Progress, and Applications
of the Human Genome Project
Sponsored by the U.S. Department of Energy Human Genome Program
Human Genome News Archive Edition
In this issue...
In the News
Genetics in Medicine
From Sequence to Systems: Looking at Proteins to Understand Genome Expression
The availability of entire genomic sequences for some 18 microbes (and many more to come) now offers investigators the opportunity to perform comparative analysis from an evolutionary perspective, identify conserved genes and metabolic capabilities based on protein sequence homology, and predict protein structures. Understanding how gene products--proteins--work together to create and maintain complex biological systems, however, requires data about the entire spectrum of protein production in the complex ecosystem of a cell.
In the account below, DOE Microbial Genome Program grantee Carol Giometti of Argonne National Laboratory (ANL) describes such studies on two microbial genomes, the heat-loving Methanococcus jannaschii and Pyrococcus furiosus, both subjects of the DOE program. [Introduction by Dan Drell, DOE Microbial and Human Genome programs]
In 1995, V. Wasinger and coworkers (University of Sydney, Australia) coined the term "proteome" to describe all the proteins encoded within a genome. Proteomics is the study of protein expression by biological systems, including relative abundance, post-translational modifications, stability within the cell, and fluctuations as a response to environment and altered cellular needs.
In contrast to genomic sequence, which captures DNA information that is stable throughout the lifetime of an organism, proteomics summarizes protein-expression patterns of a biological system at different times. Biochemical pathways and regulatory mechanisms can be deduced by manipulating the cellular environment or DNA sequence and observing coregulation of specific proteins or sets of proteins. Proteomics tools include high-resolution protein separation, detection, and quantitation methods and techniques for linking proteins to their corresponding gene sequences. These tools can be used to further annotate and validate completed genomes, reveal biochemical pathways and regulatory networks, and define targets for protein-structure determination. In the context of the DOE Microbial Genome Program, analyzing the proteomes of organisms for which complete genomes are available offers the potential for rapid identification of the organisms' major gene products.
Although M. jannaschii's complete genome sequence is publicly available and annotated according to sequence homology with other known proteins, the actual proteins synthesized by M. jannaschii and regulation of their synthesis have not been studied until now. Correlation of protein abundance, shifts in abundance in response to environmental changes, and post-translational modifications with the genome sequence will provide new information regarding gene expression and regulation in this member of the Archaea. In addition, proteome studies will serve to confirm or refute protein identifications based on sequence homologies alone.
The genome sequence of P. furiosus is virtually complete, and numerous P. furiosus enzyme activities have been well characterized. The regulation of specific gene expression (e.g., inducibility of enzyme activities of interest) is not characterized in P. furiosus, however, nor has the influence of post-translational modification been explored. Characterization of the P. furiosus proteome will bridge the gap between gene sequence and protein function by providing data on the regulation of protein synthesis. In addition, studies are in progress to determine the subcellular localization (soluble vs membrane fractions) of each P. furiosus protein.
Strategies rooted in 2-DGE are being developed to link the proteome information with existing genome sequence databases for these two Archaea. Evolving approaches to characterizing small-genome proteomes and linking proteome and genome databases will be the foundation for developing protocols for similar investigations of large mammalian proteomes. [Carol S. Giometti, ANL]
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Last modified: Wednesday, October 29, 2003
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