U.S. HGP on Fast Track for Early Completion

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By:Aaron Hall

In September 1998, advisory committees at DOE and NIH approved new 5-year goals aimed at completing the Human Genome Project (HGP) 2 years earlier than originally planned in 1990. The target date of 2003 also will mark the 50th anniversary of Watson and Crick's description of DNA's fundamental structure.

The new plan was published in the October 23, 1998, issue of Science, which also cited the contributions of international partners. These partners include the Sanger Centre in the United Kingdom and research centers in Germany, Japan, and France.

The U.S. HGP began officially in 1990 as a $3-billion, 15-year program to find the estimated 80,000 human genes and determine the sequence of the 3 billion DNA building blocks that underlie all of human biology and its diversity. The early phase of the HGP was characterized by efforts to create the biological, instrumentation, and computing resources necessary for efficient production-scale DNA sequencing. The first 5-year plan was revised in 1993 due to remarkable technological progress, and the second plan projected goals through FY 1998. The latest plan was developed during a series of individual and joint DOE and NIH workshops held over the past 2 years (see box, p. 3).

Observers have predicted that the 21th century will be the "biology century." The analytical power arising from the reference DNA sequences of several entire genomes and other genomic resources is anticipated to help jump start the new millennium.

Human DNA Sequencing

The HGP's continued emphasis is on obtaining a complete and highly accurate reference sequence (1 error in 10,000 bases) that is largely continuous across each human chromosome. Scientists believe that knowing this sequence is critically important for understanding human biology and for applications to other fields.

The plan calls for generating a "working draft" of the human genome DNA sequence by 2001. The working draft will comprise shotgun sequence data from mapped clones, with gaps and ambiguities unresolved. If these data sets can be merged with those from the private sector, they may increase the depth of the mapped draft, which scientists expect will contain about half the genes. Draft sequence will provide a foundation for obtaining the high-quality finished sequence and also will be a valuable tool for researchers hunting disease genes.

According to Ari Patrinos, DOE Associate Director for Biological and Environmental Research, "Although we have as our primary goal the finished Book of Life' by the end of 2003, we also want the working draft to be as useful as possible."

NIH and DOE sequencing centers expect their facilities to generate about 60% to 70% of the human DNA sequence, which will be made available broadly and rapidly via the Web to stimulate further research.

Sequencing Technology

Although current sequencing capacity is far greater than at the inception of the HGP, achieving the new sequencing goals will require a two- to threefold improvement. Further incremental advances in sequencing technologies, efficiency, and cost will be needed. For future sequencing applications, planners emphasize the importance of supporting novel technologies that may be 5 to 10 years in development.

Sequence Variation

A new goal focuses on identifying individual variations in the human genome. Although more than 99% of human DNA sequences are the same across the population, variations in DNA sequence can have a major impact on how humans respond to disease; environmental insults such as bacteria, viruses, toxins, and chemicals; and drugs and other therapies.

Methods are being developed to detect different types of variation, particularly the most common type called single-nucleotide polymorphisms (SNPs), which occur about once every 100 to 300 bases. Scientists believe SNP maps will help them identify the multiple genes associated with such complex diseases as cancer, diabetes, vascular disease, and some forms of mental illness. These associations are difficult to establish with conventional gene-hunting methods because a single altered gene may make only a small contribution to disease risk.

Functional Genomics

Efficient interpretation of the functions of human genes and other DNA sequences requires that resources and strategies be developed to enable large-scale investigations across whole genomes. A technically challenging first priority is to generate complete sets of full-length cDNA clones and sequences for human and model-organism genes. Other functional-genomics goals include studies into gene expression and control, creation of mutations that cause loss or alteration of function in nonhuman organisms, and development of experimental and computational methods for protein analyses.

Comparative Genomics

The functions of human genes and other DNA regions often are revealed by studying their parallels in nonhumans. To enable such comparisons, HGP researchers have obtained complete genomic sequences for the bacterium Escherichia coli, the yeast Saccharomyces cerevisiae, and the roundworm Caenorhabditis elegans. Sequencing continues on Drosophila melanogaster and the laboratory mouse. The availability of complete genome sequences generated both inside and outside the HGP is driving a major breakthrough in fundamental biology as scientists compare entire genomes to gain new insights into evolutionary, biochemical, genetic, metabolic, and physiological pathways. HGP planners stress the need for a sustainable sequencing capacity to facilitate future comparisons.

Ethical, Legal, and Social Implications (ELSI)

Rapid advances in the science of genetics and its applications present new and complex ethical and policy issues for individuals and society. ELSI programs that identify and address these implications have been an integral part of the U.S. HGP since its inception. These programs have resulted in a body of work that promotes education and helps guide the conduct of genetic research and the development of related medical and public policies.

A continuing challenge is to safeguard the privacy of individuals and groups who contribute DNA samples for large-scale sequence-variation studies. Other concerns are to anticipate how the resulting data may affect concepts of race and ethnicity; identify potential uses (or misuses) of genetic data in workplaces, schools, and courts; identify commercial uses; and foresee impacts of genetic advances on the concepts of humanity and personal responsibility.

Bioinformatics and Computational Biology

Continued investment in current and new databases and analytical tools is critical to the success of the HGP and to the future usefulness of the data it produces. Databases must adapt to the evolving needs of the scientific community and must allow queries to be answered easily. Planners suggest developing a human genome database, analogous to model organism databases, that will link to phenotypic information. Also needed are databases and analytical tools for studying the expanding body of gene-expression and functional data, for modeling complex biological networks and interactions, and for collecting and analyzing sequence-variation data.

Training

Planners note that future genomic scientists will require training in interdisciplinary areas that include biology, computer science, engineering, mathematics, physics, and chemistry. Additionally, scientists with management skills will be needed for leading large data-production efforts.

The HGP already has revolutionized biology by providing tools and resources for basic research and has catalyzed the growth of the life sciences industry. Current and potential applications of genome research address national needs in molecular medicine, waste control and environmental cleanup, agriculture and animal husbandry, biotechnology, energy sources, and risk assessment.

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