Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Comparitive genomics of multiple backcross mouse populations identifies Sgcg as a novel potential obesity-modifier gene

ABSTRACT: To nominate novel disease genes for obesity and type 2 diabetes (T2D) we recently generated two mouse backcross populations of obese and T2D- susceptible New Zealand Obese (NZO/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Comparative linkage analysis of our two female backcross populations identified seven novel body fat-associated quantitative trait loci (QTL). Only the locus Nbw14 (NZO body weight on chromosome 14) showed linkage to obesity-related traits in both backcross populations, indicating that the causal gene variant is likely specific for the NZO strain as NZO allele carriers in both crosses displayed elevated body weight and fat mass. To nominate candidate genes for Nbw14, we used a combined approach of gene expression and haplotype analysis to filter for NZO-specific gene variants in gonadal white adipose tissue (gWAT), which appeared to be the most likely target tissue. Only two genes, Arl11 and Sgcg, fulfilled our criteria. In addition, expression QTL analysis revealed cis-signals for both genes within in the Nbw14 locus. Retroviral overexpression of Sgcg in 3T3-L1 adipocytes resulted in increased glucose uptake. In humans, mRNA levels of Sgcg correlated with BMI and body weight exclusively in diabetic subjects, suggesting that Sgcg represents a novel marker for metabolically unhealthy obesity in humans. In conclusion, our comparative-cross analysis could substantially improve the mapping resolution of the obesity locus Nbw14. Future studies will shine light on the mechanism by which Sgcg protects from the development of obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE197101 | GEO | 2022/08/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Identification of two novel candidate genes for insulin secretion by comparative genomics of multiple backcross populations

Project description:To identify novel disease genes for type 2 diabetes (T2D) we generated two backcross populations of obese and diabetes-susceptible New Zealand Obese (NZO) with the two lean mouse strains 129P2 and C3H/FeJ. Subsequent whole-genome linkage scan revealed 36 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose (12 cM, LOD 13.3) and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Cdp7prox) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is unique for the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains (RCS) and metabolic phenotyping validated the phenotype. For the detection of candidate genes in the critical region (30-46 Mb) we used a combined approach of haplotype- and gene expression analysis to search for C3H-specific gene variants in the pancreatic islets, which appeared as the most likely target tissue for the QTL. Only the two genes Potassium-transporting ATPase alpha chain 1 (Atp4a) and Ribonuclease P protein subunit p29 (Pop4) fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to a decreased glucose-stimulated insulin secretion (GSIS), indicating a stimulating role of both genes in insulin secretion, thereby likely contributing to the phenotype linked to Cdp7prox. In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility genes and thus has proven to be a powerful tool for the discovery of novel disease genes.

2019-05-27 | GSE117553 | GEO

Genetic variation in Glp1r expression influences the rate of gastric emptying

Project description:A C57BL6/J (B6) x CAST/Ei (CAST) strain intercross has revealed a new quantitative trait locus (QTL) on Chromosome (Chr) 17 controlling total food volume (Tfv1; LOD=7.6). Compared with B6, the CAST mice consume 39% more food volume per body weight in a macronutrient diet selection paradigm. Linkage analyses of total food volume revealed the presence of suggestive QTL on Chrs 2, 6, and 15 and a significant locus on Chr 17. An interval-specific congenic strain, B6.CAST-17, was then developed which verified the QTL. Microarray analysis of stomach in congenic and wildtype B6 mice revealed Glp1r as an expression candidate with physiological relevance to food intake. Further functional analysis of this gene revealed this gene as potential candidate for total food volume trait in mice Keywords: Comparative gene expression analysis

2008-02-13 | GSE7756 | GEO

Identification of Positional Candidate Genes for Body Weight and Adiposity in Subcongenic Mice

