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Science 306 (5696): 629-

Copyright © 2004 by the American Association for the Advancement of Science

Solving Gene Expression

Barbara R. Jasny and Leslie Roberts

Contents
News
Getting the Noise Out of Gene Arrays
Searching for the Genome's Second Code
A Fast and Furious Hunt for Gene Regulators
Reviews and Viewpoints
The ENCODE (ENCyclopedia Of DNA Elements) Project
The ENCODE Project Consortium
Systems Biology and New Technologies Enable Predictive and Preventative Medicine
L. Hood, J. R. Heath, M. E. Phelps, B. Lin
Gene Order and Dynamic Domains
S. T. Kosak and M. Groudine
Cis-Acting Regulatory Variation in the Human Genome
T. Pastinen and T. J. Hudson
See related STKE and SAGE KE material, Editorial, Perspective, papers by Liao et al. and Stolc et al., and the Functional Genomics Web site.
W ords are static images on a page unless you know what they mean, how their meanings change depending on the context, and what the rules are for using them. Similarly, a complex regulatory code is buried within the genome, and researchers will need to decipher it to understand how genes are expressed, what their functions are, and how normal instructions are altered in disease.

Throughout the magazine and online this week are features that describe different aspects of gene expression and its control. Kosak and Groudine (p. 644) describe how genomes may be organized (linearly and within three-dimensional space in the nucleus) for the regulation of gene expression. A News story by Pennisi (p. 632) provides a clear introduction to the world of enhancers: regulatory elements that have been a pivotal force in evolution. Pastinen and Hudson (p. 647) describe the pitfalls associated with analyses of cis-acting control mechanisms governing allele-specific differences in gene expression, some of which have been associated with disease susceptibility. At Science's online Signal Transduction Knowledge Environment (STKE, www.sciencemag.org/sciext/genome2004) are features describing the dance of nuclear receptor complexes with DNA that lead to transcription (Fowler and Alaric) and approaches different organisms use to select genes within gene families for expression (Dalgaard and Vengrova).

Aware of the magnitude of the challenge of developing a complete "parts list" for all of these activities, an international consortium of scientists has begun the ENCODE (ENCyclopedia Of DNA Elements) project (p. 636), whose goal is to identify all of the structural and functional elements of the human genome. In their pilot phase, researchers are comparing multiple approaches for detecting different elements on 30 Mb of DNA.

Some of the medical applications of this information are tantalizing prospects, whereas others are already at our doorstep. Hood et al. (p. 640) present a sweeping view of how expression patterns will be combined with technological advances to further predictive medicine. However, it is not an entirely smooth path. For instance, as the number of gene array studies proliferates, some researchers are finding that they don't necessarily lead to quick diagnosis or prognosis (see News story by Marshall on p. 630). The Science Functional Genomics Web site (www.sciencemag.org/feature/plus/sfg) contains additional online discussion of whether microarrays have been oversold and how they can reach their full potential. The site also has updated links to other resources. At the Science of Aging Knowledge Environment (SAGE KE, www.sciencemag.org/sciext/genome2004) are articles describing how microarrays and other genome-scale technologies are being applied to aging research (Kaeberlein; Melov and Hubbard). The Editorial by Lord and Papoian (p. 575) explores efforts to standardize microarray data so that regulatory agencies can use gene expression studies to evaluate drug safety.

In the course of their analysis of RNA expression for protein-coding and non-protein-coding sequences during the Drosophila life cycle (p. 655), White and his group have come to see the task of assembling the functional parts of the genome as being like a Rubik's cube. Although ~4.3 x 1019 different positions are possible, the cube can be resolved from any position by 29 or fewer manipulations. As we begin to understand biological systems through carefully designed experiments and analyses, the complexity we are seeing now may begin to resolve into simpler principles.


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