In April, researchers announced the start of a 2-year project to sequence the 5.9-Mb genome of the bacterium Pseudomonas aeruginosa, a common culprit in chronic infections in cystic fibrosis (CF) and some cancer and burn patients. Data from this Pseudomonas Genome Project is now rapidly accessible on a new Web site (http://www.pseudomonas.com), with quarterly updates beginning in the final quarter of 1997.
The project represents the efforts of a consortium of researchers from the Cystic Fibrosis Foundation (http://www.cff.org), the University of Washington Genome Center (http://www.genome.washington.edu), and PathoGenesis Corp (Seattle).
"We are able to produce raw DNA sequencing data of such high quality that it is of immediate value for clinical research before completing the analysis of the full Pseudomonas genome," said Maynard Olson (University of Washington). He noted that this is the largest bacterial genome sequencing effort to be undertaken.
CF is the most common fatal genetic disease in the United States, affecting some 30,000 children and young adults whose median age of survival is about 31 years. Complete DNA sequencing will enable researchers to identify previously unknown genes that allow the bacterium to successfully colonize the respiratory tracts of cystic fibrosis patients, evade the immune system, and inactivate antibiotics currently available. Learning more about the functions of genes that confer these capabilities will suggest new avenues for drug development to penetrate the well-developed defenses of Pseudomonas.
For the first time, scientists have identified a gene abnormality that causes some cases of Parkinson's disease. The finding, reported in Science [276, 2045-47 (June 27, 1997)], confirms last fall's report that a predisposition to at least one form of Parkinson's is inherited and that a gene on the long arm of chromosome 4 is involved. Researchers have now implicated a single base-pair mutation in this alpha synuclein gene, which plays a role in the function of nerve cells.
Parkinson's disease afflicts about 500,000 people in the United States, initially causing shaking or trembling limbs, and, in later stages a slow, shuffling walk and stooped posture. It results from loss of nerve cells in a brain region that controls movement, thus creating a shortage of the brain-signaling chemical dopamine. The recent finding gives researchers a powerful new tool for understanding cellular abnormalities in Parkinson's and demonstrates a connection with research into other neurological disorders such as Alzheimer's disease.
Using information generated by the Human Genome Project, researchers rapidly located the mutation in a region containing about 100 genes, including the alpha synuclein gene. This gene was an excellent candidate for Parkinson's involvement because its potential role in neurodegenerative diseases already had been demonstrated when fragments of alpha synuclein protein were found in the characteristic amyloid plaques in the brains of Alzheimer's patients. Researchers hypothesize that the alpha synuclein protein mutation causes it to aggregate, thus attracting other proteins to form a deposit that damages cells. A common mechanism may be operating in both these neurodegenerative diseases.
Researchers suspect that the abnormal gene is responsible for a significant portion of familial Parkinson's disease with onset generally before age 60. Scientists are searching for mutations in other synuclein genes among Parkinson's patients who do not have the alpha synuclein mutation.
The paper's senior author, Robert Nussbaum (NHGRI), cautioned that, "For people with Parkinson's disease, this is a small but important step in a very long journey. . . . It is important to stress that at this point there is no direct therapeutic result from this finding." A test based on this gene abnormality would provide limited information for most people. In high-risk families, one application for such a test would be to facilitate research into possible stabilizing or preventive measures.
Discovery of the mutant alpha synuclein genes raises genetic-testing issues similar to those for such other late-onset diseases as Alzheimer's disease and Huntington's disease. Notes Francis Collins (NHGRI), "As more gene sites are identified, it will become almost routine for disease-gene hunters to find an already characterized gene waiting for them when they arrive at the neighborhood they know is involved in a disease. But this discovery, which raises the possibility of identifying healthy individuals at future risk for illness, also underlines again how crucial it is to provide legislative protections against misuse of the information, especially in health insurance and employment."
The seventh issue of The Gene Letter is on the Web (http://www.geneletter.org). Designed to inform consumers and professionals about advances in genetics and to encourage discourse about emerging policy dilemmas, the newsletter is supported by a 2-year DOE grant to the Shriver Center.
A Human Genome Project Milestone
In September, a team of scientists led by Frederick Blattner (University of Wisconsin, Madison) reported the complete sequencing of the 4.6-Mb Escherichia coli K-12 genome. The paper published in Science (277, 1453-62) represents an analysis of data collected by more than 259 people over the project's 6-year duration.
