This is an application for an NCHGR/SERCA grant (K01) to support interdisciplinary research in genomic science. The immediate objective of this research project is to develop a fully automated/robust algorithm for computer assembly of high density cosmid contigs to serve as templates for large-scale sequence-based mapping. This includes integrating the cosmid contigs with chromosome-wide YAC based maps and incorporating diverse sources of data (e.g., DNA sequence from cosmid ends, STSs and other markers, or results of specific gap-filling efforts) to resolve ambiguities and verify self-consistency. Initial efforts will be focused on the high resolution mapping and sampled sequencing of human chromosome 11. The mapping strategy employs high density cosmid contig assembly over individual 200 kb to 1 Mb regions of the chromosome coupled with DNA sequencing of the cosmid ends. The relative order and spacing of the sequence fragments is determined from the template contig resulting in a physical map of 1 to 5 kb resolution which contains up to 40% of the entire sequence at one-pass accuracy. A simple restriction-site based approach to cosmid fingerprinting will be effective, provided that the contig-building algorithm correlates fragment data from multiple restriction digests and includes labeled vector/insert end fragments to determine the orientation of individual cosmids, i.e., the orientation of the genomic insert relative to the cloning vector. The candidate is a physicist with nearly a ten year record of achievement and publication in the field of plasma fusion energy--theory/computation. The research advisor, Prof. Glen Evans, is the Principal Investigator of the Genome Science and Technology Center (GESTEC) at the University of Texas Southwestern Medical Center at Dallas, one of the top academic medical centers in the nation and the performance site of this grant. Prof. Evans is an accomplished biologist with an established record of coordinating multi-disciplinary research to develop informatics and automation for the Human Genome Project (HGP). The candidate's skills also compliment those of Prof. Harold Garner, physicist and co-Principal Investigator of GESTEC. The candidate will receive explicit training through an intensive 18 months program that includes formal course-work in the Division of Cell and Molecular Biology (at UT Southwestern), and laboratory rotations in the mapping, sequencing, and informatics units of GESTEC.
