Human Genome Project
U.S. Department of Energy

U.S. Human Genome Project Updates Goals

New 5-Year Plan Incorporates Research Advances

Unexpected advances in genome research and more-sophisticated understanding of how to achieve long-term objectives have led genome project planners at NIH and DOE to update their initial 5-year goals. The new 5-year plan appeared in the October 1 issue of Science in an article coauthored by Francis Collins, Director of the National Center for Human Genome Research, and David Galas, formerly head of the DOE Human Genome Program and Associate Director of the DOE Office of Health and Environmental Research.

The new plan extends research goals in already established categories and adds specific new goals for developing technology for gene identification and mapping. It also provides for outreach programs to distribute genome materials to the scientific community. Although the plan covers the next 5 years of the project (through September 1998), the goals were designed to address both long- and short-term needs.

Obtaining the complete human DNA sequence is still the ultimate goal of the project. Although debate continues over the value of sequencing the whole genome, researchers recognize the importance of DNA sequence information in revealing genes and other biological information that could not be obtained by smaller-scale techniques.

The new goals again assume a funding level for the whole genome program of $200 million annually, adjusted for inflation after 1990. Although this amount was also assumed when the initial goals were developed and implemented, appropriations have never reached that level. U.S. genome project funding for FY 1994 (which began October 1) is about $170 million.

A New Plan Needed

Progress over the last 3 years has put the initial goals well within reach with detailed humangenetic maps; improved physical maps of human and model organism genomes; development of DNA sequencing and informatics technology; and identification of major ethical, legal, and social issues (ELSI) concerning the increased availability of genetic information .

Although the first 5-year plan was not due to expire until September 1995, ‘Advances in genome research have already changed the way research is being done,’ Collins said. ‘We need to incorporate these advances into our present research goals to ensure that the program continues to be ambitious and cutting edge.’

The genome project has already had a profound impact on biomedical research. In just the past few years, maps generated by project researchers have helped in finding genes associated with dozens of genetic conditions, including Menkes syndrome, the X-linked immune disorder ammaglobulinemia, Huntington’s disease, myotonic dystrophy, fragile X syndrome, neurofibromatosis types 1 and 2, and others. In addition to the identification of many more disease genes, other future developments will enable researchers to explore gene mutations and health effects caused by environmental agents.

Developing New Goals

In developing the new goals, an NIH-DOE working group sought advice from scientists, other interested scholars, and public representatives, including many outside the Human Genome Project. (Reports of these meetings are available from HGMIS and the NCHGR Office of Communications.

The plan was presented to and approved by the NIH National Advisory Council for Human Genome Research and the DOE Health and Environmental Research Advisory Committee.

The following are some general observations underlying specific new goals.

Technology Development.This will continue to be crucial to future program success, particularly in the area of large-scale DNA sequencing. Accomplishments that influence research strategies include new types of genetic markers (i.e., microsatellites) assayable by the polymerase chain reaction (PCR); improved vector systems for cloning large DNA fragments and methods for assembling clones into physical maps; use of sequence tagged sites (STSs) as common physical mapping entities; and improved DNA sequencing technology and automation.

Future Mapping Efforts. These efforts should focus on regions both larger and smaller than a single chromosome, the basic unit of genome analysis to date. (An ‘average’ human chromosome contains about 150 Mb.) Production of whole-genome low-resolution maps is now feasible due to PCR and robotic developments. Increasing attention needs to be paid to fine-detail mapping of smaller DNA regions (one to a few mega¬bases) as well. One million bases is an ambitious dimension for detailed analysis, the plan says, and will provide a ‘useful bridge’ between conventional genetics and larger-scale genomics research as well as a ‘foundation for innovation’ to develop methods with applicability to larger regions. Planners note that progress already achieved allows greater focus on gene information to enrich the maps produced.

Specific goals covering the period between October 1, 1993, and September 30, 1998, have been established. More details pertaining to these goals are given below.

Genetic Map Researchers expect that the genetic map specified in the first 5-year plan will be completed on time, but technological improvements are needed to allow rapid typing of families by nonexperts and simultaneous multimarker testing of large numbers of individuals by researchers studying complex genetic diseases. Also needed are methods for automated polymorphic marker screening and new gene mapping strategies not based on a standard set of polymorphic markers.

Physical Map. An STS-based physical map of the human genome with an average resolution of about 300 kb will be completed within 2 to 3 years. Because this level of detail is not sufficiently useful to either gene mappers or sequencers, the plan calls for markers placed at 100-kb intervals. Such a map would be useful to researchers using conventional methods to isolate genes localized within 100 kb of a mapped marker or in DNA-sequencing preparations.

To facilitate gene finding and DNA sequencing, new approaches are needed for constructing higher-resolution maps and for cloning systems closely tied to development of sequencing technology. The plan also recommends improving clone libraries with regard to stability and chimerism and increasing their accessibility.

DNA Sequencing. Although sequencing costs will meet the original 1996 goal of $0.50/bp, planners estimate that $100 million per year will be needed to develop sequencing technology of sufficient sequencing rate to permit the entire human genome to be sequenced by 2005. Further cost reduction and increased ability to assess sequence accuracy are also critical. The plan recommends expanding the number of groups working on large-scale sequencing, improving conventional gel-based approaches, and developing revolutionary new methods.

Gene Identification. Mapping progress and technological improvements have now enabled project planners to specify the development of gene identification technology as a new goal. Incorporating genes into the rapidly growing body of maps and sequences of both human and model organism genomes will make these resources more useful to researchers exploring their effects on human health.

Technology Development. Cooperation is encouraged in developing vital new technologies, especially automation and robotics, that are expandable and exportable to basic science laboratories sequencing genomes not being studied in the Human Genome Project.

Model Organisms. Original goals will probably be exceeded for the mouse genetic map, Drosophila melanogaster physical map, and DNA sequencing of Escherichia coliSacharomyces cerevisiae, and Caenorhabditis elegans. Priorities include completion of the mouse map and sequencing of specified model organisms.

Informatics. Although much progress has been made, further development of accessible, user-friendly tools to collect, organize, and interpret vast amounts of data continues to be crucial to the success of the project. Major future goals are data management, analysis, and distribution.

ELSI. ELSI discussions are tied to both genomic research and use of the data it produces. Initial policy options regarding this use are being developed for four areas identified as having the greatest immediate potential impact on society: privacy, fairness, clinical applications, and professional and public education. Reports on the full range of issues will continue to be presented during the next 2 years. Policymakers must consider cultural and other social influences as they prepare policies that anticipate the increasing impact on the public of widespread genetic testing for common conditions. Also recommended and encouraged are the active involvement of concerned individuals and groups in developing policy options as well as increased public and professional education at all levels to prevent stigmatization and discrimination.

Training. Because of the increased number of genome centers, more high-quality training programs are expected to be established to meet the need for interdisciplinary training of scientists for genome research.

Technology Transfer. Many new companies have already been established to develop applications of genome research, and collaborations between government-funded genome scientists and the private sector have increased. The plan encourages further cooperation with industry but cautions that care must be taken to avoid conflicts of interest. Technology transfer from other fields to genome centers must also occur.

Outreach. The private sector is encouraged (with seed funding in some cases) to establish distribution centers for genome materials and respond quickly to the evolving needs of the scientific community. The policy on data and material sharing (within 6 months of creation) has been well accepted.

Article adapted from Science 262, 43-46 (October 1, 1993). Reprints are available from HGMIS and the NCHGR Office of Communications.