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Human Genome News Archive Edition

Human Genome News, May 1993; 5(1)

DOE Holds Contractor-Grantee Workshop To Assess Progress

Over 400 researchers, program managers, and invited guests gathered February 7-10 in Santa Fe, New Mexico, for the Third Contractor-Grantee Workshop, sponsored by the DOE Human Genome Program. The meeting was held to review current research and assess the progress and direction of the genome program.

In his welcoming remarks David Galas, DOE Associate Director for the Office of Health and Environmental Research, recognized mapping contributions made by researchers worldwide and said that major changes now in the offing may alter the program, particularly in the area of sequencing.

U.S. Senator Pete Domenici (R-NM), a major congressional supporter of the project, told attendees that genome researchers "stand poised to rewrite the health care delivery system, and those in policy positions need to be both helpful to and demanding of the Human Genome Project." He stressed the importance of developing policies on ethical, legal, and social issues (ELSI) related to genomics and agreed with Galas that researchers and policymakers need to communicate on these topics. Domenici also urged scientists to establish closer contact with the U.S. marketplace to facilitate the application of new discoveries.

The meeting was organized by Sylvia Spengler [Lawrence Berkeley Laboratory (LBL)], the DOE Human Genome Coordinating Committee, and the DOE Human Genome Program staff. Two comprehensive informatics resource rooms containing a local area network with Internet access were expertly set up and maintained by Claudia Sanders and other Los Alamos National Laboratory (LANL) computing staff.

Plenary sessions included ELSI topics, sequencing, informatics, and chromosome and cDNA mapping and sequencing. All projects were represented in informative poster sessions during the meeting. The number of funded projects has almost doubled since the last workshop in February 1991, reflecting the rapid growth of the genome program. Almost 200 projects were represented by investigators from DOE human genome centers at LBL, Lawrence Livermore National Laboratory (LLNL), and LANL; other DOE-supported laboratories; and more than 40 universities and research organizations. Some of the presentations are highlighted below.

ELSI Presentations

Michael Yesley (LANL) described the direction of the DOE ELSI program and the issues being explored, including availability and disclosure of genetic information and the possible effects of such knowledge. Joe McInerney (Colorado College), Troy Duster [University of California, Berkeley (UCB)], and Philip Reilly (Shriver Center) addressed education and policy-oriented aspects of DOE research.

McInerney discussed the objectives of the Biological Sciences Curriculum Study module, which was widely distributed to U.S. high school biology teachers. He explained that the program attempts to minimize the resurgence of biological determinism by focusing on interactions between environmental and genetic factors. The program also emphasizes the role played by ethics in the health sciences.

Duster described the assimilation of genetic information by consumers, who often attempt to process it along with their own sets of long-held beliefs. He said that their nongenetic explanations for disorders will not be discarded until more-complete explanations are available.

Reilly discussed genetic information and its potential availability to life and health insurers through databases containing medical records; insurers are not yet requiring routine genetic testing because of cost. He challenged the group to become more involved in ELSI issues and public policy matters and not to permit others to misinterpret discoveries made by individuals in the group.

Sequencing Presentations

Lloyd Smith (University of Wisconsin, Madison) opened the session by observing that complete sequencing of the human genome by 2006 will require a 500-fold rate increase (to 500 Mb/yr) and a 5-fold cost decrease over the next 7 years to meet large-scale sequencing goals. This observation led to a lively discussion of sequencing issues.

Problems of scaling up chromosome sequencing rates were discussed by several speakers. William Studier (Brookhaven National Laboratory) proposed the use of primer walking to assemble elementary sequence reads into extended sequence; the approach would eliminate subcloning and assembly steps required by other strategies [HGN 4(5), 1-4 (January 1993)]. Challenges in developing this approach include analyzing the priming capacity of hexamer strings and integrating an appropriate detection system.

Michael Palazzolo (LBL) and Robert Weiss and Raymond Gesteland (University of Utah) are generating preliminary dense maps to guide sequence assembly. Palazzolo described the production of "DOG-tag" physical maps, in which the distance (D) and orientation (O) of each gene-sized (G) sequencing template (about 3 kb from P1 clones) are known; each is tagged by a sequence tagged site (STS) from each end. No sequence assembly is required. The Utah group is developing automated processes to map transposon-based multiplex priming sites on large-insert (20 kb) cloned DNA.

Promising instrumentation includes automated colony pickers and semiautomated systems that produce data on fragment length for map construction [Joseph Jaklevic (LBL)] and capillary and ultrathin gel electrophoresis systems [Smith, Richard Mathies (UCB), Norman Dovichi (University of Alberta), Edward Yeung (Iowa State University), Barry Karger (Northeastern University)]. Mathies described his system in which fragments are separated on capillary arrays and distinguished by a binary coding scheme using only two different fluorescently labeled dye primers to identify four sets of fragments. He predicted a throughput of 200 kb per day of raw sequence in about 1 year, running 100 capillaries in parallel.

DNA chain breakage occurring at guanidine residues during DNA vaporization by laser-driven mass desorption was identified as a problem in developing mass spectroscopy as a very fast sequencing tool. These results are stimulating the search for less-harsh vaporization procedures [Klaus Schneider and Brian Chait (Rockefeller University), Winston Chen (Oak Ridge National Laboratory (ORNL)), David Schieltz and Peter Williams (Arizona State University)].

