| Autor: |
Akhirome E; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Regmi SD; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Magnan RA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Ugwu N; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Qin Y; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Schulkey CE; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Cheverud JM; Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA., Jay PY; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. |
| Abstrakt: |
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×G Nkx ) and higher-order (G×G×G Nkx ) 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×G Nkx effects, while the loci for severe, atrioventricular septal defects exert large G×G Nkx and G×G×G Nkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×G Nkx 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×G Nkx 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. |
