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UNDERSTANDING OUR GENETIC INHERITANCE
THE U.S. HUMAN GENOME PROJECT

The First Five Years: Fiscal Years 1991-1995

I. INTRODUCTION

The Human Genome Initiative is a worldwide research effort that has the goal of analyzing the structure of human DNA and determining the location of all human genes. In parallel with this effort, the DNA of a set of model organisms will be studied to provide the comparative information necessary for understanding the functioning of the human genome. The information generated by the human genome project is expected to be the source book for biomedical science in the 21st century. It will have a profound impact on and expedite progress in a variety of biological fields, including those such as developmental biology and neurobiology, where scientists are just beginning to understand the underlying molecular mechanisms. The analysis and interpretation of the information will occupy scientists for many years to come. Thus, the maximal benefit of the human genome project will only be achieved if it is surrounded by research efforts that are focussed on understanding and taking advantage of the human genetic information.

The human genome project is expected to immensely benefit medical science. It will help us to understand and eventually treat many of the more than 4000 genetic diseases that afflict mankind, as well as the many multifactorial diseases in which genetic predisposition plays an important role. New technologies emanating from the genome project will also find application in other fields such as agriculture and the environmental sciences. They will be valuable for assessing the effects of radiation and other environmental factors on human genetic material.

It is anticipated that the private sector will derive great benefit from the trained manpower, the data, and the techniques developed by the human genome program and will develop many useful applications based on the new knowledge that is produced. Within a few years, DNA sequence information will undoubtedly be a major tool in most areas of basic and applied biological research.

As a result of the enormous strides in basic research on molecular and medical genetics in the last 30 to 40 years, technology has advanced to a stage of development at which such a project can realistically be contemplated. Because of the farsighted investment in basic research by the federal government over this time period, the United States is clearly the leader in this field. Pursuit of the human genome project will allow the United States to remain at the forefront of biomedical science and to train the scientific manpower that will be able to take advantage of the immense opportunities for research and innovation emanating from this project.

The possibility of initiating such a major and significant research program was extensively discussed in the scientific community during 1986 and 1987. In the spring of 1987, a Report on the Human Genome Initiative was prepared by the Health and Environmental Research Advisory Committee (HERAC) of the Department of Energy (DOE). In early 1988, further discussion culminated in the publication of two additional, widely circulated, influential reports. The U.S. Congress' Office of Technology Assessment (OTA) report presented a comprehensive and detailed analysis of the scientific developments that had led to the promise of "mapping and sequencing" the human genome and presented a number of options as to how the United States might pursue such a project. The National Research Council (NRC) report recommended that the United States support the research effort and presented an outline for a multi-phase research plan for accomplishing the goal of sequencing human DNA over the course of the following two decades. A report to the Director of the National Institutes of Health (NIH) by the Ad Hoc Advisory Committee on Complex Genomes, also prepared in 1988, concurred with the NRC Report.

In fiscal year 1988, the Congress of the United States launched the human genome project by appropriating funds to both the DOE and the NIH specifically for support of research efforts to determine the structure of complex genomes. In the report accompanying the Senate appropriations bill for FY 1989, the Congress requested the NIH to prepare, by early 1990, a report on the optimal strategy for the conduct of the human genome program. The FY 1990 House Appropriations Committee report also asked the NIH for a comprehensive spending plan by the time of the FY 1991 appropriations hearings.

Prepared in response to those requests, the present report contains a summary of the progress that has been made in the field of genome research since the preparation of the OTA and NRC reports and presents a plan for the human genome program, with emphasis on the next five year period. Because the two agencies have been collaborating closely for the past two years in the management of the program, this plan was prepared jointly by the NIH and the DOE. The agencies plan to revise the plan approximately annually, based on the latest scientific developments.

II. PROGRAM GOALS

It is generally agreed that the overall goal of the Human Genome Initiative is to acquire fundamental information needed to further our basic scientific understanding of human genetics and of the role of various genes in health and disease. The premise is that this can be done much more efficiently, and in a more cost-effective manner, as a targeted and coordinated program. Thus, we obtain valuable basic information in the least expensive way while increasing the "benefit to cost" ratio for genetics research in general.

