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Norman Doggett (LANL) summarized the 5-year chromosome 16 mapping effort that resulted in an integrated physical-genetic-cytogenetic map. A high-resolution (1-Mb) cytogenetic breakpoint map provided the framework for constructing all levels of the integrated map. The physical map consists of both a low-resolution (0.25-Mb) YAC contig map and a high-resolution (<0.01-Mb), "sequence ready" cosmid contig map. STSs anchor the cosmid map to the YAC and cytogenetic maps, and highly informative microsatellite-based genetic markers are tightly integrated. All available markers and cloned genes have been positioned on the map. (More map details can be found in a related article.) The integrated map facilitates disease-gene and fragile-site cloning on the chromosome; genes associated with Batten's Disease and breast and prostate cancers are among those on chromosome 16.
The LANL group is now identifying DNA expressed sequences and integrating them into the map. Mike Altherr explained their choice of an exon-amplification strategy to identify the sequences, which are then mapped to specific chromosomal locations using a panel of somatic cell hybrids and clones. About 1800 exon clones have been generated, and over 800 clones have already been sequenced. Almost 700 sequences have been subjected to database analysis with cDNA INFORM to identify previously characterized genes or conserved motifs that may provide insight into their biological function. This gene annotation map is expected to facilitate identification and isolation of disease genes and functional analysis of genes for which no biological function is known.
Future LLNL plans outlined by Harvey Mohrenweiser include (1) in collaboration with Oak Ridge National Laboratory (ORNL), construction of a complete high-resolution transcript map of chromosome 19 and genomic regions of special interest in both human and mouse; (2) continued development of high-throughput sequencing methods and technologies and sequencing of selected human and mouse genomic regions; and (3) application of resources and techniques to relevant issues in disease susceptibility, biological structure and function, and environmental sciences.
Tom Slezak noted challenges in providing informatics tools to support mapping efforts at LLNL, including automation of as much map construction and integration as possible and construction of flexible tools to handle multiple viewpoints and allow scaleup. He emphasized the importance of active support and participation by biologists in informatics design. Future challenges include building informatics tools to support sequencing, expanding the system to query and navigate across multiple chromosomes and species, actively participating in the federation of genomic databases, and expanding external collaborations.
Lisa Stubbs and Richard Woychik (ORNL) discussed the mouse as a model system for predicting and identifying genes in humans and for studying gene function. Stubbs reported on collaborative efforts with LLNL that have revealed striking similarities between sections of mouse chromosome 7 and human chromosome 19. Woychik stressed the importance of developing a high-throughput transgenic and targeted mutagenesis strategy in mice to accommodate the future study of health effects caused by genes identified through human genome mapping.
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Last modified: Wednesday, October 29, 2003
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