The decision does not specifically launch large-scale sequencing on any of these organisms. Rather, it creates a pool of candidate organisms on which the institute-supported sequencing centers can choose to begin working as capacity becomes available. NHGRI supports large-scale sequencing at the Whitehead Institute/MIT Center for Genome Research in Cambridge, Mass., the Genome Sequencing Center at Washington University School of Medicine in St. Louis, Mo., and the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Tex. Since the sequencing capacity of these centers is currently committed to the human, mouse, and rat projects, new genomic sequencing efforts may not start for some months. Before the centers can start sequencing any of these other organisms, they must get final permission from NHGRI. The institute will indicate on its website when a sequencing center has begun sequencing one of these organisms, as well as the strategy to be employed, and a timetable for the project.
"We've recently learned surprising things by comparing the mouse to the human genome," said Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute, a part of the National Institutes of Health. "The addition of other genomes helps us find the important parts of the genome that have been conserved. For example, we already have good matches between 22,500 genes in the mouse with genes identified in human. But that leaves more than half of the closest matches between the mouse and human genome without an explanation. These matching regions are highly conserved and must be important, but we don't yet know what they do."
Acquiring the sequence of various genomes is driving the development of a new field of biological research called comparative genomics. By comparing the genomes of different organisms, researchers can understand the structure and function of the human genome. It also will provide a powerful tool for studying evolution. Currently, researchers are completing analysis of the human, mouse and rat genomes. A number of other organisms also have been sequenced, including a long list of microbes, yeast, fruit fly, roundworm, rice and a plant called Arabidopsis thaliana.
"The best way to tease out the secrets of the human genome is to compare it with the other organisms' genomes," said Eric Lander, director of Whitehead Institute/MIT Center for Genome Research. "By finding the features that evolution has carefully preserved over hundreds of millions of years, we should be able to pinpoint the signals that control gene function. This information will, in turn, translate into practical biomedical knowledge that will spur the development of better therapies in the future."
An evolutionary perspective should also prove valuable for medical researchers. "Chimpanzees, for example, do not suffer from some of the diseases that strike humans, such as malaria and AIDS," said Robert H. Waterston, M.D., Ph.D., director of the Washington University School of Medicine sequencing center. "If we see genetic variants in the human population that we don't see in chimp, then we'll know that the genetic change occurred after humans evolved from the non-human primates and may be important for disease susceptibility."
The successful sequencing of the human genome showed that such large projects could be done for a reasonable cost and that the sequence data are of inestimable value for biomedical research. As a result, interest in sequencing the genomes of many other organisms has risen dramatically.
Last summer, NHGRI gathered leading researchers interested in various experimental organisms to help the institute decide how to select the next ones to be sequenced. A unique process emerged in which advocates for each experimental model were encouraged to submit white papers to NHGRI (researchers were also encouraged to publish these white papers to stimulate discussion in the research community). The selection process is based on peer review of the white papers by a distinguished panel, with a focus on the scientific issues to be addressed by new sequence data. This process allows the broad scientific community, the sequencing centers, and the NHGRI to participate in a process for setting priorities. New organisms will be prioritized for genomic sequencing on the basis of specific, well-defined scientific goals. The specific instructions for preparing a white paper proposal for sequencing a new organism are posted at http://www.nhgri.nih.gov/About_NHGRI/Der/org_request/seq_target_genome.html.
"This selection of high-priority organisms will bracket some of the most important evolutionary transitions," said Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center. "The white papers are the ticket to the 21st century Noah's Ark."
The first set of white papers was submitted in February 2002 and reviewed by a new NHGRI review group called the Genome Resources and Sequencing Priority Panel (GRASPP) in March 2002. The review included an assessment of the medical importance of the proposed project, its importance to basic biological and evolutionary studies, the size of the research community interested in the DNA sequence, and the availability of additional research tools that would allow investigators to take maximal advantage of the new genomic sequence data. Based on this assessment, proposals were ranked as high, moderate, or low priority, with no intention of providing rankings within each category.
The panel's recommendations were then reviewed by the National Advisory Council for Human Genome Research and approved at its May 21, 2002, meeting. Before sequencing can begin, a center must show that it has capacity to commit to a new sequencing project. The center's principal investigator will need to negotiate with NHGRI to select the next organism to sequence from the approved priority list, and the investigator will prepare a detailed plan, including a strategy and timetable for sequence. The plan will then be reviewed by the Sequencing Advisory Panel (SAP); approval by the SAP will be necessary, and sufficient, for the sequencing project to begin.
