With the increasing number of available complete genome sequences, the challenge shifts to understanding how the stored information is interpreted to enable life. We are exploring ways to contribute to the understanding of two of these genomes, those of the human and the nematode worm, C. elegans.
C. elegans offers unique advantages in understanding the regulatory circuitry that underpins development. The ability to follow the invariant pattern of cell divisions in real time offers an opportunity to describe gene expression patterns at an exceptional level of detail in time and space. To exploit this property, we are seeking to automate the determination of the lineage, and in turn overlay any pattern of gene expression on the lineage pattern. As a first step we have created GFP-histone fusion genes to label the nuclei and have used 4-d microscopy to record the full development of the animal. We are now developing computer programs to detect cell divisions and thereby reconstruct the cell lineage. Aided by comparative genome analysis we have also begun to create promoter-GFP fusions for a series of test genes to be introduced into the GFP-histone background to document patterns of gene expression. Initial efforts will be directed toward known transcription factors and in turn building up a likely network of interactions.
For the human genome, we are using comparative sequence analysis, first with mouse and currently with chimpanzee, to explore the ways comparative analysis can illuminate the function of the human genome. Longer term, we hope to be able use human polymorphism to aid in the assignment of likely gene function.
Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, et al.: Initial sequencing and analysis of the mouse genome. Nature 2002; 420(6915): 560-562.
International Human Genome Sequencing Consortium: Initial sequencing and analysis of the human genome. Nature 2001; 409: 860-921.
The International Human Genome Mapping Consortium: A physical map of the human genome. Nature 2001; 409(6822): 934-941.
The International SNP Map Working Group: A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001; 409: 928-933.
The C. elegans Sequencing Consortium: Genome sequence of the nematode C. elegans: A platform for investigating biology. Science 1998; 282: 2012-2018.