Guilt by Association: Contextual Information in Genome Analysis

The genome sequences churned out by the “genomic revolution” have challenged both computational and experimental biologists to come up with new methods to decipher the secrets of the encoded proteins. The experimental biologists have largely concentrated on a variety of large-scale methods to assay gene expression and protein–protein interactions (Brown and Botstein 1999; Uetz et al. 2000; Walhout et al. 2000). The computational biologists, however, have deeply mined the genomes for evolutionary information in the form of homology between genes (Tatusov et al. 1997; Koonin et al. 2000;Ponting et al. 2000,). Over the past few years there has been increasing interest in the kinds of information that exist in the context in which a protein or a domain thereof is encoded in the genome (Mushegian and Koonin 1996; Dandekar et al. 1998). Recently, contextual information has been offered as a strong handle on the problem of in silico inference of protein function (Enright et al. 1999; Marcotte et al. 1999a,b; Overbeek et al. 1999; Pellegrini et al. 1999; Huynen et al. 2000). Understanding the scope and limitations of the use of these methods may be critical for the experimental biologists seeking to use computational guidelines for large-scale investigations of protein function. Here, we outline the recent advances in this direction and briefly illustrate the new leads they provide in understanding protein function.

Contextual information comes in several overlapping grades, each with a different degree of specificity with regards to a particular protein's role (Fig. 1). The most general form of contextual information is a phyletic profile, that is, the pattern of occurrence of orthologs of a particular gene in a set of genomes under comparison (Pellegrini et al. 1999; Tatusov et al. 2000). In this setup, …