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Human Genome News Archive Edition

Human Genome Quarterly, Winter 1990; 1(3)

DOE Holds First Human Genome Contractor/Grantee Workshop

Genome Data To Spark Expansion in Biological Research
At the first Contractor/Grantee Workshop for the DOE Human Genome Program, Benjamin J. Barnhart, Program Manager, told participants that data produced by the international human genome effort will impact the manner in which biological research is conducted and provide information needed for significant progress in many areas of research.

The meeting was held in Santa Fe, New Mexico, November 3 and 4, 1989, and the 150 attendees were audience to a total of 31 platform and 57 poster presentations representing each of the three major program areas: biological resources, instrumentation, and informatics capability development.

In addition to contractors and grantees, the workshop attracted staff from the DOE Office of Health and Environmental Research (OHER), the NIH National Center for Human Genome Research, the National Science Foundation, the U.S. Department of Agriculture, and the privately funded Howard Hughes Medical Institute (HHMI).

Charles R. Cantor, Director of the Lawrence Berkeley Laboratory (LBL) Human Genome Center and Chairman of the DOE Human Genome Coordinating Committee, told participants: "Technology will change dramatically; the key is implementation. I believe that the balance between the number of projects that are developing new technologies and the number of projects that are producing new map data is about right." He also said that progress in the Human Genome Project is on target-maybe ahead. Cantor congratulated Sylvia Spengler and her staff at LBL on their coordination of the meeting.

Workshop participants saw the meeting as useful in promoting the exchange of information and observed the spirit of cooperation critically necessary for the successful completion of the genome project. Moreover, the workshop has led to close coordination of work, including interlaboratory meetings among the directors of national laboratory human genome projects, as well as among key investigators developing computational capabilities for handling and analyzing data in databases.

Barnhart stated in his opening remarks that human genome research for OHER is an outgrowth of four decades of work at the national laboratories. He said that OHER continues to address the technical problem of detecting infrequent human DNA mutations induced by low levels of ionizing radiation and energy-related chemicals. Only when the total DNA sequence is elucidated-the long-term goal of the genome project-will a full understanding of the health effects of mutations be possible.

Barnhart specified three resource and technology development program areas and their related objectives that are being pursued by the DOE-sponsored genome program:

  1. Physical mapping:
    • Development of more cost-effective methods for linear ordering of chromosomal DNA sequences.
    • Completion of linear ordering of cloned DNAs from chromosomes 16, 17, 19, 21, and X.
    • Construction of ordered DNA clones for additional chromosomes.
  2. Sequencing technologies:
    • Development of innovative technologies for cost-effective and accurate sequencing.
    • Development of a technology transfer program.
  3. Informatics capabilities:
    • Development of data management and networking tools.
    • Development of advanced algorithms for DNA sequence interpretation.

Highlights of Presentations

Map Production Efforts
Presentations indicated that research on the physical mapping of chromosomes is progressing well. Many research groups engaged in physical mapping studies are using robotics and computer software and hardware to complete their analyses. Listed below are some highlights of physical mapping studies undertaken by DOE-funded researchers.

In his remarks as chairman for the chromosome mapping session, Lawrence Livermore National Laboratory (LLNL) Genome Project Director Anthony Carrano noted that the OHER-sponsored National Laboratory Gene Library Project (NLGLP) is carried out jointly by LLNL and Los Alamos National Laboratory (LANL). Larry Deaven (LANL) and Marvin Van Dilla (LLNL) spoke of their respective programs within the NLGLP. Investigators in the NLGLP begin with flow-sorter-purified chromosomes to produce chromosome-specific partial-digest human DNA libraries for studying the molecular biology of genes, studying and diagnosing genetic diseases, and constructing physical maps of chromosomes.

Over 2000 libraries and other materials have been distributed by the NLGLP to many laboratories that could not economically produce these materials themselves.

Glen Evans (The Salk Institute) reported on progress being made using a variety of physical mapping methods to construct a map of the distal tip of the long arm of chromosome 11. The map, developed in a collaborative effort with Peter Lichter's group at the Yale University School of Medicine, is already useful clinically.

Over 100 human genetic disorders have been localized to the 150-Mbp X chromosome. David L. Nelson (Baylor College of Medicine) reported his group's results for mapping the X chromosome using Alu polymerase chain reaction (PCR) mapping strategies. Pieter de Jong (LLNL) discussed the use of similar new Alu PCR methodologies for mapping chromosome 19.

Carrano reported that the LLNL automated fluorescence-based method for clone fingerprinting has been validated and coupled to software used for contig assembly, data storage, and graphical display of map information. The procedures are being successfully applied to the development of a cosmid and YAC contig map of chromosome 19. Of the 2200 cosmids processed for fingerprint analysis, over 900 are in contigs with an average contig length of about 3 cosmids.

Ed Hildebrand (LANL) informed meeting attendees that nearly 70% of chromosome 16 has been fingerprinted with 2261 DNA clones in 389 contigs. One strategy being employed at LANL for physical mapping-the use of repeat sequences as nucleation sites-results in contig maps with landmarks that are useful for rapid integration of the genetic and physical maps.

Hong Fang (LBL) described the use of single-copy DNA probes-previously assigned to locations on the genetic map-as anchor points in physical mapping studies.

Informatics Presentations
Informatics is a term used to denote algorithms, databases, and hardware that support physical mapping and sequencing activities. This hardware and software-necessary for storing, retrieving, analyzing, and distributing data-must be available for the use of biologists as soon as possible. Genome projects generate computation problems in the following areas: image analysis, primary DNA and protein sequence analysis, prediction of tertiary structures of DNA and proteins, and database management and use.

