Home > Archives > Additional Archives > Andrei Osterman   Andrei Osterman Integrated Genomics, Inc. Chicago, IL andrei@integratedgenomics.com http://www.integratedgenomics.com/   Abstract: Missing Genes In Genome Context: Looking From Behind A Lab Benc The rapidly increasing number of sequenced genomes produces a remarkable impact on our ability to characterize cellular networks. It is now possible to associate thousands of genes with predicted enzymatic functions in alarge number of identified pathways. These pathways can be further connected to larger functional blocks, laying a foundation for a whole-cell functional reconstruction. In addition to bringing about an improvement in fundamental understanding and straightforward applications such as industrial strain improvement, and identification of novel drug targets, the efforts in reconstructing pathways reveal a growing number of "missing genes". We use this term with respect to known enzymatic and other protein functions that cannot be connected to genes in all or some of the organisms with completely sequenced genomes. We are focusing our research efforts on those missing genes that represent a part of a relatively limited set of about 2,000 central components of the machinery of life. Filling in the missing pieces of the "core machinery" is both critically important, and it is becoming clearly feasible due to the progress in comparative genomics. On the order of 200 rather universal core functions are encoded by genes that have not yet been identified in any organism. By our estimates, there are at least five times as many cases in which a known version of a gene cannot be recognized in a significant sub-set of organisms, although a corresponding function is expected to be present in those organisms based o na whole-genome functional reconstruction. I will present a "selfish" biochemist’s perspective of comparative genomics. We use a comparative genomic and biological context analysis to produce conjectures for previously uncharacterized versions of genes (missing genes). This integrated approach includes a synergistic combination of functional reconstruction, chromosomal gene clustering, predicted regulons and a few other established computational techniques. The conjectures produced are further refined using high-throughput experimental tools such as expression micro-arrays and whole-genome gene essentiality. Specific functional predictions are verified by focused experiments in vitro and in vivo. Some of the computational and experimental techniques are currently restricted in their applicability to microbial genomes. However, due to a remarkable diversity of microbes, and intrinsic conservation in the core machinery, many specific results can be successfully projected onto higher eukaryotes including Homo sapiens. Examples from our research in vitamin/co-factor biosynthesis will be provided.
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