As refined through the discussions over the last half of the 1980's and defined in the NRC report, the Human Genome Initiative has several interrelated goals:

construction of a high-resolution genetic map of the human genome;
production of a variety of physical maps of all human chromosomes and of the DNA of selected model organisms, with emphasis on maps that make the DNA accessible to investigators for further analysis;
determination of the complete sequence of human DNA and of the DNA of selected model organisms;
development of capabilities for collecting, storing, distributing, and analyzing the data produced;
creation of appropriate technologies necessary to achieve these objectives.

At the time the NRC and OTA reports were written, the consensus of the scientific community was that state of the art technology was sufficient for the development of detailed genetic and limited physical maps. That technology, however, was not considered sufficient for completion of the physical map of a genome as large and complex as that of the human. Nor was the technology available for DNA sequencing considered to be adequate for the task of sequencing the 3 billion base pairs of human DNA. At that time, the largest continuous human sequence that had been determined was that of the human growth hormone gene, only 67,000 nucleotides long.

Thus, the NRC committee and others recommended a multi-phase program, in which the initial phase would consist of:

expansion of the human genetic map to a resolution of one centimorgan;
construction of complete physical maps of the DNA of certain model organisms and beginning the construction of physical maps of human chromosomes;
development of new technology to increase the efficiency and accuracy, and lower the cost, of physical mapping and of DNA sequencing.

In these recommendations, the task of sequencing the complete human DNA was reserved to a later phase, one that would only be embarked upon if methods could be developed that would allow the sequence to be obtained at a reasonable cost. The overall program was expected to take at least fifteen years to complete. Technology development was to be an integral part of the project throughout.

This general plan is still appropriate, but some of the details must be changed as improvements in the technology have occurred in the last two years. In order to prepare the present report, advisors to and staff of the NIH and the DOE have joined forces to examine the state of the science and develop the plan to be followed over the next five years. This document represents the consensus of the two agencies regarding the conduct of genome research and will be updated periodically.

The rosters of the various advisory groups that participated in the plan's development are appended [Appendices not included here]. These are the Health and Environmental Research Advisory Committee (HERAC) of the DOE (Appendix 1), and the Program Advisory Committee on the Human Genome (PACHG) of the NIH (Appendix 2). The primary working group for these committees was the joint subcommittee of the HERAC and the PACHG (Appendix 3) that was specified in the NIH-DOE Memorandum of Understanding (see below and Appendix 4), supplemented by additional experts (Appendix 5).

The plan addresses specific scientific goals to be achieved in the next five years in the following areas:

Mapping and Sequencing the Human Genome
Mapping and Sequencing the DNA of Model Organisms
Data Collection and Distribution
Ethical, Legal, and Social Considerations
Research Training
Technology Development
Technology Transfer

Also presented are the implementation strategies that will be used to achieve these goals with respect to:

Administration of Research
Roles of NIH and DOE
Roles of Other Federal Agencies
International Collaboration

Finally, the report addresses budget projections. The five year period covered by the plan will begin with FY 1991. It is assumed that funding levels for the combined NIH and DOE programs will rapidly reach the level recommended by the NRC report, approximately $200 million per year, adjusted for inflation. Although five year goals are presented with some specificity, and although substantial progress has been made in technology development in the past two years, it must be stressed that the next five years will still be a time in which rapid advances in methods and strategies will be necessary if the program is to meet the goals outlined. Extreme flexibility and diligence on the part of program management, for both the research and its administration, will be needed during this period of experimentation and technological development.

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File posted April 3, 1995.

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UNDERSTANDING OUR GENETIC INHERITANCE THE U.S. HUMAN GENOME PROJECT

The First Five Years: Fiscal Years 1991-1995

I. INTRODUCTION

II. PROGRAM GOALS

UNDERSTANDING OUR GENETIC INHERITANCE
THE U.S. HUMAN GENOME PROJECT