Platform presentations on informatics were given on the following topics:

  • new computer chips that will speed up sequence-matching queries [e.g., the biological information signal processor (BISP) now being implemented in 1-µm cMOS technology] (Tim Hunkapiller, California Institute of Technology);
  • methods to assess the reliability and quality of results produced by fingerprint mapping strategies (Elbert Branscomb, LLNL);
  • development of techniques to predict the probability of overlap in a pair of cosmid clones for mapping fingerprint data (David Torney, LANL);
  • management of digitized autoradiographic, confocal, and scanning tunneling microscopic data and implementation of a comprehensive chromosome-21 information system (William Johnston, LBL);
  • establishment of more open communication between biologists and computer analysts (Ross Overbeek, Argonne National Laboratory); and
  • a repository of well-characterized, cloned DNA segments to support gene structure and function studies and genomic mapping efforts for use by molecular biologists performing basic research (William Nierman, American Type Culture Collection).

New Approaches to Mapping, Sequencing, and Manipulating DNA
Mapping
Among presenters discussing new approaches to mapping and sequencing, Cassandra Smith (LBL) discussed end-game strategies for completing chromosome mapping in which actual sequence data including and adjacent to rare restriction enzyme cutting sites would serve as anchor points for further physical mapping activities.

Leonard Lerman (Massachusetts Institute of Technology) proposed a new mapping strategy that would exploit thermal stability differences between different domains within the DNA double helix.

Sherman Weissman (Yale University Medical School) reported progress in developing selection and cloning methods to be used in conjunction with the new techniques for in situ hybridization and chromosome mapping.

Sequencing
Edward Yeung (Ames Laboratory) discussed a novel "indirect fluorescence" technique for detection of DNA bands during electrophoresis. The gel matrix fluoresces, but the DNA bands do not.

New sequencing technologies being developed in the DOE Human Genome Program were the subject of a number of presentations during this workshop and included:

  • scanning tunneling microscopy (LBL, LLNL, Oak Ridge National Laboratory (ORNL), and University of New Mexico researchers);
  • resonance ionization mass spectrometry sequencing using stable isotopes (Bruce Jacobson, ORNL/Atom Sciences, Inc.);
  • single-molecule DNA sequencing by flow-cytometry (Richard Keller, LANL);
  • sequencing with reusable libraries of oligonucleotide primers of length 8, 9, or 10 for cost effectiveness [William Studier, Brookhaven National Laboratory (BNL)];
  • computer-assisted multiple DNA sequencing methods (George Church, Harvard University Medical School);
  • multiplex DNA sequencing and innovative large-scale sample processing methods (Robert Weiss, University of Utah Medical Center);
  • methods for substantially increasing the reliability of a core DNA-sequencing step of the Sanger strategy, through genetic engineering of bacteriophage T7 DNA polymerase and modification of polymerase reaction conditions (Stanley Tabor, Harvard University Medical School); and
  • oligonucleotide sequencing by hybridization (Radomir Crkvenjakov, Genetic Engineering Center, Belgrade, Yugoslavia).

Some of the projects listed above have the same goals but different modes of implementation. Multiple approaches are necessary (as recommended in the 1988 NRC report: Mapping and Sequencing the Human Genome) because many of the methodologies remain unproven for large-scale genome mapping and sequencing efforts.

Manipulating DNA
New methods presented for manipulating DNA included:

  • development of a single-molecule counter-3 orders of magnitude more sensitive than conventional fluorescence-detection systems-for detecting DNA in sequencing gels (Richard Mathies, University of California, Berkeley);
  • methylation of restriction recognition sites to create larger DNA fragments for mapping studies (Michael McClelland, California Institute of Biological Research);
  • creation of synthetic endonucleases to recognize and map functionally important DNA regions (Betsy Sutherland, BNL);
  • determination of conditions for selective cleavage of single-stranded DNA and RNA adjacent to hybridization sites (i.e., oligonucleotide-directed nucleases) (David Corey, LBL); and
  • use of crossed oscillating electric and magnetic fields to yield high-resolution separations between DNA fragments (Gunter Hofmann, BTX, San Diego).

Hood Discusses Project Implementation
In his summary of the workshop, Leroy E. Hood (Director of the NSF Center for Integrated Protein and Nucleic Acid Chemistry and Biological Computation and Director of the Cancer Center at the California Institute of Technology) outlined the future course of the genome project.

He said that in the first five years, mapping and sequencing technologies should be developed, individual human chromosomes and the chromosomes of model organisms mapped, and small regions of human chromosomes and other genomes sequenced.

In the second five years, increased development should be pursued in the areas of technologies for large-scale mapping and sequencing, mapping studies, sequencing of small human chromosomes, and interpretation of sequence data. Hood also commented that the technologies "spun-off" from the genome project will be used for medical applications and to spur basic research.

In the final five years of the project, Hood proposed, the sequencing task should be completed, and intensive genome interpretation studies should be initiated. Scientists from many areas of biological research will be involved in sequence interpretation and in the identification of genes.

He further commented that, because of the interdisciplinary approaches needed in biological research, students should be mentored by representatives of many other disciplines such as computer science, chemical engineering, chemistry, English, and mathematics.

With the sequence data in hand, Hood related, the way in which biology is studied will be fundamentally reoriented. Research will proceed in the opposite direction from the traditional approach: investigators will begin with the DNA code for a gene and proceed "backward" to look for the function of that gene. Lexicons of protein structure motifs will be used to make generalizations and predictions of three-dimensional protein structure and, ultimately, to understand the function of proteins within the cell.


Written by Betty K. Mansfield and Judy M. Wyrick
HGMIS, ORNL

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Human Genome Program, U.S. Department of Energy, Human Genome News (v1n3).

Human Genome Project 1990–2003

The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.

Human Genome News

Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.