The production of regular anchored arrays of oligonucleotides has allowed the sequencing-by-hybridization technology to begin efficacy testing [Stephen Fodor (Affymax), Robert Foote (ORNL), Michael Pirrung (Duke University)]. Fodor reported using light-directed chemical synthesis to fabricate high-density probe arrays and the construction of partial sequencing chips for probing, sequence checking, and mutation screening [HGN 4(5), 3-4 (January 1993)].

Informatics Presentations

Chair David Kingsbury (Johns Hopkins University) commented on the 1992 review of DOE-funded informatics projects and recommendations by a group of genome informatics experts. The purpose of the review was to evaluate the (1) balance of support provided by informatics programs to various genome centers and the genomics community, and (2) responsiveness of the informatics program to changes in mapping and sequencing. The oversight group identified the need for central direction and enhanced communication among developers and consumers of informatics tools. Cohousing bench scientists and informatics groups was recommended for better integration of informatics activities with centers. The group also recommended that guidelines for review of informatics proposals be developed.

Kingsbury noted that the reviewers found many impressive off-site projects and applauded DOE for supporting activities having broad, long-term views of genome project informatics needs.

Several researchers described or demonstrated software for mapping and sequencing analysis [Michael Cinkosky (LANL), Ed Thiel (LBL), Ed Uberbacher (ORNL)]. Hands-on demonstrations of popular software were available throughout the meeting. Tom Marr [Cold Spring Harbor Laboratory (CSHL)] described an interactive, unified database that will link Genome Data Base (GDB), the Jackson Laboratory mouse database, FlyBase, ACEDB for Caenorhabditis elegans, CSHL Fission Yeast database, and others. The object-oriented computer program uses an organism-independent underlying data model to unify data across eukaryotic organisms. Marr explained that this will help researchers who study gene function by analyzing conserved genes.

A recurrent theme in the informatics session was the need to improve map representation and define map types needed by investigators. Ken Fasman (GDB) proposed a three-tiered organization of map information: (1) "nascent" maps containing low-level map data, (2) individual observed maps constructed from nascent maps, and (3) consensus maps containing data about the whole population. Setting up such maps will require coordinate systems to describe genome locations and provide two resolution levels: (1) global coordinates (reference markers representing order and genetic distance) overlaid by (2) local coordinates pinned to local landmarks (defined relative to markers at the base-pair level) representing genomic variation.

Increasing sequence-analysis speed will become more critical as the rate of data doubling increases. GenBank® now receives 3 Mb/yr, with the rate of data receipt doubling every 15 months. This increase presents challenges for managing data output and improving processing speed. Manfred Zorn (LBL) discussed a toolkit [parallel object-oriented environment and toolkit (POET)] that uses existing software to exploit the power of parallel processing and accomplish sequence analysis more quickly. The output display module shows sequence matches and provides a graphical user interface, while hiding implementation details.

Mapping Presentations

Groups led by Anthony Carrano at LLNL and Robert Moyzis at LANL are approaching closure of chromosomes 16 and 19. Many talks focused on vector development, with bacterial artificial chromosomes (BACs) representing a major new resource. With an average insert size of 200 kb, BACs are some 4 to 5 times larger than cosmids, have no detected instability and chimerism problems, and are much easier to purify than yeast artificial chromosomes (YACs) [Bruce Birren (California Institute of Technology), Pieter de Jong (LLNL)]. In describing the large-insert cloning systems at LANL, MaryKay McCormick noted the extremely low frequency of chimeras (0 to 10%) found in the YAC libraries for chromosomes 5, 9, 16, and 21 and in the total genomic library.

Glen Evans (Salk Institute) indicated that chromosome 11 will be sequenced directly from cosmid templates with no subcloning. Evans described his group's plans to complete low-resolution YAC contig maps of this chromosome and begin assembling high-resolution clone maps as a prelude to sequencing. The Salk team is collaborating with Harold Garner (General Atomics) to develop high-throughput robotic and informatics tools that address known bottlenecks.

Reagents and technologies developed in the Human Genome Project are now used for human-disease analysis. Daniel Pinkel (University of California, San Francisco) discussed medical diagnostic applications of hybridization technologies, probes, and digital microscopy for clinically important problems such as prenatal and neonatal disorders and cancer. The chromosome painting technology of Pinkel's group was transferred to industry 2 years ago. The team recently developed a method using comparative genomic hybridization to measure chromosomal deletions and duplications in tumor cells and provide a "copy number karyotype."

cDNA Presentations

Sequences from several thousand cDNAs are now available for generating STSs [James Sikela (University of Colorado Health Sciences Center), J. Craig Venter (The Institute for Genomic Research)]. cDNA mapping is proceeding by fluorescence in situ hybridization (FISH) [Julie Korenberg (Cedars-Sinai Medical Center), Joseph Gatewood (LANL)] and polymerase chain reaction analyses on somatic hybrid panels [Mihael Polymeropolous (National Institute of Mental Health), Donna Maglott and William Nierman (American Type Culture Collection)]. Sikela is using a two-step cDNA mapping approach, in which he assigns cDNAs to gridded YACs and maps the YACs by FISH. Massively parallel oligomer fingerprinting of cDNA clones [Radomir Crkvenjakov and Radoje Drmanac (Argonne National Laboratory)] is providing a means for rapidly distinguishing cDNA clones and identifying related cDNAs and uncharacterized cDNAs. Mapping of cDNAs, which is preceeding more slowly than cDNA sequencing, continues to be challenging.

[Reported by Denise K. Casey (HGMIS, ORNL) and Marvin Stodolsky (DOE Human Genome Program)]

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Human Genome Project 1990–2003

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