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Transcriptional profiling of chromosome 17 quantitative trait Loci for carbohydrate and total calorie intake in a mouse congenic strain reveals candidate genes and pathways.

ABSTRACT: The genetic basis for ingestive behaviors is virtually unknown. Quantitative trait loci (QTLs) for carbohydrate and energy intake map to mouse chromosome 17 and were previously confirmed by a congenic strain bearing CAST/Ei (CAST) donor segment on the C57BL/6J (B6) background.We used microarray technology to facilitate gene identification. Gene expression was compared between the B6.CAST-17 (BC-17) congenic and B6 strains in two diets: (1) chow, and (2) carbohydrate/protein vs. fat/protein.Within the QTL and unique to macronutrient selection, Agpat1 (acylglycerol-3-phosphate O-acyltransferase 1) was differentially expressed in hypothalamus. Irrespective of diet, the gene with the highest fold difference in congenic mice was trefoil factor 3 (Tff3) in liver. Several genes involved in fat metabolism were decreased in carbohydrate-preferring congenic mice, while genes associated with carbohydrate metabolism were increased. In particular, the glyoxalase pathway was enhanced including Glo1, Glo2, and dLDH. Higher expression of Glo1 mRNA in BC-17 congenic mice corresponded to increased protein expression revealed by Western blot, and to higher GLO1 activity in blood.These genes represent new candidates for nutrient intake phenotypes. We propose that increased GLO1 in the BC-17 strain supports its need to protect against dietary oxidants resulting from high carbohydrate intake.

SUBMITTER: Kumar KG

PROVIDER: S-EPMC2745168 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Transcriptional profiling of chromosome 17 quantitative trait Loci for carbohydrate and total calorie intake in a mouse congenic strain reveals candidate genes and pathways.

Kumar K Ganesh KG Smith Richards Brenda K BK

Journal of nutrigenetics and nutrigenomics 20080117 4

<h4>Background/aims</h4>The genetic basis for ingestive behaviors is virtually unknown. Quantitative trait loci (QTLs) for carbohydrate and energy intake map to mouse chromosome 17 and were previously confirmed by a congenic strain bearing CAST/Ei (CAST) donor segment on the C57BL/6J (B6) background.<h4>Methods</h4>We used microarray technology to facilitate gene identification. Gene expression was compared between the B6.CAST-17 (BC-17) congenic and B6 strains in two diets: (1) chow, and (2) ca ...[more]

PMID: 19776624

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Project description:The specific genes regulating the quantitative variation in macronutrient preference and food intake are virtually unknown. We fine mapped a previously identified mouse chromosome 17 region harboring quantitative trait loci (QTL) with large effects on preferential macronutrient intake-carbohydrate (Mnic1), total kilcalories (Kcal2), and total food volume (Tfv1) using interval-specific strains. These loci were isolated in the [C57BL/6J.CAST/EiJ-17.1-(D17Mit19-D17Mit50); B6.CAST-17.1] strain, possessing a ? 40.1 Mb region of CAST DNA on the B6 genome. In a macronutrient selection paradigm, the B6.CAST-17.1 subcongenic mice eat 30% more calories from the carbohydrate-rich diet, ? 10% more total calories, and ? 9% more total food volume per body weight. In the current study, a cross between carbohydrate-preferring B6.CAST-17.1 and fat-preferring, inbred B6 mice was used to generate a subcongenic-derived F2 mapping population; genotypes were determined using a high-density, custom SNP panel. Genetic linkage analysis substantially reduced the 95% confidence interval for Mnic1 (encompassing Kcal2 and Tfv1) from 40.1 to 29.5 Mb and more precisely established its boundaries. Notably, no genetic linkage for self-selected fat intake was detected, underscoring the carbohydrate-specific effect of this locus. A second key finding was the separation of two energy balance QTLs: Mnic1/Kcal2/Tfv1 for food intake and a newly discovered locus regulating short term body weight gain. The Mnic1/Kcal2/Tfv1 QTL was further de-limited to 19.0 Mb, based on the absence of nutrient intake phenotypes in subcongenic HQ17IIa mice. Analyses of available sequence data and gene ontologies, along with comprehensive expression profiling in the hypothalamus of non-recombinant, cast/cast and b6/b6 F2 controls, focused our attention on candidates within the QTL interval. Zfp811, Zfp870, and Btnl6 showed differential expression and also contain stop codons, but have no known biology related to food intake regulation. The genes Decr2, Ppard and Agapt1 are more appealing candidates because of their involvement in lipid metabolism and down-regulation in carbohydrate-preferring animals.

Project description:Trauma- and stress-related disorders are clinically heterogeneous and associated with substantial genetic risk. Understanding the biological origins of heterogeneity of key intermediate phenotypes such as cognition and emotion can provide novel mechanistic insights into disorder pathogenesis. Performing quantitative genetics in animal models is a tractable strategy for examining both the genetic basis of intermediate phenotypes and functional testing of candidate quantitative traits genes (QTGs). Here, existing and newly collected data were used for collaborative genome-wide mapping of cued fear acquisition and expression in 65 mouse strains from the BXD genetic reference panel. For fear acquisition, we identified a significant locus on chromosome (Chr) 10 and eight suggestive loci on Chr 2, 4, 5, 11, 13, and 15. For fear expression, we identified one significant and another highly suggestive locus on Chr 13, as well as four suggestive loci on Chr 10, 11, and X. Across these loci, 60 putative QTGs were identified. The quantitative trait locus on distal Chr 13 contained a single, highly promising gene at the location of the peak likelihood ratio statistic score. The gene, hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1), regulates neuronal excitability. Validation experiments using behavioral pharmacology revealed that functional Hcn channels in the basolateral amygdala are necessary for conditioned fear acquisition and expression. Hcn1, together with the other candidate QTGs, thus provide new targets for neurobiological and treatment studies of fear learning and trauma- and stress-related disorders.There is a knowledge gap in understanding the genetic contributions to behavioral heterogeneity in typical and atypical populations. Mouse genetic reference panels (GRPs) provide one approach for identifying genetic sources of variation. Here, we identified three loci for conditioned fear acquisition and expression in a mouse GRP. Each locus contained candidate quantitative trait genes (QTGs). One locus had a single QTG, Hcn1 (hyperpolarization-activated cyclic nucleotide-gated channel 1), which has been implicated in neuronal excitability and learning. This discovery was validated using behavioral pharmacology, revealing that Hcn channels in the basolateral amygdala are required for fear acquisition and expression. The study thus identifies novel candidate QTGs that may contribute to variation in emotional learning and highlight the utility of mouse GRPs for the identification of genes underlying complex traits.

Dataset Information

Transcriptional profiling of chromosome 17 quantitative trait Loci for carbohydrate and total calorie intake in a mouse congenic strain reveals candidate genes and pathways.

Publications

Transcriptional profiling of chromosome 17 quantitative trait Loci for carbohydrate and total calorie intake in a mouse congenic strain reveals candidate genes and pathways.

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