Compensating for alien genes…

This post was chosen as an Editor's Selection for“FROM the perspective of a bacterium, higher eukaryotes are oversexed, unadventurous and reproduce in an inconvenient way.” So says Pål Johnsen and Bruce Levin in their commentary of today’s article for discussion, and nary a truer word said. Of course, one may state that inconvenient as reproduction may be, bacteria clearly have no sense of fun.

There was once an idea that we could address the problem of antibiotic resistant bacterial strains by removing the ailing antibiotic from clinical use. In the absence of selective pressure it was thought that the evolutionary traits that enable the strain to resist the antibiotic would actually put the strain at a competitive disadvantage compared with a strain that doesn’t have such antibiotic resistance. The proposed cause of this? Fitness costs – these are imposed by a resource-expensive set of mutations, or carriage of alien DNA, that make the resistant strain compete less well once its non-resistant brethren are no longer being killed off by the antibiotic.

However, some years ago now experimental evidence suggested that this is not always the case; it may in fact be often not the case. It is worth mentioning at this point that it has been shown that in some circumstances (alt) the number of infections caused by a particular antibiotic-resistant pathogenic bacterium have become fewer on reduction (or removal) of the antibiotic to which that strain is resistant, but to assume this would be the case with all strains/antibiotics is naïve.

It is true, with few exceptions, that initially both plasmid and chromosomally encoded resistances result in fitness losses. However, when resistance has a cost it is possible for compensatory mutations in a cell to ameliorate these costs, usually without the loss of resistance. The type of compensatory mutations that mitigate the fitness cost of acquiring antibiotic resistance, or any other incoming DNA that encodes potentially useful genes, will depend very much upon the environment in which the bacteria finds itself. These include the availability of resources, i.e. the growth environment of the bacteria, the environment of the genes (mobile or chromosomal), or whether the genes are being selected for by an external factor, such as the presence of antibiotics in the case of resistance genes.

So what sort of ‘nips and tucks’ might a bacterial population undergo in order to maintain a battery of costly genes, but that may provide an ongoing advantage? Well, this is the subject of much ongoing research; one example indicated that, in the absence of selective pressure, costly genes are simply silenced – a molecular mechanism often found in higher organisms that prevents a gene from being ‘switched on’. Thus a reservoir of drug resistance determinants may remain in populations that have compensated for their presence, remaining ‘inactive’ until a selective pressure removes the silencing.

A recent study by Peter Lind (et al.), a grad student working in the lab of Dan Andersson at Uppsala, Sweden, addresses a particularly pertinent question of compensatory mutations: those associated with genes acquired by horizontal gene transfer (HGT). HGT bypasses the slow and haphazard process of evolution (via random mutation, selection and recombination) by offering an opportunity for bacteria to receive fully fledged genes encoding pathogenicity factors (genes that make bacteria better at causing disease) as well as genes that encode resistances to disinfectants and/or antibiotics, amongst others. There is no doubt that such incoming DNA may pose significant fitness costs, so Lind et. al. set out to quantify the nature of compensatory mutations on such incoming DNA.

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