| ember 1998, advisory committees at DOE and | | | | type called single-nucleotide polymorphisms (SNPs), |
| NIH approved new 5-year goals aimed at | | | | which occur about once every 100 to 300 bases. |
| completing the Human Genome Project (HGP) 2 | | | | Scientists believe SNP maps will help them identify |
| years earlier than originally planned in 1990. The | | | | the multiple genes associated with such complex |
| target date of 2003 also will mark the 50th | | | | diseases as cancer, diabetes, vascular disease, and |
| anniversary of Watson and Crick's description of | | | | some forms of mental illness. These associations |
| DNA's fundamental structure. | | | | are difficult to establish with conventional |
| The new plan was published in the October 23, | | | | gene-hunting methods because a single altered |
| 1998, issue of Science, which also cited the | | | | gene may make only a small contribution to |
| contributions of international partners. These | | | | disease risk. |
| partners include the Sanger Centre in the United | | | | Functional Genomics |
| Kingdom and research centers in Germany, Japan, | | | | Efficient interpretation of the functions of human |
| and France. | | | | genes and other DNA sequences requires that |
| The U.S. HGP began officially in 1990 as a $3-billion, | | | | resources and strategies be developed to enable |
| 15-year program to find the estimated 80,000 | | | | large-scale investigations across whole genomes. |
| human genes and determine the sequence of the | | | | A technically challenging first priority is to generate |
| 3 billion DNA building blocks that underlie all of | | | | complete sets of full-length cDNA clones and |
| human biology and its diversity. The early phase | | | | sequences for human and model-organism genes. |
| of the HGP was characterized by efforts to | | | | Other functional-genomics goals include studies into |
| create the biological, instrumentation, and | | | | gene expression and control, creation of |
| computing resources necessary for efficient | | | | mutations that cause loss or alteration of function |
| production-scale DNA sequencing. The first 5-year | | | | in nonhuman organisms, and development of |
| plan was revised in 1993 due to remarkable | | | | experimental and computational methods for |
| technological progress, and the second plan | | | | protein analyses. |
| projected goals through FY 1998. The latest plan | | | | Comparative Genomics |
| was developed during a series of individual and | | | | The functions of human genes and other DNA |
| joint DOE and NIH workshops held over the past | | | | regions often are revealed by studying their |
| 2 years (see box, p. 3). | | | | parallels in nonhumans. To enable such |
| Observers have predicted that the 21th century | | | | comparisons, HGP researchers have obtained |
| will be the "biology century." The analytical power | | | | complete genomic sequences for the bacterium |
| arising from the reference DNA sequences of | | | | Escherichia coli, the yeast Saccharomyces |
| several entire genomes and other genomic | | | | cerevisiae, and the roundworm Caenorhabditis |
| resources is anticipated to help jump start the | | | | elegans. Sequencing continues on Drosophila |
| new millennium. | | | | melanogaster and the laboratory mouse. The |
| Human DNA Sequencing | | | | availability of complete genome sequences |
| The HGP's continued emphasis is on obtaining a | | | | generated both inside and outside the HGP is |
| complete and highly accurate reference sequence | | | | driving a major breakthrough in fundamental |
| (1 error in 10,000 bases) that is largely continuous | | | | biology as scientists compare entire genomes to |
| across each human chromosome. Scientists | | | | gain new insights into evolutionary, biochemical, |
| believe that knowing this sequence is critically | | | | genetic, metabolic, and physiological pathways. |
| important for understanding human biology and | | | | HGP planners stress the need for a sustainable |
| for applications to other fields. | | | | sequencing capacity to facilitate future |
| The plan calls for generating a "working draft" of | | | | comparisons. |
| the human genome DNA sequence by 2001. The | | | | Ethical, Legal, and Social Implications (ELSI) |
| working draft will comprise shotgun sequence | | | | Rapid advances in the science of genetics and its |
| data from mapped clones, with gaps and | | | | applications present new and complex ethical and |
| ambiguities unresolved. If these data sets can be | | | | policy issues for individuals and society. ELSI |
| merged with those from the private sector, they | | | | programs that identify and address these |
| may increase the depth of the mapped draft, | | | | implications have been an integral part of the U.S. |
| which scientists expect will contain about half the | | | | HGP since its inception. These programs have |
| genes. Draft sequence will provide a foundation | | | | resulted in a body of work that promotes |
| for obtaining the high-quality finished sequence and | | | | education and helps guide the conduct of genetic |
| also will be a valuable tool for researchers hunting | | | | research and the development of related medical |
| disease genes. | | | | and public policies. |
| According to Ari Patrinos, DOE Associate Director | | | | A continuing challenge is to safeguard the privacy |
| for Biological and Environmental Research, | | | | of individuals and groups who contribute DNA |
| "Although we have as our primary goal the | | | | samples for large-scale sequence-variation studies. |
| finished Book of Life' by the end of 2003, we also | | | | Other concerns are to anticipate how the resulting |
| want the working draft to be as useful as | | | | data may affect concepts of race and ethnicity; |
| possible." | | | | identify potential uses (or misuses) of genetic |
| NIH and DOE sequencing centers expect their | | | | data in workplaces, schools, and courts; identify |
| facilities to generate about 60% to 70% of the | | | | commercial uses; and foresee impacts of genetic |
| human DNA sequence, which will be made | | | | advances on the concepts of humanity and |
| available broadly and rapidly via the Web to | | | | personal responsibility. |
| stimulate further research. | | | | Bioinformatics and Computational Biology |
| Sequencing Technology | | | | Continued investment in current and new |
| Although current sequencing capacity is far | | | | databases and analytical tools is critical to the |
| greater than at the inception of the HGP, | | | | success of the HGP and to the future usefulness |
| achieving the new sequencing goals will require a | | | | of the data it produces. Databases must adapt to |
| two- to threefold improvement. Further | | | | the evolving needs of the scientific community |
| incremental advances in sequencing technologies, | | | | and must allow queries to be answered easily. |
| efficiency, and cost will be needed. For future | | | | Planners suggest developing a human genome |
| sequencing applications, planners emphasize the | | | | database, analogous to model organism |
| importance of supporting novel technologies that | | | | databases, that will link to phenotypic information. |
| may be 5 to 10 years in development. | | | | Also needed are databases and analytical tools for |
| Sequence Variation | | | | studying the expanding body of gene-expression |
| A new goal focuses on identifying individual | | | | and functional data, for modeling complex biological |
| variations in the human genome. Although more | | | | networks and interactions, and for collecting and |
| than 99% of human DNA sequences are the | | | | analyzing sequence-variation data. |
| same across the population, variations in DNA | | | | Training |
| sequence can have a major impact on how | | | | Planners note that future genomic scientists will |
| humans respond to disease; environmental insults | | | | require training in interdisciplinary areas that include |
| such as bacteria, viruses, toxins, and chemicals; | | | | biology, computer science, engineering, |
| and drugs and other therapies. | | | | mathematics, physics, and chemistry. Additionally, |
| Methods are being developed to detect different | | | | scientists with management skills will be needed |
| types of variation, particularly the most common | | | | for leading large data-production efforts. |