The list of organisms that were accorded either high or moderate priority, and the white papers themselves, will be posted at http://www.nhgri.nih.gov/DER/Sequencing/proposals.html. The organisms judged to be of high priority for sequencing and the rationale for the recommendation are (listed in alphabetical order):
- Chicken (Gallus gallus)-The chicken is widely used as a non-mammalian vertebrate system for investigating several important biomedical research problems, including the development of the embryo (particularly the nervous system) and the causes of birth defects. It is the only avian (bird) system with sufficient research resources currently in place to justify a genome-sequencing project. The chicken genome sequence is also important in agriculture; the U.S. Department of Agriculture has expressed interest in helping to support the project and discussions are underway about possible co-funding by NHGRI and USDA.
- Chimpanzee (Pan troglodytes)-The interest in sequencing the chimpanzee genome arises from its very close relationship to the human; there is only 1.2% sequence divergence between the two genomes. It may be possible to better understand the distinct differences between the two organisms by studying the two sequences. Comparing the human and chimp genomes, in particular, may provide insights into human diseases because there are a number of medical conditions that affect humans but not chimpanzees. Chimpanzees themselves cannot -- and will not -- be used in any experimental studies. A working group will be established to advise NHGRI on such issues as the appropriate strategy, timetable, and cost. As an additional benefit, it is hoped that the availability of the chimpanzee genome sequence will assist in conservation efforts of the species.
- Fungi (various species)-The genome sequences of a number of fungi are of interest because of their medical significance, evolutionary position, and agricultural and industrial importance. Fungal infections are an important cause of illness, and learning more about the genomes of a set of well-chosen fungi should facilitate the development of better treatments for disease.
- Honey Bee (Apis mellifera)-The honey bee is a very interesting organism from several points of view: 1) its powerful social instincts and unique behavioral traits make it particularly useful to neurobiologists, 2) it is important to the agricultural community in the U.S. as a pollinator, and 3) it is relevant to human health in several ways, including the potentially serious consequences of bee stings, and as a model for antibiotic resistance, immunity, allergic reaction, development, mental health, diseases of the X chromosome and longevity. Because of its agricultural relevance, other federal agencies, such as USDA, are also interested in collaborating on the sequencing of the honeybee genome.
- Sea Urchin (Strongylocentrotus purpuratus)-The sea urchin has been an important model system for many years in the study of basic biology, particularly in developmental biology. The sea urchin occupies an important evolutionary position with respect to vertebrates and humans. There is a large body of information about gene expression in the sea urchin and there are a number of genomic resources available, making the sea urchin an ideal organism for learning how pathways of genes and proteins regulate growth and development, with potentially profound implications for understanding human biology.
- Tetrahymena thermophila -Studies of the protozoan Tetrahymena have made major contributions to genetics and cell biology. Scientists used this organism to study the structure of telomeres (ends of chromosomes) and the telomerase enzyme, which has profound importance in cancer and aging. Tetrahymena research also has shed light on general phenomena of biology including programmed genome rearrangements. Two organisms, a protozoan (Oxytricha trifallax) and the rhesus macaque (Macaca mulatta) were accorded moderate priority for sequencing.
A white paper proposing the sequencing of the cow was deferred. Although there are persuasive reasons to sequence the cow's genome, white papers for other organisms from this evolutionary group (dogs, cats and pigs) have yet to be received, but are expected. The panel felt that it could not prioritize the cow genome without considering the related genomes at the same time. The considerable size of genomes in this group (the same size as the human genome), and budget limitations require careful decision-making. For some of these organisms, such as the cow and pig, there are potential major agricultural benefits that will likely lead to a partnership with the U.S. Department of Agriculture.
"USDA is excited about this new collaboration with NHGRI to sequence the genomes of important agricultural species," said Joseph Jen, Ph.D., USDA Undersecretary for Research, Education and Economics. "The peer review process that has placed the chicken and honey bee in the high priority category is good news to these industries. As coordinator of the newly established Domestic Animal Genome Interagency Work Group (IWG), it is USDA's hope to eventually investigate DNA sequencing of all important livestock species that are an integral part of our nation's food system. We look forward to NHGRI's contributions as an important member of the IWG. This is an excellent example of inter-agency cooperation to leverage the nations infrastructure of high-throughput DNA sequencing."
As researchers submit additional white papers to NHGRI, more organisms will be added to the priority groups that can be sequenced by the centers. NHGRI currently allocates $155 million per year to the support of the sequencing centers. Many other NIH institutes have provided additional funding in the past, usually for specific sequencing projects such as the mouse and rat genomes. Several institutes have already expressed interest in supporting additional sequencing efforts in the future.