenotypical characterization of backcross mice were performed, as previously described ( Vogel et al, 2018 ). Recombinant congenic mice were bred by repeated backcrossing of mice positive for the Nidd/DBA locus with NZO.…”

“…However, with advances in bioinformatics and increasing capacity to deal with large and complex datasets, particularly involving the availability of genome-wide sequence coverage of common laboratory mouse strains, it has been advantageous to perform multiple crosses in parallel. We have recently carried out a collective diabetes cross ( Vogel et al, 2018 ) using four lean inbred mouse strains (B6, DBA, C3H, and 129P2), each with varying susceptibility to T2D, to be individually crossbred with the obese and diabetes-prone New Zealand obese (NZO) mouse. This strategy addresses the current gaps in the knowledge of the genetic basis for T2D.…”

“…Here, we focus on the diabetes quantitative trait loci (QTL) Nidd/DBA on chromosome 4 which we identified as most prominent diabetes QTL in the NZOxDBA cross ( Vogel et al, 2018 ). In the past, several QTL have been identified in the mid-region of mouse chromosome 4 in the proximity of the leptin receptor gene ( Lepr ) relating to hyperglycemia and hypoinsulinemia ( Leiter et al, 1998 ; Plum et al, 2002 ; Scherneck et al, 2009 ; Davis et al, 2012 ; Kluge et al, 2012 ).…”