The fitness cost of a congenital heart defect shapes its genetic architecture

In humans, distinct forms of congenital heart disease vary in severity and incidence. Severe defects are rarer than mild ones for reasons unknown. We show here how genetic interactions contribute to the relationship in a mutant mouse model. Interactions between the disease-causing mutation and other genes affect the risk of severe more than mild defects, consistent with the need to surpass the higher liability thresholds for more severe defects. In addition, we find evidence in inbred mouse strains for the prior selection of genotypes between interacting genes that confers robustness to a new mutation. These results address fundamental questions regarding how the fitness cost of a disease relates to its genetic architecture and the evolutionary basis of robustness.