International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

C1 Biological Annotation of Drosophila Genome Sequence

Gerald M. Rubin. University of California, Berkeley

The nucleotide sequence of the Drosophila melanogaster genome will soon be available and the current state of the genomic and cDNA sequencing effort will be briefly summarized. The value of these sequence data will be enormously enhanced if the structure of each transcription unit and the functions of its protein products can be established. Gene sequence and expression pattern databases will be extremely powerful tools. However, the function of a protein in a multicellular organism depends on context and will almost certainly need to be determined by experimental analysis. How are these data sets being collected in Drosophila?

Neither the intellectual framework nor experimental tools for analyzing complex gene networks are currently in place. There is reason for cautious optimism that the complete genomic sequence of organisms will enable the necessary global approaches to study gene function and regulation. The conservation of gene structure and function during evolution will allow for the linking and sharing of information garnered in different experimental systems. But what data should be collected and how to interpret these data are much less clear.

Genetic screens for loss-of-function mutations that affect a particular process have and will continue to play a crucial role in understanding the function of genes. Such screens have been carried out for decades in Drosophila. With the continual incorporation of more clever and sophisticated phenotypic analyses this experimental approach has been applied to an increasingly wide range of developmental, physiological and behavioral processes. These studies share a lot in common with modern genome research in that they are wide in scope -- all the genes in the genome are being assayed in a single experiment-- and they are usually not intended to test a specific hypothesis. Such genetic approaches have proven to be very powerful in grouping genes together in pathways and in allowing an unbiased -- or, ignorance-driven -- attack on a problem. To facilitate such studies, the Berkeley Drosophila Genome Project (BDGP) is carrying out gene disruption projects, using transposable-element mediated insertional mutagenesis, of unprecedented scale in a metazoan organism. To date over one-quarter of all essential genes have been mutated (Spradling et al. 1999). Mapping the location of P element insertions in the BDGP strain collection relative to cDNA 5' ends and open reading frames observed in the genomic DNA sequence provides a powerful means of gene identification. These gene disruption experiments are now being extended to include transposable elements that can cause controlled misexpression of the gene at the site of insertion (see Rorth et al. 1998).

However, these approaches have many inherent limitations. Genetics is an abstract science and its true power is only realized when combined with biochemistry. Moreover, it is becoming increasingly clear that few if any simple linear pathways exist and that one must learn to deal with complex, dynamic networks of interacting gene products. These networks are highly resilient; disruption in only one in three genes has an obvious phenotype in yeast, worms, flies or mice. Of the 14,000 genes thought to exist in Drosophila, only 4,000 are likely to mutate to recognizable lethal, sterile, visible or behavioral phenotypes. Even when a phenotype is observed it reflects only that part of a gene's function that cannot be compensated for, rather than revealing the complete role of the gene in development and physiology.

In an attempt to better understand the power and limitations of current methods to annotate a Drosophila genomic sequence with features of biological interest -- as well as to get a glimpse of the detailed organization of the Drosophila genome -- we carried out an analysis of a contiguous sequence of nearly 3-Mb from the genome of Drosophila melanogaster (Ashburner et al. 1999). Because this region has been genetically characterized to a greater degree than any other comparable region in any metazoan, it offered an unparalleled opportunity to correlate a sequence and genetic analysis. Perhaps the most interesting results from this study came from comparing the properties of the genes with and without observable phenotypes. Genes known to have mutant phenotypes are more likely to be represented in cDNA libraries, and far more likely to be have products similar to proteins of other organisms, than are genes with no known mutant phenotype.

Ashburner, M. et al., 1999. An Exploration of the sequence of a 2.9-megabase region of the genome of Drosophila melanogaster - the 'Adh' region. Genetics 153: 179-219.

Rorth, P., et al., 1998. Systematic gain-of-function genetics in Drosophila. Development 125: 1049-1057.

Spaldling, A. C.,et al., 1999. The BDGP gene disruption project: single P-element insertions mutating 30% of Drosophila autosomal genes. Genetics 153: 135-177.


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