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Human Genome News Archive Edition

Human Genome News, September 1992; 4(3)

NIH Launches New Genome Center To Unify Fruit Fly Mapping Efforts

Three-Year Grant Will Centralize Drosophila Resources, Technologies

A new multicampus research center based at the University of California, Berkeley (UCB), will spearhead a project to map the complete genome of the fruit fly Drosophila melanogaster. The center, directed by Gerald Rubin (UCB), will unify Drosophila mapping efforts and provide a centralized source of technologies and materials for the large number of scientists studying fruit fly genetics. The NIH National Center for Human Genome Research (NCHGR) awarded the 3-year grant that includes $1,651,562 for the first year.

The center comprises the four investigators listed below with their laboratories.

  • Rubin (UCB);
  • Daniel Hartl (Washington University, St. Louis; Harvard University in January 1993);
  • Allan Spradling (Carnegie Institution of Washington); and
  • Michael Palazzolo [Lawrence Berkeley Laboratory (LBL)].

"The information gathered on the fruit fly thus far gives scientists the best opportunity to combine knowledge about DNA sequence and gene function in a complex organism," observed Rubin. "Maps constructed by center researchers will provide a natural stepping stone to sequencing the fly's DNA," he continued.

A Valuable Model

One reason for including Drosophila studies in the Human Genome Project is that extensive biological information on fly genes is already available or rapidly being adquired. Large numbers of genes of known function, timing, and tissue-specific expression or genes whose disruption is lethal to the organism will all be localized along the physical map. The map's very high biological content will be useful for Drosophila biologists and will provide the opportunity to study the genomic organization of many identified fly genes. Studying genomic organization on the human map lies several years in the future.

Functional information about fruit fly genes is also valuable in deciphering human gene function. Many fruit fly protein types, such as receptors, regulatory proteins, and enzymes, are already known to have direct counterparts in humans, indicating that the most significant protions of the two genomes have been preserved during evolution. To date, over 400 Drosophila genes with human counterparts have been described.

An additional reason for the fruit fly's value as a model organism is the giant polytene chromosomes found in cells of the insect's salivary glands. Each of these chromosomes is made up of more than 1000 identical strands of DNA instead of the usual 1 strand. Each gene is therefore present 1000 times, with the copies lined up adjacent to each other. This alignment makes the chromosomes so large that they can be seen under a simple light microscope, and their DNA sequences can be mapped by in situ hybridization with a resolution of 20,000 to 80,000 bp (about 100-fold better than that possible for human chromosomes). This technique can be used to correlate the cytogenetic positions of known genes and transposable element insertion sites with the physical map.

Representative Clone Set

To make more-detailed physical maps of the fruit fly genome, center investigators will use P1 bacterial virus vectors capable of holding a cloned piece of DNA about 100,000 bp long. By mapping the overlapping sections of the DNA pieces using a nonrandom sequence-tagged-site (STS) selection scheme and STS-content-mapping procedure, the team will construct contiguous segments covering large portions of each of the four Drosophila chromosomes. This cloning system should provide to the research community a readily accessible, truly representative set of clones for sequencing the 165-Mb Drosophila genome.

Production-Level Automation

LBL, one of the subcontractors under the grant, is also the home of a DOE-sponsored human genome center, whose ongoing development of automated instrumentation and processes is contributing significantly to mapping both the Drosophila and human genomes.

A key to the center's approach is the use of large-scale automation to provide the throughput necessary for efficient experiments of this scale. Working closely with the Human Genome Center instrumentation group, biologists at LBL have achieved a high degree of automation in several areas of production-level physical mapping: robotic preparation for polymerase chain reactions, large-scale loading and running of gels using a robot-compatible format, and automatic image acquisition and interpretation. Efforts are well under way to integrate these and other essential biological protocols into an automated, robot-controlled system for large-scale map production.

Informatics Resources

A mapping project of this size and complexity requires software for (1) accurate and efficient tracking of clones, DNA preparations, and laboratory results (including imaged data); (2) directing the experimental strategy; (3) communicating among the different experimental sites; and (4) local assemby of a physical map consistent with all the data. The genome center informatics group at LBL is now constructing a system in which AceDB (the Caenorhabditis elegans database) is being adapted for management, query, retrieval, and graphical display of Drosophila data. LBL has developed a new display that presents map information beside a digitized image of the polytene chromosome. Digitized images of actual microscopic in situ hybridization results are being added to the database.

Drosophila Maps Available

Fly genome maps will be contributed to and available for use by the very large and diverse research community, which includes biochemists, cell biologists, neurobiologists, geneticists, and molecular biologists. Supported by the sophisticated status of Drosophila genetics, this cooperation should lead to rapid exploitation of mapping and sequence information derived from the genome center.

The fruit fly has been intensely studied by geneticists for over 80 years. Examples of major genetic principles established by Drosophila researchers in the early 1900s are nondisjunction and its consequences, the genetic behavior of chromosome aberrations, the mutagenicity of ionizing radiation, and the discovery of chemical mutations. Modern investigators have used the organism to learn how combinations of genes control the head-to-tail and side-to-side development of the insect's body. More precise knowledge about rules governing body formation will help researchers understand human fetal development and errors resulting in birth defects.

In addition to the NCHGR center grant and DOE support through LBL, the fly project receives funds from the Howard Hughes Medical Institute for the work of Rubin and Spradling.


Reported by Leslie Fink, Chief
Office of Communications
NIH NCHGR

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