Project description:We previously constructed a congenic mouse, B6.S-D2Mit194-D2Mit311 (B6.S-2) with SPRET/Ei donor DNA on distal chromosome 2 in a C57BL/6J background that captured an obesity quantitative trait locus (QTL). Mice homozygous for SPRET/Ei alleles at the donor region had decreased body weight and obesity related phenotypes. The B6.S-2 congenic donor region spanned a minimum of 26 Mb. In this study, we constructed five overlapping subcongenics with smaller SPRET/Ei donor regions to fine map the underlying gene(s). One of the five subcongenic lines derived from the B6.S-2 founding congenic, B6.S-2A, captures most of the body weight and adiposity phenotypes in a donor region with a maximum size of 7.4 Mb. Homozygous SPRET/Ei donor alleles in both the founding congenic and the derived B6.S-2A subcongenic exhibit significant decreases in body weight, multiple fat pad weights with the greatest decrease in mesenteric fat pad weight, and Adiposity Index (total fat pad weight divided by body weight). Interval specific microarray analysis in four tissues for donor region genes from the founding B6.S-2 congenic identified several differentially expressed genes mapping to the B6.S-2A subcongenic donor region, including prohormone convertase 2 (PC2). Quantitative real-time PCR confirmed a modest decrease of PC2 expression in whole brains of mice homozygous for SPRET/Ei donor alleles. Analysis of the relative levels of mRNA for B6 and SPRET/Ei in heterozygous congenic mice showed differentially higher expression of the C57BL/6J allele over the SPRET/Ei allele indicating a cis regulation of differential expression. Using subcongenic mapping, we have successfully narrowed a body weight and obesity QTL interval and identified PC2 as a positional candidate gene. Keywords: Two strain comparison for gene discovery

2008-09-22 | GSE6115 | GEO

Methylated DNA Immunoprecipitation (MeDIP) using a custom type 2 diabetes and related phenotypes array

Project description:Custom array designed to tile Linkage Disequilibrium Blocks of T2D GWAS SNPs, monogenic candidates for T2D and Obesity, and all plausible imprinted loci from human and mouse data.

2010-12-01 | GSE20553 | GEO

Methylated DNA Immunoprecipitation (MeDIP) using a custom type 2 diabetes and related phenotypes array

2010-12-01 | E-GEOD-20553 | biostudies-arrayexpress

Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [liver]

Project description:Genetic and lifestyle factors greatly impact the development of metabolic diseases including Type 2 Diabetes (T2D). It is an ongoing challenge to determine how these factors and their interplay specifically contribute to risk of T2D. Mouse models allow precise control of environment and genetic replication, and mouse strains fed an unhealthy diet show variable signs of metabolic dysfunction ranging from overt diabetes to diet-induced obesity to complete resistance. When fed a high-fat high-sugar (HFHS) diet, NZO/HlLtJ (NZO) mice become severely obese and many become diabetic, C57BL/6J (B6J) mice develop obesity but seldom overt diabetes, and CAST/EiJ (CAST) mice are resistant to obesity and glucose intolerance. We present deep molecular and metabolic profiling of these three genetically diverse mouse strains fed control (low fat, no sugar) and HFHS diets to define inherited aspects of metabolism that may impact diabetes risk. Transcriptomic analysis of eight tissues revealed significant tissue-specific molecular variability underpinning the metabolic differences across strains. The most distinct diet responses were observed in adipose and pancreas. In adipose tissue, differences in immunometabolism, lipid metabolism, and oxidative phosphorylation pathways parallel the susceptibility to obesity and diabetes across strains. In pancreatic islets, there was inflammation associated with HFHS diet in NZO mice that is expected to contribute to beta cell dysfunction. Taken together, physiological and molecular profiling of these genetically diverse mouse strains provides a foundation for deeper understanding the molecular basis of individual differences in susceptibility to metabolic diseases.

2023-12-31 | GSE235054 | GEO

Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [Ovary]

2023-12-31 | GSE234959 | GEO

Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [kidney]

2023-12-31 | GSE234957 | GEO

Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [Islets 1]

2023-12-31 | GSE234956 | GEO

Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [Dorsal Vagal Complex]

2023-12-31 | GSE234951 | GEO