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Human Genome News, Jan.-Feb. 1995; 6(5): 2

DOE Contractor-Grantee Workshop
Mapping Sessions

Physical Mapping

Chromosome 16

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.

Doggett, Callen

Norman Doggett (Los Alamos National Laboratory) and David Callen (Adelaide Women and Children's Hospital) interpret chromosome 16 map data.

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.

Chromosome 5

Deborah Grady (LANL) described progress in constructing a low-resolution physical map of chromosome 5. A YAC contig centers on regions associated with Cri-du-Chat syndrome; with a frequency of 1 in 45,000 births, this is the most common human terminal-deletion disorder. Common clinical features include mental retardation and a characteristic high-pitched, cat-like cry. A complete, nonchimeric YAC contig of 5p15.2 has been identified and characterized; deletion of this region (about 2 Mb) correlates with all clinical features except the cry, which maps to 5p15.3. A YAC contig of this latter region has been constructed and is being characterized. [Genomics 24(1), 63-68 (November 1994).]

Chromosome 19

Linda Ashworth (LLNL) described the 4-year strategy for constructing the high-resolution metric map, which currently consists of 63 islands of known order and distance that span 90% (45 Mb) of the noncentromeric portion of chromosome 19. The map provides clonal continuity in YACs, BACs, PACs, and cosmids. Brigitte Brandriff discussed the map foundation, which consists of 802 fluorescently fingerprinted cosmid contigs. These contigs were anchored to the map by FISH, allowing determination of order and distance and providing a "to-scale" framework (metric) map. Over 75% (>38 Mb) of the chromosome has already been defined to the level of EcoR I restriction sites. The group has also assigned genes, cDNAs, STSs, polymorphic markers, and ESTs to the map. Overall coverage is about 1 marker per 147 kb, with the goal of 1 marker per 100 kb (see High-Resolution Physical Maps of Chromosomes 16 and 19 Completed).

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.

Parrish, Stubbs

Julia Parrish (Baylor College of Medicine, 1992 DOE Human Genome Program Distinguished Postdoctoral Fellow) and Lisa Stubbs (Oale Ridge NstionalLaboratory) exhibit their respective posters during a postsr session.

Chromosome X

David L. Nelson (Baylor College of Medicine) discussed use of LLNL flow-sorted cosmids to increase resolution of the X chromosome short-arm YAC map; he believes these cosmids will become common currency for exchanging X chromosome mapping information. His group is using WWW-based browsers for entering, annotating, and correcting information. Nelson stressed the need to develop joint databases that provide researchers worldwide with access to information on each flow-sorted chromosome library.

Chromosome 11

Glen Evans (University of Texas Southwestern Medical Center at Dallas) reported that YAC contigs spanning chromosome 11 are nearly complete. His laboratory has begun constructing higher-resolution maps based on a sampled-sequencing approach to ordered cosmids that generates maps displaying likely locations of gene hits, STSs, polymorphisms, and other sequence features. [Genome center and chromosome 11 information (http://mcdermott.swmed.edu).]

Denise Casey, HGMIS

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