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Epistatic regulation of complex traits and gene expression in mice

ABSTRACT: The genetic contribution of additive versus non-additive (epistasis) effects in the regulation of hematologic and other complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate and powerful model for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTLs) were identified using a modified backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. By analyzing the transcriptomes of offspring from this cross, we identified and mapped additive QTLs regulating the expression of 768 genes, and epistatic QTLs for 519 genes. Similarly, we identified additive QTLs for fat pad weight, platelets, and percentage of granulocyte in the blood as well as epistatic QTLs controlling the percentage of lymphocytes in the blood and red cell distribution width. The variance attributed to the epistatic QTLs was approximately equal to that of the additive QTLs, demonstrating the importance of identifying genetic interactions to understand the genetic basis of complex traits. Of particular note, even the epistatic QTLs identified that accounted for the largest variances were undetected in our single loci GWAS-like association analyses, highlighting the need to account for epistasis in association studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE145607 | GEO | 2020/10/05

REPOSITORIES: GEO

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