"The historic effort to produce a reference sequence of the human genome was successfully completed in April 2003. But our work is far from over. There remains a compelling need to sequence the genomes of many more organisms," said NHGRI Director Francis S. Collins, M.D., Ph.D. "The ability to compare the genomic sequences of different species has opened a powerful new window into how our own genome functions.
"Given the power of such comparisons, there is a growing hunger among biologists and medical researchers for free and publicly available sequence data on a wide variety of organisms. Our sequencing centers will feed that hunger. And the dramatic decrease in the costs of genome sequencing, spurred on by the Human Genome Project, makes production of this data a bargain by any estimate."
Over the next three years, the five centers in NHGRI's Large-Scale Sequencing Research Network will use high-throughput, robotic technologies to sequence a strategic set of animal genomes totaling as much as 54 billion base pairs, or the equivalent of 18 human genomes. For fiscal year (FY) 2004, NHGRI has earmarked $163 million for the sequencing centers, which were selected through a competitive, peer-reviewed process. The centers will be operated under cooperative agreements in which substantial programmatic involvement is anticipated among NHGRI and the recipients during performance of the scientific activities. Funding levels for FY 2005 and 2006 are planned to be $163 million and $133 million respectively.
The NHGRI-supported, large-scale sequencing centers, their principal investigators and their approximate FY 2004 funding levels are: Agencourt Bioscience Corp., Beverly, Mass., Douglas R. Smith, Ph.D., $10 million; Baylor College of Medicine, Houston, Richard Gibbs, Ph.D., $35 million; The Eli & Edythe L. Broad Institute, Massachusetts Institute of Technology (MIT), Eric Lander, Ph.D., Cambridge, Mass., $59 million; The Institute for Genomic Research, J. Craig Venter Science Foundation Joint Technology Center, Rockville, Md., J. Craig Venter, Ph.D., $10 million; and Washington University School of Medicine, Saint Louis, Richard K. Wilson, Ph.D., $49 million.
These centers will make up the NHGRI Large-Scale Sequencing Research Network, encompassing representatives of academia, private industry and the non-profit sector. Their primary mission is to produce a publicly available resource of high quality assembled genome sequences that researchers can use to address human biology and human health. By comparing genome sequences from carefully chosen organisms, scientists are able to identify specific DNA sequences that have been conserved throughout the evolution of different species, which is a strong indicator that these sequences reflect functionally important regions of the genome.
For instance, conserved sequences may be involved in turning genes on and off during development and in regulating how much protein a gene produces in various types of cells. Already, comparative genomic analysis of six species of yeast has prompted scientists to significantly revise their initial catalog of yeast genes and to predict a new set of functional elements thought to play a role in regulating genome activity. Experiments to validate the existence of these and other predicted elements, and study their function within the cell, are expected to enhance understanding of how the human genome works.
Another important goal of the large-scale sequencing program is to develop significant improvements in sequencing efficiency and costs so that sequencing will remain a cutting-edge technology for modern biology. "I am confident that this unparalleled network of sequencing technology and scientific experience will meet and even surpass our ambitious sequencing goals. From the Human Genome Project, we have learned that teamwork really pays off when it comes to scientific discovery," said Dr. Collins, who noted that over the past five years, the MIT, Washington University and Baylor centers were major participants in the highly successful public effort to sequence, assemble and analyze the genomes of the human and several other organisms commonly used in biomedical research.
In addition to sequencing the 3 billion letters in the human genetic instruction book, researchers involved in the Human Genome Project have already sequenced the genomes of a number of important model organisms that are commonly used as surrogates in studying human biology. These are the mouse, the rat, two puffer fish, two fruit flies, two sea squirts, two roundworms, baker's yeast and the bacterium Escherichia coli.
Currently, NHGRI-supported sequencing centers are close to completing working drafts of the genomes of additional organisms that improve the understanding of genomes that have already been sequenced and provide insights into the evolution of humans. The genome sequences of the chimpanzee, the chicken, the sea urchin, the honeybee and a set of four fungi are nearly in draft form. The sequence of the domestic dog, which is a major model for studying genetic diseases and developing pharmaceuticals, is also approaching deep draft coverage. This summer, the centers also began initial sequence production for creating a reference version of the genome of the rhesus macaque, which is a monkey that is widely used in studies of human immunodeficiency virus (HIV) infection.
Other organisms currently on NHGRI's high-priority list for sequencing are: the cow; the South American gray, short-tailed opossum (a marsupial); the red flour beetle; the acorn worm; the flatworm Schmidtea mediterranea; 10 more species of fruit fly; four more species of fungi; and two ciliated microorganisms, Oxytricha trifallax and Tetrahymena thermophila. Details of when those sequencing projects will begin and what centers will participate in each project are being finalized.
"The availability of the human genome sequence, as well as other genomic resources, has profoundly affected biomedical research and thinking. Information about whole genomes is now available for the first time," said NHGRI's Associate Director of Extramural Research Jane Peterson, Ph.D. "Previously, scientists were limited to gaining such information from one gene at a time. By making complete sets of genes from different types of organisms available, we can learn much more about how genes are turned on and off, and how genes interact with each other. The possibilities are endlessly exciting."
To produce a comprehensive plan for the large-scale sequencing program that will yield the most insights into human biology, NHGRI recently instituted a new process for choosing target organisms for comparative sequencing. Rather than placing the entire responsibility for advocating for the sequencing of various organisms upon individual researchers, NHGRI has established three working groups comprised of experts from across the research community. Each working group will develop a well thought-out plan for sequencing organisms that advances knowledge in one of three scientific areas: understanding the human genome, understanding the genomes of major biomedical model systems and evolutionary biology of genomes. Direct requests from researchers will also continue to be accepted and considered together with the working group plans.
"We felt a need for a more coherent approach to selecting sequencing targets. To do so, we needed to establish a process to enable members of the research community to carefully consider and discuss all the alternative targets that could be sequenced to address the goals of our institute, and then select the best target for the purpose," said Dr. Peterson, who is also program director for the NHGRI's Large-Scale Sequencing Research Network.
After evaluating the relative merit of a number of candidate genomes, each working group will formulate an overarching proposal for the genomic sequencing needs relevant to its particular area of science. A newly established coordinating committee will then consolidate the three working groups' recommendations into a proposal for a final priority list of sequencing targets. This will be reviewed by the National Advisory Council for Human Genome Research, which will then forward its recommendations to the NHGRI director. For more information on the new process for selecting sequencing targets, go to: www.genome.gov/Sequencing OrganismSelection.
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). The NHGRI Division of Extramural Research supports grants for research and for training and career development at sites nationwide. Additional information about NHGRI can be found at its Web site, http://www.