Widespread epistasis regulates glucose homeostasis and gene expression

<div><p>The relative contributions of additive versus non-additive interactions in the regulation of complex traits remains controversial. This may be in part because large-scale epistasis has traditionally been difficult to detect in complex, multi-cellular organisms. We hypothesized that it would be easier to detect interactions using mouse chromosome substitution strains that simultaneously incorporate allelic variation in many genes on a controlled genetic background. Analyzing metabolic traits and gene expression levels in the offspring of a series of crosses between mouse chromosome substitution strains demonstrated that inter-chromosomal epistasis was a dominant feature of these complex traits. Epistasis typically accounted for a larger proportion of the heritable effects than those due solely to additive effects. These epistatic interactions typically resulted in trait values returning to the levels of the parental CSS host strain. Due to the large epistatic effects, analyses that did not account for interactions consistently underestimated the true effect sizes due to allelic variation or failed to detect the loci controlling trait variation. These studies demonstrate that epistatic interactions are a common feature of complex traits and thus identifying these interactions is key to understanding their genetic regulation.</p></div

Examples of synergistic and antagonistic ieQTLs.

<p>Each dot represents the gene expression data from one mouse. The horizontal bar indicates the mean value for each strain (A) An antagonistic ieQTL regulates the expression of <i>Agxt</i> in the liver. (B) A synergistic ieQTL regulates the expression of <i>Cyp3a16</i> in the liver. The red horizontal line indicates the predicted trait level based on a model of additivity.</p

Identification of 4 ieQTLs that regulate the hepatic expression of Agt.

<p>Gene expression levels of Agt in the liver are shown for strain B6, 5 single CSS strains, and 4 double CSS strains. Each dot represents Agt expression in an individual mouse. The mean value for each strain is indicated by a solid line. The expected expression level of Agt in the double CSS strains based on a model of additivity is indicated with a red line. The Agt gene is located on mouse chromosome 8.</p

Contribution of epistasis to the genetic regulation of hepatic gene expression.

<p>Diagrams representing the estimated proportion of genetic variation due to interactions for (A) all genes expressed in the mouse liver whose expression was under genetic control in the CSS strains studied, (B) the same data segregated based on the statistical evidence supporting an effect of interaction on gene expression, and (C) a comparison of the genes with the most significant evidence for regulation by genetic interactions (FDR < 0.05) and a simulation study with artificial data that model the absence of any genetic interactions.</p

Identification of meQTLs that regulate hepatic gene expression.

<p>A circos plot of meQTL locations in the genome where each layer of the circle represents the comparison between a CSS strain and control B6 mice. From the inner circle, the CSS strains are (B6 x B6.A5)F1, (B6.17 x B6)F1, (B6.A3 x B6)F1, (B6.A6 x B6)F1, (B6 x B6.A10)F1, (B6 x B6.A4)F1, (B6.A14 x B6)F1 and (B6 x B6.A8)F1. Cis-meQTLs and trans-meQTLs are marked with red and blue, respectively. The width of each chromosome is proportional to its physical size. The height of each meQTL bar is proportional to the number of meQTLs in that genomic interval.</p

Interection effects on gene expression.

<p>Interection effects on gene expression.</p

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction

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