Document Type
Article
Publication Date
9-1-2021
Publication Title
Genes
Volume
12
Issue
9
Pages
1-14
Publisher Name
MDPI
Abstract
In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/− mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×GNkx) and higher-order (G×G×GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×GNkx effects, while the loci for severe, atrioventricular septal defects exert large G×GNkx and G×G×GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved.
Identifier
85114494854 (Scopus)
Recommended Citation
Akhirome, Ehiole; Regmi, Suk D.; Magnan, Rachel A.; Ugwu, Nelson; Qin, Yidan; Schulkey, Claire E.; Cheverud, James M.; and Jay, Patrick Y.. The genetic architecture of a congenital heart defect is related to its fitness cost. Genes, 12, 9: 1-14, 2021. Retrieved from Loyola eCommons, Biology: Faculty Publications and Other Works, http://dx.doi.org/10.3390/genes12091368
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
