As efforts to build working drafts of the honeybee and chimpanzee genomes near completion, scientists are moving forward to sequence the genomes of other important model organisms, including the dog, the National Human Genome Research Institute (NHGRI) reported.
NHGRI director Francis S. Collins, M.D., Ph.D., presented an update on genome sequencing efforts for a wide range of model organisms at Monday's meeting of the National Advisory Council for Human Genome Research (NACHGR), a federally chartered committee that advises NHGRI on program priorities and goals.
"Comparing the human genome sequence with those of other organisms helps us to identify regions of similarity and difference, providing critical clues about the structure and function of human genes. This information should point us toward better strategies for treating and preventing human disease," Dr. Collins said. "With each genome that we sequence, this approach becomes more powerful."
As part of its effort to support the rapidly growing field of comparative genomics, NHGRI has given the green light to a project to sequence the genome of the domestic dog ("Canis familiaris"). The breed of dog to be sequenced is the boxer, which was chosen after analyses of 120 dogs representing 60 breeds showed it was one of the breeds with the least amount of variation in its genome and therefore likely to provide the most reliable reference genome sequence. The actual choice of breed is not terribly crucial since all dog breeds are more than 99 per cent identical at the DNA level. The dog genome project, which is expected to cost about $50 million, will get underway in early June at the Whitehead/MIT Center for Genome Research in Cambridge, Mass.
Over the years, canine models have played a crucial role in advancing biomedical knowledge and techniques, including the development of bone marrow transplantation methods that have saved the lives of thousands of human cancer patients.
In addition, due to a long history of selective breeding, many types of dogs are prone to genetic diseases like cancer, heart disease, deafness, blindness and autoimmune disorders that are very difficult to study in humans. The dog is also an important model for the genetics of behavior and is used extensively in pharmaceutical research.
"Once we are able to compare the dog genome with the human genome, the dog will likely prove to be man's best friend in more ways than we ever imagined," said Dr. Collins, who notes that the genome sequencing effort will also benefit dogs by helping veterinary researchers develop new and better ways of combating canine diseases.
The dog genome is similar in size to the genomes of humans and other mammals, containing an estimated 2.8 billion DNA base pairs. The Whitehead/MIT team expects to complete a high-quality draft of the dog genome sequence within the next 12 months. After the genome of the boxer is sequenced, researchers plan to sample and analyze DNA from 10 to 20 other dog breeds, including the beagle, to study genetic variation within the canine species.
Kerstin Lindblad-Toh, Ph.D., leader of the dog genome project at the Whitehead/MIT Center, said she expects that, for both humans and their pets, the sequencing of the dog genome "will be a wonderful basic resource that will rapidly propel the discovery of disease genes forward."
In April 2003, the International Human Genome Sequencing Consortium, led in the United States by NHGRI and the U.S. Department of Energy, announced the successful completion of the Human Genome Project. In addition to sequencing the 3 billion DNA letters in the human genetic instruction book, researchers involved in the Human Genome Project sequenced the genomes of a number of organisms commonly used in biomedical research, including a bacterium ("Escherichia coli"), baker's yeast, two types of roundworm, a fruit fly ("Drosophila melanogaster"), two types of sea squirt, two types of puffer fish, the mouse and the rat.
The availability of data from different organisms showed comparative analysis of different genome sequences to be even more valuable than scientists had anticipated. To take full advantage of the power of comparative genomics, NHGRI will continue to utilize capacity at NHGRI-supported sequencing centers for work on additional organisms.
By June, researchers from the Whitehead/MIT Center and the Genome Sequencing Center at Washington University School of Medicine expect to complete the sequencing work (approximately four-fold coverage) necessary to create an initial working draft of the genome of the chimpanzee ("Pan
troglodytes"). The groups, funded by NHGRI, then will assemble the chimp genome sequence into a working draft using the human genome sequence as a guide. After that, they will explore the differences and similarities between the two genome sequences.
"The chimp genome sequence will be important for many reasons, including the fact that it is the organism that is genetically closest to humans," said Richard K. Wilson, Ph.D., director of the Genome Sequencing Center at Washington University School of Medicine.
Identifying the genes that seem unusually divergent between humans and chimps may prove extremely helpful in understanding disease susceptibility. For example, even though the chimpanzee DNA sequence is 98.8 per cent identical to that of the human, chimps do not suffer from some diseases that strike people, such as AIDS and malaria.
A more detailed comparison of the sequences of the two genomes may reveal that there are genetic reasons for such differences, suggesting new approaches for preventing and treating human disease. The same approach recently identified a gene, "FOXP2," that may have played a role in the development of language.
NHGRI-supported sequencing work is also expected to be completed soon on the honeybee, an insect valued by agriculture for its role in crop pollination and by science for its model of social organization. Researchers from Baylor College of Medicine report that they expect to finish assembling a working draft of the honeybee sequence by mid-July, at which time analysis will begin.
The Baylor group also will complete a working draft of the genome of another insect -- the fruit fly, "Drosophila pseudoobscura" -- by early June. Because this fruit fly represents the second species of "Drosophila" to have its genome sequenced, the working draft will offer scientists an unprecedented opportunity to more closely study the genetics of evolution and speciation.
In addition to its work on insects, the Baylor group is currently sequencing the genome of the sea urchin, an animal that is widely studied by biologists interested in how genes are turned on and off during development. A working draft of the sea urchin's genome is expected to be finished in the fall, according to Baylor researchers.
Another model organism currently in the NHGRI-supported sequencing pipeline is the chicken. Besides its obvious importance for the agriculture and food industries, the chicken is a key model for studying embryonic development and the role of viruses in cancer. The chicken genome sequence should also prove extremely useful in helping to identify which genes and regulatory features are essential in vertebrates. Both chickens and humans are vertebrates, a group of animals that have skulls and backbones. However, the two organisms are separated by about 600 million years of evolution. Researchers at Washington University are currently sequencing the chicken genome and expect to have a working draft done in early 2004.
Meanwhile, at the Whitehead/MIT Center, other sequencers are reporting significant progress in the "Fungal Genome Initiative." A set of fungi approved by the NHGRI for sequencing features some organisms that prose serious threats to human health, as well as some that serve as models for biological research.
As for model organism sequencing projects on the horizon, NHGRI has authorized the Baylor College of Medicine to begin sequencing work this summer on the rhesus macaque ("Macaca mulatta"), a monkey that, because of its response to the simian immunodeficiency virus (SIV), is widely recognized as the best animal model for human immunodeficiency virus (HIV) infection. The rhesus macaque is also an important system in drug development, as well as in behavioral research.
In March, NHGRI gave the Baylor group conditional approval to sequence the cattle genome. However, the official start date for the bovine genome project has not been set because that project is contingent upon non-NHGRI funds being raised to match NHGRI's 50 per cent contribution.
To nominate a particular organism for sequencing at an NHGRI-supported center, scientists must write a proposal, or "white paper," that justifies why substantial funds should be spent sequencing that animal's genome. These white papers are reviewed by the Genome Resources and Sequencing Priority Panel (GRASPP), a blue-ribbon group established by NHGRI that assigns each proposal a rating of high, moderate or low priority. GRASPP then forwards its recommendations to the institute's advisory panel, NACHGR, for a final decision.
Dr. Collins emphasized that even a high-priority ranking does not represent a commitment from NHGRI to sequence an organism's genome; rather, the rankings simply indicate the medical and biological opportunities posed by various proposals.