Comparitive genomics of multiple backcross mouse populations identifies Sgcg as a novel potential obesity-modifier gene
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA808983 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2022-08-01 | GSE197101 | GEO
Project description:To nominate novel disease genes for obesity and type 2 diabetes (T2D), we recently generated two mouse backcross populations of the T2D-susceptible New Zealand Obese (NZO/HI) mouse strain and two genetically different, lean and T2D-resistant 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 identify 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, defined as the main QTL-target tissue. Only two genes, Arl11 and Sgcg, fulfilled our candidate criteria. In addition, expression QTL analysis revealed cis-signals for both genes within the Nbw14 locus. Moreover, retroviral overexpression of Sgcg in 3T3-L1 adipocytes resulted in increased insulin-stimulated glucose uptake. In humans, mRNA levels of SGCG correlated with body mass index and body fat mass exclusively in diabetic subjects, suggesting that SGCG may present a novel marker for metabolically unhealthy obesity. In conclusion, our comparative-cross analysis could substantially improve the mapping resolution of the obesity locus Nbw14. Future studies will throw light on the mechanism by which Sgcg may protect from the development of obesity.
| S-EPMC9703946 | biostudies-literature
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
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/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Subsequent whole-genome linkage scans revealed 30 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose [12 cM, logarithm of the odds (LOD) 13.3] and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Nbg7p, NZO blood glucose on proximal chromosome 7) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is contributed by the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains 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 to be the most likely target tissue for the QTL. Two genes, Atp4a and Pop4, fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to decreased glucose-stimulated insulin secretion, indicating a regulatory role of both genes in insulin secretion, thereby possibly contributing to the phenotype linked to Nbg7p In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility candidate genes, and thus has been proven to be a valuable tool for the discovery of novel disease genes.
| S-EPMC6283180 | biostudies-literature
Project description:Identification of two novel candidate genes for insulin secretion by comparative genomics of multiple backcross populations
| PRJNA482445 | ENA
Project description:Intestinal cancer modifier RNA-Seq
| PRJNA624066 | ENA
Project description:Intestinal cancer modifier MeDIP-Seq
| PRJNA624088 | ENA
Project description:The vacuolar-vesicular protein sorting (vps) factors are involved in vesicular trafficking in eukaryotic cells. The wobbler mouse is an animal model of amyotrophic lateral sclerosis. Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse. The effect of the wobbler modifier in Chr. 10 on gene expression levels in testis. Keywords: cDNA array, Wobbler, testis
2007-04-01 | GSE7251 | GEO
Project description:Saccharomyces cerevisiae strain:BY4716xYJM789 backcross strains Raw sequence reads
| PRJNA325521 | ENA
Project description:Citrus disease resistance breeding has been advanced to introduce CTV resistance of trifoliate orange to citrus. Because the quality of the fruit of trifoliate ogate was low, backcross with citrus was necessary. In the case of citrus, it takes several years from flowering to obtaining next-generation seeds. Therefore, we generated transformants for the early flowering genes (citrus FLOWERING LOCUS T: CiFT) using CiFT co-expression vector construct and promoted generation. In Japan, it is difficult to plant transformants in the field. Therefore, it was decided to select null segregant lacking transgene from backcross progenies. In order to prove that the transgene has been completely removed, it is necessary to prove that no vector conract is present on the genome. Tthis matter was proved by CGH analysis.
2019-07-30 | GSE135027 | GEO