A quadratic paradigm describes the relationship between phenotype severity and variation

In 1942 Waddington observed that phenotype variation among mutant animals is greater than in wild types. Here we update this observation to depict unexpected relationships between phenotype severity and variation. Using a zebrafish mef2ca allelic series representing a range in craniofacial phenotype severity, we tested the straightforward hypothesis that as phenotype severity increases, variation increases. We found that severity and variation were positively correlated, but only to a point. Variation collapsed in the most severe conditions. Mathematically, we found that the best fit for the relationship between severity and variation is a quadratic function. Across both zebrafish craniofacial phenotypes and human genetic disease, wild-type conditions produced low variation, moderate severity was associated with high variation, and conditions of extreme severity resulted in low variation. We propose that the quadratic relationship between severity and variation is a universal principle of biology that until now has not been formally tested.