Interspecific Conservation of cis-Regulatory Modules: Why It Works the Way It Does

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Intellectual Merit The sequence differences that have occurred in functionally well characterized cis-regulatory modules over the course of evolution will be examined in order to reveal the rules of change in this information-rich segment of the genome. There now exists a set of libraries from well known non-chordate deuterostome species and functionally characterized candidate genes which comprise one of the most comprehensive experimental platforms ever assembled to address these questions. Compared to the reference species Strongylocentrotus purpuratus, the six comparable species' divergence times span from 20 to 540 million years. Candidate genes have been previously analyzed by gene transfer in the reference species and experimental and computational tools have been developed to undertake these comparative studies. From 8 candidates will be gathered the sequences of putative cis-regulatory modules at varying evolutionary distances. These will be compared to gauge the quality and quantity of changes that have occurred and their function will be verified using gene transfer of large-insert recombinant reporter constructs in the reference species. Besides supporting a theory of cis-regulatory module sequence evolution, the rules that emerge from these mechanisms will provide better predictive methods for discovering cis-regulatory modules in genomes where little previous experimental data is available. Broader Impacts Understanding how cis-regulatory modules evolve lies at the nexus of several major questions in modern biology. The mechanisms operating here will help explain us how the genome works, how development works and how evolution works. The application of the principles learned here will be disseminated through the usual academic channels including journal publications, meeting presentations, graduate and undergradate teaching, and books. The PI and Co-PI have a history of involving undergraduates in laboratory research through the Caltech Summer Undergraduate Research Fellowships (SURF), often funded by REU supplements to NSF grants. Additionally, the PI routinely serves on SURF ad hoc review boards. The training of graduate and post-doctoral personnel is an important component of the operation of the Davidson Laboratory, the Center for Computational Regulatory Genomics and the Genome Facility.