Invertible DNA regions commonly contain promoters, a type of gene regulatatory element, which can be oriented in the ON orientation such the promoter activates gene transcription or in the backwards or OFF orientation, where the promoter cannot initiate gene transcription. Invertible regions may contain other regulatory elements such as terminators.
Invertible regions play a role in phase variation in bacteria, a system in which bacteria generate frequent reversible changes at specific hypermutable genetic loci, which introduces diverse phenotypes into clonal populations. The different phenotypes mediate adaptation to selective events like abrupt changes to their environment. Phase variation plays a crucial role in colonization by commensal bacterial and infection by pathogens. The rate of inversion is one every 100 to 1000 cells in Escherichia coli, which is high than the rate of point mutations by at least three orders of magnitude.
Research groups lead by Eric Alm and Ramnik Xavier at the Broad Institute at MIT and Harvard reported in Science in 2019 the discovery of invertons containing promoters that regulate antibiotic resistance genes. These promoters switch to the ON orientation after antibiotic treatment in metagenomic data and in vitro experiments. The researchers suggest that a fitness cost in expressing antibiotic resistance genes could explain reversion to the OFF orientation in most of the bacteria population in the absence of antibiotic treatment but that invertons act like an insurance for future conditions where the bacteria may need to resist antibiotics. This system may contribute to a longer persistence of antibiotic resistance genes in microbial communities.
The Alm and Xavier research team found that inversions occurred between fecal microbiota transplant donors and recipients, which expanded on previous work on invertons that regulate capsular polysaccharide biosynthesis operons of human gut bacteria.
The distribution of invertons across environmental niches showed a higher prevalence in host-associated and gut-associated species. The team found that 73% of invertible promoters regulate genes involved in the biosynthesis of polysaccharides, fimbriae, outer membrane proteins and autotransporters. A high proportion of genes regulated by invertons were found to be those that express gene products that are located on the exterior of the cell and exposed to the host immune system or phages.
Flippable DNA switches help bacteria resist antibiotics and are more common than thought