Elsevier

Genomics

Volume 84, Issue 3, September 2004, Pages 449-457
Genomics

Review
The genomics of gene expression

https://doi.org/10.1016/j.ygeno.2004.05.002Get rights and content

Abstract

The study of gene regulation on a genomic scale has been constrained by the modest pace with which new trans-regulatory factors have been identified and by the fact that cis-regulatory sequences have to date been described even in part for only a small fraction of vertebrate genes. An indirect approach for assessing the significance of cis- and trans-regulatory mechanisms on a global scale is to utilize gene expression as a surrogate for transcriptional regulation and to combine genome-scale transcriptional profiling with studies of genetic variation, classical genetic techniques such as linkage analysis, and examination of allelic expression patterns that reveal cis-regulatory variability. A number of recent studies employing these methods provide insight into questions of central importance to our understanding of the larger role of transcriptional regulation in the organization of the human and other complex genomes.

Section snippets

Natural variation in gene expression

Evolution requires variation, and it has long been hypothesized that natural selection may be more dependent on variability in gene expression than on variation in protein coding sequences [17]. The following three related questions are considered below: (i) What proportion of genes exhibit natural variation in expression? (ii) How heritable are patterns of gene expression? And (iii) what proportion of such patterns can be accounted for by cis-acting versus trans-acting components?

Numerous

Microarray analysis of individualized gene expression

Microarrays have been heavily utilized to analyze the expression patterns of large numbers of genes across different tissues or within the same tissue under a variety of experimental conditions or even between species. Several groups have now taken advantage of this platform to perform global analyses of the variability of gene expression between naturally occurring populations of the same species and between individuals within populations.

Direct examination of allelic variation

An alternative to expression profiling is direct measurement of allelic expression, which may be effected through design of allele-specific primers that exploit known coding sequence polymorphisms. Quantitative methods of allele discrimination can then be applied to individual subjects who are heterozygous for the marker polymorphism to measure relative allelic expression [16]. A key advantage of allelic studies is that they circumvent many of the difficulties noted above for microarray-based

Allelic variation in mammalian gene expression

Apart from one study conducted in mice [27], systematic surveys of allelic variation in gene expression performed to date have analyzed human populations. Salient finds from these studies are summarized in Table 1. An important preliminary observation that may be made from these findings is that while cis-regulatory variability appears to be a common phenomenon among genes, the alleles that underlie such variability for a given gene appear to be uncommon or rare.

In an attempt to discern the

Implications for the genomic organization of gene regulation

The prevalence of allelic variation in human gene expression suggests a high frequency of polymorphism in cis-regulatory sequences. The existence of such variability, in combination with certain distinguishing architectural features of cis regulation in higher eukaryotes, may have played an important role in shaping complex genomes.

Vertebrate gene expression is regulated by several different classes of cis-regulatory DNA sequences, including enhancers, silencers, insulators, and promoters [38],

Implications for human disease

Common diseases are characterized by polygenic inheritance and by quantitative variation in specific phenotypic traits. A major biological mechanism contributing to quantitative phenotypic variation is expected to be heritable variation in the regulation of gene expression, which has been predicted to reside principally within cis-regulatory sequences [55]. Since individual trans-regulatory transcriptional factors typically interact with a wide network of genes, variation affecting these

Conclusion

Our understanding of the process of transcriptional regulation on a genomic scale, while nascent, is poised for rapid expansion. Clear evidence is now emerging for heritable variation in gene expression, a significant component of which, at least in humans, appears to be cis-regulatory variability. Quantitative approximation of this component is likely to be conservative given that much cis variation may be subtle and therefore beyond the limits of detection using current methodologies. The

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