The gene regulatory basis of the genotype-phenotype map

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PROJECT SUMMARY This research program seeks to reveal how morphological traits are genetically encoded during development and modified during evolution. Gene regulatory networks are key to generating the physical features of an organism, as they govern the spatial and temporal expression of each gene during its development. It is now well accepted that phenotypic differences between species and within populations, including the human population, are often caused by changes to regulatory networks which alter expression levels or timing. Despite much progress in this field, our understanding of network function and evolution is lacking in several major areas: (1) how do new traits emerge from changes to networks? (2) how do networks influence the behavior of cells in developing tissues? (3) how do mutations that affect gene regulation permeate networks and populations to cause traits? This research will leverage the highly tractable Drosophila melanogaster model to answer these questions. The first theme of this program will address a gene regulatory network controlling a rapidly evolving three- dimensional anatomical structure in Drosophila. The network which patterns this structure will be dissected to determine how individual components became integrated into the network. In parallel, the proposed studies will trace the connections between these networks and the cellular processes that drive morphogenesis. Finally, genetic changes which alter the three-dimensional shape of these structures will be identified. Performing these studies will provide an unprecedented view of how gene regulatory networks are assembled and modified to generate physical differences in tissue structure and produce elaborate morphologies. The second theme comprises studies on Drosophila pigmentation traits that differ among populations and between species. Most traits involve multiple loci, and much of this polygenic variation will be derived from standing variants that persist in populations without phenotypic consequences. The accumulation of multiple genetic changes will be traced and connected to a putatively adaptive pigmentation trait in Drosophila melanogaster. The pigmentation trait under study is controlled by Hox transcription factors, which are highly conserved body-patterning genes shared between flies and humans. This project will examine Hox gene function and evolution in populations and between species to determine how the gene regulatory network for this trait arose and diversified. This work will provide a deep molecular understanding of how phenotypes are generated, informing the nature of these processes in less tractable systems, including humans.