Lethal Genes Present A Barrier to Bacterial Horizontal Gene Transfer

Author:  Getz Matthew

Date:  November 2007

Some genes when transferred between bacteria could be lethal to the recipient, barricading the transmission of genetic material between the organisms, an analysis by the U.S. Department of Energy Joint Genome Institute (DOE JGI) revealed in the October 19 edition of the journal Science. Eddy Rubin, director of DOE JGI, suggested that this research could present a novel approach to the discovery of new antibiotics.

In the study, Rubin and his team postulated that the industrial-scale "shotgun" DNA sequencing process resembles the transmission of DNA from one organism to another, a mechanism called horizontal gene transfer. This transfer event, although rare in animals, occurs frequently in microorganisms and is one of the main factors contributing to the development of antibiotic resistant bacteria.

The shotgun sequencing approach involves shearing the organism's DNA into manageable fragments and then inserting them into a disarmed strain of E. coli, where the fragments multiply and produce large amounts of target DNA. This is the part of the sequencing process that is similar to horizontal gene transfer. The target DNA is then sequenced and the sequenced fragments are assembled via computers, which use the overlap that occurs among the different fragments to place the DNA sequence in its proper place in the genome.

However, there are roadblocks along the way to fully sequencing a complete genome. Rubin explained these difficulties, "When you sequence a genome, you never get the whole genome reconstructed in one pass. You always get gaps in the assembly.Our breakthrough was in understanding that gaps occur because some genes cannot be transferred to E. coli – because they are lethal."

In the analysis, Rubin and his colleagues sifted through more than nine billion nucleotides to assess gaps in 80 different microbial genomes. They found that the same genes repeatedly caused these gaps, meaning that they could not be transferred into the E. coli.

These lethal genes could provide better reference points for building phylogenic trees – the means to represent evolutionary relationships between organisms – since they sometimes exist as only a single copy in the genome and are not laterally transferred between organisms.

Rubin explained the broad applicability of the study, "The genes we categorized, while providing us a lesson in the evolutionary history of the organism, now suggest a short-cut for finishing genomes. In addition, it offers a new strategy for screening molecules that may represent the next generation of broad-spectrum antibiotics. We expect that many organisms, not just E. coli, are susceptible to being killed if they take up certain genes that are over-expressed. We have strong evidence that most microbes behave like that."

Written by Matthew Getz

Reviewed by Suvash Shrestha

Published by Pooja Ghatalia.