Obtaining the complete DNA sequence of the E. coli genome has been a goal of the Human Genome Project, both to help develop sequencing and gene-finding technology and to facilitate studies on gene function and organization. More than 4200 E. coli genes have been identified, although the functions of over one-third of them remain unknown. Because of similarities found in genes across species, this work provides a valuable starting point for identifying and understanding genes in other organisms, including humans.
"Determination of the complete inventory of the genes of organisms is one of the major goals of biology--analogous to development of the periodic table of the elements in chemistry," said Blattner. "Once they are all known and relationships between them become evident, a classification system for understanding the basic functions of life can be erected."
For more than 70 years E. coli, a natural inhabitant of the lower intestinal tract of animals, has been one of the most studied organisms for scientists exploring fundamental processes in biochemistry, genetics, and physiology. In recent years it has become the workhorse of biotechnology and serves as a living factory for producing human insulin and other medicines.
The strain used in this study does not cause disease, but related toxic strains have been associated with an increasing number of human food poisonings. The new data will enable scientists to compare the genes of nontoxic and pathogenic strains to pinpoint those responsible for toxicity, laying the groundwork for the development of drugs to treat diseases associated with E. coli.
Web Sites for E. coli Sequence Data
Data have been available through online databases such as GenBank since January. A revised and updated sequence is now available at GenBank, NCBI (http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/framik?db=Genome&gi=115), and the E. coli Genome Project Web site (http://www.genetics.wisc.edu). Annotation is ongoing, and comments to the authors are appreciated.
Sequence file in GenBank flat file format containing both sequence and annotations (available uncompressed or compressed):
[no longer available]
FASTA file (no annotation) of entire sequence:
[no longer available]
E. coli Genome Navigator: Web-based visual interactive display and query resource for the complete E. coli genome. It graphically displays coding sequences and other genome elements by functional category and allows users to browse the genome and query external data sources about any of these elements (http://www.mpimg-berlin-dahlem.mpg.de/~andy/GN/E.coli). (no longer a valid link)
In 1995 and 1996, leaders in genetics and primary healthcare met at Cold Spring Harbor, New York, to consider how genetic advances could benefit public health and to discuss the integration of genetic knowledge and technologies into mainstream medicine. The book Toward the 21st Century: Incorporating Genetics into Primary Health Care summarizes the meetings and lays out such key concerns as adequate training of healthcare providers; ensuring access to appropriate care; and patient autonomy including ethical, social, and cultural considerations. Paper, 100 pp., 1997. [Cold Spring Harbor Laboratory Press; 10 Skyline Dr.; Plainview, NY 11803-2500 (800/843-4388 or 516/349-1930, Fax: -1946, cshpress@cshl.org, http://www.cshl.org)]
In July, researchers reported the construction of a high-resolution physical map for human chromosome 7 [Genome Research 7(7), 673-92]. With an average STS spacing of about 79 kb, the new map exceeds the Human Genome Project goal and provides a framework for future chromosome 7 sequencing. The map, which covers virtually all the 170-Mb chromosome, was built using a YAC-based, STS-content approach and includes 22 YAC contigs integrated with the genetic, radiation hybrid, and cytogenetic maps generated for that chromosome.
Collaborators on the project included researchers at the NIH National Human Genome Research Institute, Washington University School of Medicine (St. Louis), Généthon (France), and the University of Washington. [Information: http://www.nhgri.nih.gov/DIR/GTB/CHR7 ]
Genome Therapeutics Corporation (GTC) announced in September that the complete genome sequence of Methanobacterium thermoautotrophicum has been updated on the GTC Web site, including annotation, comparative analysis, and maps (http://www.genomecorp.com/programs/sequence_data_meth.shtml). GTC has also released preliminary data from the first full shotgun assembly of the 4.1-Mb Clostridium acetobutylicum genome, including BLASTP2 summaries for probable coding open reading frames (http://www.genomecorp.com/programs/sequence_data_clost.shtml). This work is supported by the DOE Microbial Genome Program. [Contact: Douglas Smith (617/893-5007, Fax: -9535, doug.smith@genomecorp.com)]
A summary of the Second International Strategy Meeting on Human Genome Sequencing held in Bermuda on February 27-March 2 is now on the Web (no longer avaiable June 2000). The summary includes principles endorsed by attendees on sequence quality, submission and annotation, and claims and etiquette. The next meeting is planned for the end of February 1998 in Bermuda.