The fitness cost of a congenital heart defect shapes its genetic architecture
| Autor: | Nelson Ugwu, Rachel A. Magnan, Suk D. Regmi, Yidan Qin, Claire E. Schulkey, James M. Cheverud, Ehiole Akhirome, Patrick Y. Jay |
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| Rok vydání: | 2019 |
| Předmět: |
Genetics
0303 health sciences Mutation Heart disease Robustness (evolution) Heritability Biology medicine.disease_cause medicine.disease 01 natural sciences Genetic architecture 010104 statistics & probability 03 medical and health sciences Inbred strain medicine Epistasis Atrioventricular Septal Defect 0101 mathematics 030304 developmental biology |
| DOI: | 10.1101/531988 |
| Popis: | BackgroundIn newborns, severe congenital heart defects are rarer than mild ones. The reason why is unknown, but presumably related to a liability threshold that rises with the severity of a defect. Because the same genetic mutation can cause different defects, other variables may contribute to pushing an individual past a defect-specific liability threshold. We consider here how variables in the genetic architecture of a heart defect depend upon its fitness cost, as defined by the likelihood of survival to reproductive age in natural history studies.MethodsWe phenotyped ~10,000Nkx2-5+/-newborn mice, a model of human congenital heart disease, from two inbred strain crosses. Genome-wide association analyses detected loci that modify the risk of an atrial septal defect, membranous or muscular ventricular septal defect, or atrioventricular septal defect. The number of loci, heritability and quantitative effects on risk of pairwise (G×GNkx) and higher-order (G×G×GNkx) epistasis between the loci andNkx2-5mutation were examined as a function of the fitness cost of a defect.ResultsNkx2-5+/-mice have pleiotropic heart defects; about 70% have normal hearts. The model recapitulates the epidemiological relationship between the severity and incidence of a heart defect. Neither the number of modifier loci nor heritability depends upon the severity of a defect, but G×GNkxand G×G×GNkxeffects on risk do. Interestingly, G×G×GNkxeffects are three times more likely to suppress risk when the genotypes at the first two loci are homozygous and from the same, rather than opposite strains in a cross. Syn- and anti-homozygous genotypes at G×G×GNkxinteractions can have an especially large impact on the risk of an atrioventricular septal defect.ConclusionsGiven a modestly penetrant mutation, epistasis contributes more to the risk of severe than mild congenital heart defect. Conversely, genetic compatibility between interacting genes, as indicated by the protective effects of syn-homozygosity at G×G×GNkxinteractions, plays a newfound role in the robustness of cardiac development. The experimental model offers practical insights into the nature of genetic risk in congenital heart disease. The results more fundamentally address a longstanding question regarding how mutational robustness could arise from natural selection. |
| Databáze: | OpenAIRE |
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