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Human Genome News, January 1991; 2(5)
Model Projects To Facilitate Human Genome Mapping, Sequencing, and International Collaboration
The genomes of organisms such as the roundworm, yeast, bacteria, and mycoplasma are similar to the human genome in many ways. Because of the characteristics of these simpler organisms, investigators can use them in human gene research as models to study gene identity, organization, and function; to examine the processes and diseases that have counterparts in humans; and to aid in the search for homologous genes.
To meet DOE-NIH 5-Year Plan objectives, the NIH National Center for Human Genome Research (NCHGR) is funding studies of these nonhuman models for human genome mapping, sequencing, and international collaboration. NCHGR may fund additional model organism studies in the future.
Investigators already understand more about the cellular development and physiology of one of the simplest organisms with a nervous system, the roundworm Caenorhabditis elegans, than of any other species. A pilot project to sequence 3Mb in 3 years, jointly funded by NCHGR and the U.K. Medical Research Council (MRC), is now beginning to sequence this tiny nematode's 100-Mb genome. Research groups led by Robert Waterston (Washington University) and John Sulston (MRC Laboratory of Molecular Biology) will collaborate in the effort, which aims at an eventual cost of about $.50 per base.
Currently the only extensive sequencing effort for a multicellular organism, this pilot project is expected to generate new sequencing strategies and data that will lead to a greater understanding of gene function. Information about the worm's DNA sequence will help scientists interpret molecular signals triggering growth and development in this animal.
C. elegans has been intensively studied for over 30 years. Building on the pioneering work of Sydney Brenner (MRC), scientists published in 1986 a diagram of the anatomy of the worm's nervous system. Sulston and his colleagues have traced the developmental lineage of each of the 959 adult somatic cells-an achievement that allows them to relate specific behaviors to particular cells.
Waterston, Sulston, and Alan Coulson (MRC) had the wholehearted cooperation of the roundworm investigative community in developing highly detailed physical maps of C. elegans' six chromosomes to accompany the previously established genetic linkage map. Investigators are now working out efficient sequencing strategies to determine the entire base sequence.
The C. elegans physical map database, publicly available via modem or Internet since November 1988, has been set up on a VAX system running VMS in Cambridge, England, and in several places in the United States. Investigators are working on a Unix-based database that will run on workstations and allow access to generated sequences, the physical map, a genetic map, references, and strain lists.
The widely studied common brewer's yeast-the single-celled fungus Saccharomyces cerevisiae-has been a valuable model because its biochemistry and cellular structure (e.g., cell membranes, a defined nucleus, and other cellular components and processes) are very similar to those of humans. Functions of many major proteins have been shown to be conserved between yeast and higher eukaryotes such as humans. The relationships between genetics and biochemistry and between structure and function are better understood in yeast than in any other eukaryote.
A Stanford University group led by David Botstein and Ronald Davis is beginning to sequence the 12.5-Mbp yeast genome. Yeast DNA sequence data will be correlated with existing chromosome maps, helping to lead researchers to important yeast genes.
The common intestinal bacterium E. coli has been the most frequently studied model organism for many decades. With the discovery of restriction enzymes in the early 1970s, E. coli became the first genetically engineered organism and now underpins the international biotechnology industry.
Fred Blattner (University of Wisconsin) and his colleagues are sequencing the complete E. coli genome that consists of 5 Mb on a single circular chromosome. Because much is already known about E. coli genetics, sequence data will enable researchers to investigate biochemical mechanisms responsible for the control of gene expression.
Walter Gilbert (Harvard University), a Nobel laureate who pioneered DNA sequencing in the mid-1970s, is leading efforts to sequence the genome of Mycoplasma capricolum. Strains of this mycoplasma cause pneumonia in a number of animals, including humans. M. capricolum, a wall-less bacterium whose genome is estimated to be about 750 kb and to contain only 600 genes, is among the smallest free-living organisms. Although it lacks the complexity of E. coli, M. capricolum contains all the essential genes for cell growth and division.
Gilbert's group plans to sequence the one-chromosome mycoplasma without first constructing a map of its genome, which is about 4 times larger than that of the 240-kb cytomegalovirus-the largest genome completely sequenced so far. (Larger genomes require strategies for isolating, cloning, mapping, and sequencing the DNA piece by piece.)
A group led by Eric Lander (Whitehead Institute and Massachusetts Institute of Technology) has established a Center for Genome Research to develop a yeast artificial chromosome (YAC) library of the mouse genome, using YACs to construct physical maps of chromosomes 1, 11, and X, with the eventual goal of making a detailed comparison between the mouse and human genomes. The YACs will be available to the mouse genetics community.
David Housman and coworkers will work to achieve continuity across selected regions of the mouse genome by developing ways to connect ordered contigs into a complete physical map. The project will also begin to sequence mouse DNA to detect microsatellite repeats.
The DOE-NIH 5-Year Plan summarized the value of model organism studies to scientific investigation and the Human Genome Project in the following words:
For more information on the C. elegans project, contact:
Written by Leslie Fink, NCHGR
Office of Human Genome Communication
and Anne E. Adamson
HGMIS, Oak Ridge National Laboratory
The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v2n5).
The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.
Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.
