Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

Lawson, Heather A.; Cady, Janet; Partridge, Charlyn; Wolf, Jason B.; Semenkovich, Clay F.; Cheverud, James M.

doi:10.1371/journal.pgen.1002256

Cited by 50 publications

(53 citation statements)

References 94 publications

(107 reference statements)

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“…We confirm that the effect of genetic variation is highly context dependent [66]; in other words, the allelic effects differ greatly depending on whether the mouse is male or female or on which diet it has recently been fed. Considering that little variance is accounted for by genotype in human obesity studies, which total 10,000 times more subjects than in the animal study we report here [67], it is likely that human genotype effects on obesity are also highly context dependent and that the mixture of subjects with different diets dilutes the genetic effects, making them harder to detect.…”

Section: Discussionsupporting

confidence: 70%

QTL Analysis of Dietary Obesity in C57BL/6byj X 129P3/J F2 Mice: Diet- and Sex-Dependent Effects

et al. 2013

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Obesity is a heritable trait caused by complex interactions between genes and environment, including diet. Gene-by-diet interactions are difficult to study in humans because the human diet is hard to control. Here, we used mice to study dietary obesity genes, by four methods. First, we bred 213 F2 mice from strains that are susceptible [C57BL/6ByJ (B6)] or resistant [129P3/J (129)] to dietary obesity. Percent body fat was assessed after mice ate low-energy diet and again after the same mice ate high-energy diet for 8 weeks. Linkage analyses identified QTLs associated with dietary obesity. Three methods were used to filter candidate genes within the QTL regions: (a) association mapping was conducted using >40 strains; (b) differential gene expression and (c) comparison of genomic DNA sequence, using two strains closely related to the progenitor strains from Experiment 1. The QTL effects depended on whether the mice were male or female or which diet they were recently fed. After feeding a low-energy diet, percent body fat was linked to chr 7 (LOD = 3.42). After feeding a high-energy diet, percent body fat was linked to chr 9 (Obq5; LOD = 3.88), chr 12 (Obq34; LOD = 3.88), and chr 17 (LOD = 4.56). The Chr 7 and 12 QTLs were sex dependent and all QTL were diet-dependent. The combination of filtering methods highlighted seven candidate genes within the QTL locus boundaries: Crx, Dmpk, Ahr, Mrpl28, Glo1, Tubb5, and Mut. However, these filtering methods have limitations so gene identification will require alternative strategies, such as the construction of congenics with very small donor regions.

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Section: Discussionsupporting

confidence: 70%

QTL Analysis of Dietary Obesity in C57BL/6byj X 129P3/J F2 Mice: Diet- and Sex-Dependent Effects

et al. 2013

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“…The genetic effects at the QTL are non-additive and show significant diet and dominance-by-diet interactions (Figure1a and 1b). Previously published microarray data suggest that 2 genes in liver (Inppl1, Smpd1) and 6 genes in white adipose tissue (reproductive fatpad; Arfip2, Frag1, Hpx, Lrrc51, Prkcdbp, Rhog) are differentially expressed on low-fat versus high-fat diets in both the LG/J and SM/J parental strains in this genomic region (19, 20). This pattern of diet-dependent, but not strain-dependent, differential expression is consistent with the diet-dependent genetic effects at the QTL.…”

Section: Resultsmentioning

confidence: 98%

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

et al. 2017

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Background/Objectives Elevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects. Subjects/Methods Hemopexin was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both reproductive fatpads and livers of mice representing three strains, LG/J (n = 25), SM/J (n = 27) and C57Bl/6J (n = 19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n = 18) and of metabolically normal (n = 24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n = 18). Results Hemopexin expression in mouse adipose tissue, but not liver, was regulated by dietary fat regardless of genetic background. Hemopexin increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of hemopexin based on metabolic disease status (p < 0.05), and circulating hemopexin levels were correlated with serum triglycerides in these subjects (r = 0.33; p = 0.03). Hemopexin was also found in an unbiased proteomic screen of human atherosclerotic plaques, and shown to display differential abundance based on extent of disease and triglyceride content (p < 0.05). Conclusions Our findings suggest that hemopexin is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.

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“…To derive the polymorphism densities in different genic regions, we intersected QTL intervals and associated genomic annotations with SNPs at which the parental lines LG/J and SM/J differ. These SNPs were previously identified by comparing the full genomic sequences of LG/J and SM/J with C57BL6/J (Lawson et al 2011). This list of SNPs is available at dbSNP (Sherry et al 2001) under the handle “cheverud.” We used transcription factor binding site (TFBS) track (Yale/Stanford ENCODE [Euskirchen et al 2007]) in UCSC genome browser to retrieve predicted TFBSs.…”

Section: Methodsmentioning

confidence: 99%

Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice

Pavličev¹,

Wagner²,

Noonan³

et al. 2013

Genome Biology and Evolution

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Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here, we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the loci associated with the degree of autonomy between fore- and hind limb long bone lengths (loci affecting the relationship between traits, relationship quantitative trait loci [rQTL]). These loci have been proposed to interact locally with the products of pleiotropic genes, thereby freeing the local trait from the variational constraint due to pleiotropic mutations. Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside. We find that these two classes of QTL intervals harbor different kinds of molecular variation. SNPs in rQTL intervals more frequently reside in limb-specific cis-regulatory regions than SNPs in intQTL intervals. The intQTL loci modified by the rQTL, in contrast, show the signature of protein-coding variation. This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms. For both types of QTL intervals, the underlying candidate genes are enriched for genes involved in protein binding. This finding suggests that rQTL effects are caused by local interactions among the products of the causal genes harbored in rQTL and intQTL intervals. This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation.

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Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

Cited by 50 publications

References 94 publications

QTL Analysis of Dietary Obesity in C57BL/6byj X 129P3/J F2 Mice: Diet- and Sex-Dependent Effects

QTL Analysis of Dietary Obesity in C57BL/6byj X 129P3/J F2 Mice: Diet- and Sex-Dependent Effects

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice

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