The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost.

Ehiole Akhirome,Nelson Ugwu,Patrick Y Jay,Suk D Regmi,Yidan Qin,Rachel A Magnan,Claire E Schulkey,James M Cheverud

doi:10.3390/genes12091368

Ehiole Akhirome, Nelson Ugwu + Show 6 more

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https://doi.org/10.3390/genes12091368

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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.

Highlights

Have different developmental bases but similar pathophysiological consequences. We note this because epidemiological studies typically combine membranous and muscular ventricular septal defects (VSD), making VSD appear more common than atrial septal defects (ASD) [1]
Normal cardiac development is crucial for survival to reproductive age, but Congenital heart disease (CHD)
Normal cardiac development is crucial to reproductive age, butsevere defects are rarer than mild ones evolutionary basis

Summary

Introduction

Congenital heart disease (CHD) is recognized as the most common birth defect, but cardiac malformation encompasses anatomically distinct phenotypes in which the severity and incidence of a defect are inversely related. Secundum atrial septal defects (ASD), which are compatible with survival into middle age, are three times more common than atrioventricular septal defects (AVSD), which can cause death during infancy (Figure 1a) [1,2]. No simple or single hypothesis explains the epidemiological relationship, such as a genotype–phenotype correlation or a lower frequency of the causes of severe defects. The fetoplacental circulation enables severe defects to be compatible with survival to birth. The inverse relationship does suggest that each defect has a liability threshold related to its fitness cost: the higher the threshold, the rarer a defect is. The developmental pathways that lead to a severe defect are more robust to perturbation than the ones to a mild defect

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