Genetics

C.J. Bult, O. White, G.J. Olsen, L. Zhou, R.D. Fleischmann, G.G. Sutton, J.A. Blake, L.M. FitzGerald, R.A. Clayton, J.D. Gocayne, A.R. Kerlavage, B.A. Dougherty, J.F. Tomb, M.D. Adams, C.I. Reich, R. Overbeek, E.F. Kirkness, K.G. Weinstock, J. M. Merrick, A. Glodek, J.L. Scott, N.S.M. Geoghagen. J.F. Weidman, J.L. Fuhrmann, D. Nguyen, T.R. Utterback, J. M. Kelley, J.D. Peterson, P.W. Sadow, M.C. Hanna, M.D. Cotton, K.M. Roberts, M.A. Hurst, B.P. Kaine, M. Borodovsky, H.P. Klenk, C.M. Fraser, H.O. Smith, C.R. Woese, J.C. Venter, "Complete Genome Sequence of the Methanogenic Archaeon, Methanococcus jannaschii," Science, 273:1058-73, 1996. (Cited more than 470 times to date) Comments by J. Craig Venter, president and director, The Institute for Genomic Research, Rockville, Md. These days, the dictum that the more you learn, the more you know how little you've learned seems particularly apt for genetics. A case in point is this paper. It describes the first whole genome sequencing of an organism in what is considered to be a third major evolutionary branch, the Archaea. Yet, senior author J. Craig Venter , president and director of The Institute for Genomic Research (TIGR) in Rockville, Md., now believes that the paper's support for the division of life into three evolutionary domains "was probably a little premature. I think that as work goes forward, it will become apparent that there is more of a continuum between the three branches." The Archaea possess characteristics of both other branches--the Bacteria, which are prokaryotes, microorganisms that lack a membrane-bound nucleus, and the Eucarya, organisms with a membrane-bound nucleus and cellular organelles, including all plants and animals. The Archaea are prokaryotic in cellular cytology, but they resemble the eukaryotes in their molecular information-processing and secretion systems. University of Illinois evolutionary biologist Carl R. Woese, a coauthor of this paper, developed the postulate of the Archaea as a third evolutionary domain, based on comparisons of individual genes between the branches. The complete sequencing of Methanococcus jannaschii, a methane-producing microbe that lives in boiling thermal vents in deep-sea floors, identified 1,738 protein-coding genes. Although this more than doubled the previously known Archaea genes, only 38 percent of the M. jannaschii genes could be assigned cellular roles. Just two bacterial genomes had ever been completely sequenced at that point. Comparison of M. jannaschii with them and with the several hundred megabase pairs of eukaryotic sequence data then available suggested that most of the genes involved in transcription, translation, and replication in the archaeon were more similar to those of the eukaryotes than to the prokaryotic bacteria. But Venter explains that what had seemed like evidence that the eukaryotes and the Archaea were specifically related was actually "an artifact of low sampling." Nowadays, the cellular functions encoded by about 85 percent of M. jannaschii's genes are known, strengthening Venter's belief in an evolutionary continuum less distinct than that of a deeply rooted, tripartite branching. This paper was also significant in providing the first complete sequence of an autotrophic organism, which needs only carbon dioxide or carbonates and an inorganic nitrogen compound for metabolic synthesis. Its sequencing therefore was a vital step toward understanding the capacity of an organism to make the building blocks of life from inorganic constituents. Venter stresses the team effort involved in the paper, particularly because of the technical aspects of the whole genome shotgun sequencing method used. It involves making thousands of copies of all the DNA in a cell, fractionating the copies, and determining genetic sequence by analysis and reassembly of overlapping segments. He gives particular credit to lead author and colleague Carol J. Bult, to Woese, and to Hamilton O. Smith in the department of molecular biology and genetics at Johns Hopkins University School of Medicine. Smith assembled the gene libraries. Since the paper's publication, the number of complete genomes sequenced by TIGR has risen to seven, with more than 40 other microbial projects in process. The complete genomes of tuberculosis and cholera will be done this year, and the first chromosome of malaria has been finished. Last year alone, the institute released to the public domain 40 million base pairs of sequencing. Venter says he has lost count of how many genes TIGR has identified in humans, plants, and microbes, but he estimates well over 100,000. Currently, he notes, hundreds of genomics projects are under way worldwide. "The comparative aspects [concept] is where the real value is going to come from," he observes. "We know so little about biology and gene diversity of what's really there. This [paper] was a first dive into the new biology ... Having the genomes will be the basis for the future of biology."

Genetics

The Scientist Staff

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