Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis
Autor: | Soha Yazbek, Joseph H. Nadeau, Colleen M. Croniger, Jonathan M. Geisinger, Gabriel E. Zentner, Sabrina H. Spiezio, David A. Buchner, Lindsay C. Burrage, Chang-Wen Hsieh, Peter C. Scacheri |
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Rok vydání: | 2011 |
Předmět: |
Male
Quantitative Trait Loci Congenic Context (language use) Quantitative trait locus Biology Mice Mice Congenic Genetics Animals Homeostasis Humans Glucose homeostasis Obesity Gene Genetics (clinical) Research Body Weight Gluconeogenesis Chromosome Mapping High-Throughput Nucleotide Sequencing Chromosome Hep G2 Cells Sequence Analysis DNA Chromosomes Mammalian Phenotype Genetic architecture Diet Glucose Diabetes Mellitus Type 2 Gene Expression Regulation Models Animal Nucleotide Transport Proteins Insulin Resistance |
Zdroj: | Genome Research. 21:1065-1073 |
ISSN: | 1088-9051 |
Popis: | Although central to many studies of phenotypic variation and disease susceptibility, characterizing the genetic architecture of complex traits has been unexpectedly difficult. For example, most of the susceptibility genes that contribute to highly heritable conditions such as obesity and type 2 diabetes (T2D) remain to be identified despite intensive study. We took advantage of mouse models of diet-induced metabolic disease in chromosome substitution strains (CSSs) both to characterize the genetic architecture of diet-induced obesity and glucose homeostasis and to test the feasibility of gene discovery. Beginning with a survey of CSSs, followed with genetic and phenotypic analysis of congenic, subcongenic, and subsubcongenic strains, we identified a remarkable number of closely linked, phenotypically heterogeneous quantitative trait loci (QTLs) on mouse chromosome 6 that have unexpectedly large phenotypic effects. Although fine-mapping reduced the genomic intervals and gene content of these QTLs over 3000-fold, the average phenotypic effect on body weight was reduced less than threefold, highlighting the “fractal” nature of genetic architecture in mice. Despite this genetic complexity, we found evidence for 14 QTLs in only 32 recombination events in less than 3000 mice, and with an average of four genes located within the three body weight QTLs in the subsubcongenic strains. For Obrq2a1, genetic and functional studies collectively identified the solute receptor Slc35b4 as a regulator of obesity, insulin resistance, and gluconeogenesis. This work demonstrated the unique power of CSSs as a platform for studying complex genetic traits and identifying QTLs. |
Databáze: | OpenAIRE |
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