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Body weight at weaning is the main predictor for diabetic phenotype in male TallyHo/JngJ mice

ABSTRACT: TallyHo/JngJ (TallyHo) mice are a polygenic mouse model for type 2 diabetes (T2D), first described in 2001 and characterized by obesity due to an increased mass of fat pads. We aimed to discover whether environmental condition(s) during early life time or epigenetic factors across generations could be responsible for the varying penetrance of the metabolic phenotype of male and female TallyHo mice. Therefore, we set up the subsequent study in which we analyzed parameters of glucose homeostasis and environmental factors of individual TallyHo mice rather than relying on group averages.

ORGANISM(S): Mus musculus

PROVIDER: GSE235792 | GEO | 2026/06/02

REPOSITORIES: GEO

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Project description:Understanding how polygenic traits evolve and respond to selection is a major unsolved problem, because challenges exist for identifying genes underlying a complex trait and understanding how multi-locus selection operates in the genome. Here we used artificial selection experiments to study polygenic response to selection. Inbred strains from seven independent long-term selection experiments in mice for extreme bodyweight (M-bM-^@M-^\HighM-bM-^@M-^] lines weigh 77-42g vs. 40-16g in M-bM-^@M-^\ControlsM-bM-^@M-^] lines), were genotyped at 527,572 SNPs to identify genetic variants controlling bodyweight. We identified 67 high-resolution parallel selected regions (PSRs) where multiple High lines share variants rarely found among the Controls. By comparing allele frequencies in one selection experiment against its unselected control, we found classical selective sweep signatures centered on the PSRs. Multiple lines of evidence support two G protein-coupled receptors GPR133 and Prlhr, as positional candidate genes controlling bodyweight. Artificial selection may mimic natural selection in the wild: compared to control loci, we detected reduced heterozygosity in PSRs in wild populations of unusually large mice on islands. Many PSRs overlap loci associated with human height variation, possibly through evolutionary conservation of functional pathways. Our data suggest that parallel selection on complex traits may evoke parallel responses at many genes involved in diverse but relevant pathways. These samples were used to test the enrichment of certain gene functional categories. Mouse tissue samples (muscle and liver) were collected from 44 and 45 days old males from each of the nine out of thirteen lines (5 High lines: BEHi, DUHi, EDHi, MUHi, ROHi and 4 Control lines: BELi, EDLi, MULi and ROLi; n=23 total) at the University of Edinburgh. Frozen tissue samples were stored at -80M-BM-:C until use. Tissues were dissociated using TissueLyser II with steel beads (both Qiagen) following manufacturersM-bM-^@M-^Y instructions. mRNA was extracted and purified using TRIzol Reagent and the PureLink RNA Mini Kit (Life Technologies GmbH, Darmstadt, Germany). cDNA was synthesized using Maxima First Strand cDNA synthesis kit (Thermo Fisher Scientific, St. Leon-Rot, Germany). Muscle and liver cDNA samples were hybridized on a Mouse GE 4x44k Microarray (Agilent Technologies, Inc., Waldbronn, Germany) according to manufacturerM-bM-^@M-^Ys recommendations. Three technical replicate each was done on pooled cDNA samples from each mouse line.

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Body weight at weaning is the main predictor for diabetic phenotype in male TallyHo/JngJ mice

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