Developmental context and the genotype‐phenotype map

Abstract

Much of what we know about phenotypic variation comes from the study of mutations and disease phenotypes that arise as genetic and environmental influences interact within a developmental program. These studies routinely analyze disease traits as isolated phenomena. Though of clinical significance, such analyses ignore the importance of developmental context in the production of these traits. Variation in human disease traits is often attributed to genetic background and environmental influences, but when environment and genotype are experimentally controlled in animal models, quantitative analysis of disease phenotypes can reveal persistent variation. Variation is produced at least in part by developmental context, loosely defined as the combination of genetic background and the individual growth trajectory, with growth trajectory driven in part by epigenetic factors that are not under strict genetic control (e.g., rates of cell‐cell and tissue‐tissue interactions). Focusing on a specific disease trait, premature cranial vault suture closure, we use an experimental mouse model system to demonstrate why analysis of the disease phenotype (suture patency) cannot explain the variation observed. In our experience, differences in developmental timing and the interaction of developing tissues contribute to the mechanisms by which phenotypic variation is realized.