International Consortium Completes Human Genome Project

“From the beginning, one of the operating principles of the Human Genome Project has been that the data and resources it has generated should rapidly be made available to the entire scientific community,” said Robert Waterston, M.D., Ph.D., of the University of Washington, Seattle. “Not only does the rapid release of data promote the best interests of science, it also maximizes the benefits that the public receives from such research.”

In 1996, at a meeting in Bermuda, Dr. Waterston and John Sulston, Ph.D., then director of the Sanger Centre (now The Wellcome Trust Sanger Institute), led the International Human Genome Sequencing Consortium to adopt the so-called “Bermuda Principles,” which expressly call for automatic, rapid release of sequence assemblies of 2,000 bases or greater to the public domain.

Scientists have been quick to mine this new trove of genomic data, as well as to utilize the genomic tools and technologies developed by the Human Genome Project. For example, when the Human Genome Project began in 1990, scientists had discovered fewer than 100 human disease genes. Today, more than 1,400 disease genes have been identified.

For scientists seeking to understand the role of genetics in human health and disease, the Human Genome Project's finished sequence represents a significant advance over the "working draft" that was announced in June 2000. The working draft covered 90 percent of the gene-containing part of the sequence, 28% of which had reached finished form, and contained about 150,000 gaps. The finished version of the human genome now contains 99 percent of the gene-containing sequence, with the missing parts essentially contained in less than 400 defined gaps.

These remaining gaps represent regions of DNA in the genome with unusual structures that cannot be reliably sequenced with current technology. These regions, however, appear to contain very few genes. Closing these gaps will require individual research projects and new technologies, rather than industrial-scale efforts of the Human Genome Project. The high-throughput sequencing of the human genome has thus reached its natural conclusion.

“This is the day that our planning group dreamed of,” said Bruce Alberts, Ph.D., chairman of the 1988 National Research Council Committee on Mapping and Sequencing the Human Genome, which produced the original recommendations for the Human Genome Project. “And the quality of the sequence would have amazed us. In 1988, we weren't sure that accuracy rates of 99.9 percent were possible, and we were uncertain that continuity over distances of millions of base pairs could be achieved. The finished human sequence is a fabulous outcome. Biomedical researchers now have tremendous foundation on which to build the science and medicine of the 21st century.” Dr. Alberts is now the president of the National Academy of Sciences.

In addition to the improved accuracy, the average DNA letter now sits on a stretch of 27,332,000 base pairs of uninterrupted, high-quality sequence – about 334 times longer than the 81,900 base-pair stretch that was available in the working draft. Access to uninterrupted stretches of sequenced DNA can make a major difference to researchers hunting for genes, dramatically cutting the effort and expense required to search regions of the human genome that may contain small and often rare mutations involved in disease.

"The Human Genome Project represents one of the remarkable achievements in the history of science. Its culmination this month signals the beginning of a new era in biomedical research,” said Eric Lander, Ph.D., director of the Whitehead-MIT Center for Genome Research. “Biology is being transformed into an information science, able to take comprehensive global views of biological systems. With knowledge of all the components of the cells, we will be able to tackle biological problems at their most fundamental level.”

The essentially complete version of the human genome sequence also represents a major boon to the growing field of comparative genomics: researchers are attempting to learn more about human genetic makeup and function by comparing our genomic sequence to that of other organisms, such as the mouse, the rat or even the fruit fly.

“One of the most powerful tools for understanding our own genome is to study it within the context of a much larger framework. That framework is being created by ongoing efforts to sequence and analyze the genomes of many other organisms,” said Richard Gibbs, Ph.D., director of Baylor College of Medicine's Human Genome Sequencing Center. “As we identify the similarities – and the differences – among the genes of mammals and other organisms, we will begin to gain valuable new insights into human evolution, as well as human health and disease.”

The impact of the Human Genome Project, however, extends far beyond laboratory analysis. Under the guidance of Dr. Watson, the Human Genome Project became the first large scientific undertaking to dedicate a portion of its budget for research to the ethical, legal and social implications (ELSI) of its work. NHGRI and DOE each set aside 3 to 5 percent of their genome budgets to study how the exponential increase in knowledge about human genetic make-up may affect individuals, institutions and society. An example of how ELSI research has helped to inform public policy is the fact that more than 40 states in the United States have passed genetic non-discrimination bills, many based on model language that grew out of this research. These efforts will be even more crucial in the coming years as the results of genomic research begin to appear in the clinic.

“Achieving the goals of the Human Genome Project is a historic milestone. But this is no time to rest and relax,” said Dr. Collins. “With this foundation of knowledge firmly in place, the medical advances promised from the project can now be significantly accelerated.”

To spur such acceleration, NHGRI's “A Vision for the Future of Genomics Research” sets forth a series of "Grand Challenges" intended to energize the scientific community in using the newfound understanding of the genome to uncover the causes of disease and to develop bold new approaches to the prevention and treatment of disease. The plan was the outcome of more than a year of intense discussions with nearly 600 scientific and public leaders from government, academia, non-profit organizations and the private sector.

In the publication in Nature, the challenges facing genomic research are depicted as a three-story house rising from the foundation of the Human Genome Project. The three floors, representing the three major thrusts of this new vision – Genomics to Biology, Genomics to Health and Genomics to Society – are interconnected by vertical supports, representing computational biology, ELSI, education, training, technology development and resources.

Many of the challenges in the vision are aimed at utilizing genome research to combat disease and improve human health. The recommendations include calls for researchers to work toward:

• New tools to allow discovery in the near future of the hereditary contributions to common diseases, such as diabetes, heart disease and mental illness.
• New methods for the early detection of disease.
• New technologies that can sequence the entire genome of any person for less than $1,000.
• Wider access to tools and technologies of “chemical genomics” to improve the understanding of biological pathways and accelerate drug discovery.

NHGRI and its partners in genome research have already begun tackling a number of these challenges. For example, in November 2002, a team of researchers from six nations launched the International HapMap Project, an effort to produce a map of common human genetic variations aimed at speeding the search for genes that contribute to cancer, diabetes, heart disease, schizophrenia and many other common conditions.

"The completion of the Human Genome Project should not be viewed as an end in itself. Rather, it marks the start of an exciting new era – the era of the genome in medicine and health," said Dr. Collins. "We firmly believe the best is yet to come, and we urge all scientists and people around the globe to join us in turning this vision into reality."

NHGRI's U.S. partner in the Human Genome Project, DOE, has also developed its own forward-looking plan for genome research. The DOE plan, published in the April 11 issue of the journal Science, is focused on understanding the ways in which microbes can provide new opportunities for developing clean energy, reducing climate change and cleaning the environment. To achieve that vision, DOE has begun the “Genomes to Life” program, which will combine research in biology, engineering and computation with the development of novel facilities for high-throughput biology projects.

NHGRI is one of the 27 institutes and centers at the National Institutes of Health, an agency of the Department of Health and Human Services (DHHS). Additional information about NHGRI can be found at its Web site, www.genome.gov.

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