Abstract
The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. However, genome wide association studies identify and localize the contribution of individual genes to phenotypic variation, seldom targeting the coordinated influence of multiple genes on phenotypes. Here, we explicitly model the joint effect of biologically coherent collections of genes on craniofacial shape in a sample of n = 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. Our process-centered view of cranial shape variation allows us to consider fundamental issues that are difficult to address with existing methods, such as the extent to which variation in different processes relevant to the same phenotype correspond to similar axes of shape variation, and whether the direction of the effect of experimental mutations to a pathway gene is similar to the primary axis of shape variation associated with that pathway. Finally, we introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.
Competing Interest Statement
The authors have declared no competing interest.
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