An ongoing challenge for biologists is to reveal the full spectrum of genes and genetic interactions that contribute to normal variation in craniofacial shape. Mutagenesis screens in model systems have provided broad insights into how the vertebrate head is patterned, but such studies are generally biased toward the effects of mutations that produce extreme variation in form, and limited with respect to understanding subtle, quantitative variation in shape. Genome-wide association studies, on the other hand, have provided new insights into the alleles that contribute to variation in complex traits, however these methods have only been able to explain a faction of the heritable variation in most complex traits. Thus, several key questions remain unanswered in the field: (1) What are the genes that contribute to craniofacial shape? (2) To what extent do they differ from genes implicated in early craniofacial development? (3) How do these loci interact with themselves and the environment to effect variation in facial form? To date, there hasn't been an experimental system with which to comprehensively address these questions. Here I propose a new model, African cichlid fishes, with which to characterize the genetic/genomic basis of craniofacial variation, including gene, gene-by-gene, and gene-by-sex effects. In addition, given the conservation of developmental processes across vertebrates, gene candidate identified in cichlids can be validated in experimental models such as the zebrafish. Cichlids have undergone extensive evolutionary modifications of their skulls and jaws in a very brief period of time. Given their recent origins, phenotypically distinct cichlid lineages continue to segregate ancestral polymorphisms through recombination and hybridization, and in this way are similar to comparisons between diverse human populations. Systems characterized by extensive phenotypic variation in the context of overall genomic uniformity are ideal for genetic/genomic mapping. This proposal aims to leverage these advantages as well as the genetic/genomic resources that my lab as accumulated over the past 5+ years to provide a more comprehensive understanding of the myriad genetic mechanisms that influence variation in vertebrate facial form. In doing so we will test three different hypotheses: (1) The shape of the craniofacial skeleton is determined by a unique set of genes that are distinct from those that pattern the head early in development; (2) Genetic models that allow for genetic interactions and environmental effects (in this case sex) will explain a significantly greater proportion of the phenotypic variation than will single locus models; (3) Skeletal geometry is influenced through the combined effects of the primary cilia and Hedgehog signaling pathway. Preliminary data strongly support all three hypotheses.
How the complex geometry of the vertebrate head is specified over development is an area of active investigation that is directly relevant to human health and disease. The work proposed here aligns squarely with this imperative, as it seeks to significantly expand our understanding of the genetic, genomic and developmental factors and interactions that participate in craniofacial development.
