Science in Society Archive

Gene Expression Is Global

Availability of microarrays of the entire genome of E. coli bacterium makes it possible to determine the expression of all genes by measuring the level of the corresponding species of RNA present. Researchers [1] used this method to compare global gene expression in the presence of ammonia, the preferred nitrogen substrate, with non-preferred sources.

Their study revealed that the products of many many genes are affected. For example, genes that had previously not been known to be subject to nitrogen regulation are responsible for scavenging amino acids and peptides, among them, the dipeptide D-alanyl-D-alanine. Under conditions of stress, including limitation of nitrogen, E. coli switches the mechanism for cross-linking the cell wall using the dipeptide, to one that releases the dipeptide into the growth medium. This leads to the activation of the 'ddp operon'(an operon is a unit of gene regulation containing several genes) comprising the genes for transporting the dipeptide into the cell and for cleaving it, thereby enabling the cell to replenish the nitrogen store.

Ammonia is the preferred nitrogen substrate, because it is efficiently incorporated into glutamate and glutamine, the precursor molecules for all nitrogen compounds in the cell. The decline of glutamine in the cell due to ammonia starvation is the signal for activating other genes which leads to increase in transcription of many further genes, among them, the enzyme glutamine synthetase, to com-pensate for the reduced availability of ammonia and to increase the intracellular concen-tration of glutamine. However, this system is subject to negative feedback, so that the increased concentration of glutamine switches off the original activation signal. Consequently, the rate of glutamine production from the non-preferred nitrogen source is slower than the rate of its production from ammonia. Thus, nitrogen regulation amel-iorates, but does not cure ammonia deficiency. Replace-ment of ammonia by other nitrogen sources will result in effects not directly related to nitrogen regulation but rather to slower growth rate due to the general decline of synthesis of proteins and nucleic acids.

Thus, the researchers point out, microarrays alone cannot unequivocally identify the genes whose expression is subject directly to nitrogen regulation. In order to do so, it is necessary to have mutants that block downstream processes, where, ideally, "the expression of the regulated genes does not affect the physiology of the cell"(!), a condition referred to, aptly, as "gratuity".

This research and commentary are of interest in revealing how molecular geneticists attempt to analyse the organic complexity of gene regulation by creating artificial conditions that have limited relevance, at best, for the real world.

The moral of the story is that gene expression is regulated globally, and the effects of each gene cannot be isolated, except by artificial means. This is yet another blow to genetic determinism.

1. See Magasnik, B. (2000). Global regulation of gene expression. PNAS 97, 14044-5

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