This week we profile a recent publication in Nature Communications from Dr. Houra Merrikh and
Dr. Christopher Merrikh (pictured) in the UW Department of Microbiology.
Can you provide a brief overview of your lab’s current research focus?
The research in Houra Merrikh’s lab is focused on bacterial DNA replication, repair, mutagenesis, and evolution. Our studies on DNA replication are focused on identifying the way cells handle the inevitable collisions between the replication and transcription machineries. We have found that these events increase mutagenesis in a gene-specific manner and increase the ability of bacteria to rapidly evolve. These discoveries have helped us identify important molecular mechanisms that allow bacteria to develop antibiotic resistance. It is our hope that in the future, we will be able to repress some of these key pathways and preserve or even improve the effectiveness of many antibiotics.
What is the significance of the findings in this publication?
The current paper is concerned with identifying the driving forces that have shaped bacterial genomes. In particular, we asked how gene inversion events change the prevalence of head-on genes (those encoded on the lagging strand). We are concerned about these genes, because they cause transcription to run head-on into the DNA replication fork. Such interactions are particularly difficult for the replication fork to overcome. Presumably as a result of this issue, all known bacterial genomes are comprised mainly of co-directionally oriented genes (encoded on the leading DNA strand). These observations have led people to speculate about the many remaining head-on genes present in all known bacterial genomes; some suggest that these genes are never transcribed, avoiding the problem of conflicts. Others suggest that evolution will eventually drive all genes to be co-directional. While still others think that bacterial genomes are constrained, keeping some genes in the head-on orientation. These important models were never tested, possibly because we lacked a robust means of identifying the gene inversions that occurred over the course of natural evolution. Yet, a few lesser known publications have done just that – they analyzed genomic sequence patterns (the so-called “GC skew”) to identify fragments of bacterial chromosomes that inverted at some point in the past. When I found that no one had ever applied this method systematically, I felt it was an exciting opportunity. So, I calculated GC skew values for every gene in the genome for many bacteria, and looked for those with negative values – a potent indicator that an inversion has occurred. What I found was completely counter to every expectation we had encountered in the field: our data showed that the number of head-on genes is not being reduced over long time scales. Rather, new head-on genes are being produced! These patterns repeated across every major bacterial phyla. Together, our findings suggested that head-on genes, and by extension head-on replication-transcription conflicts, might actually be desirable for many genes.
Our data also provide a potential explanation for why head-on replication-transcription conflicts could actually be beneficial overall (despite the problems they cause for DNA replication): We found that head-on genes have a higher mutation rate and evolve faster than co-directional genes. This appears to be useful for certain types of genes that are expected to need to evolve quickly. In particular, virulence and antibiotic resistance genes. For example, in M. tuberculosis, both virulence and antibiotic resistance genes evolve faster when they’re encoded in the head-on orientation. We suggest that in the future, scientists may want to emphasize targeting proteins encoded by co-directional genes with new antibiotics, because they should gain resistance mutations more slowly. They might also pay special attention to head-on virulence genes as these genes could be important drivers of bacterial variation and adaptation to the host cell environment.
What are the next steps for this research?
We would like to understand the evolutionary history of head-on genes in greater detail. We are now teaming up with evolutionary biologists to get a better sense of the dynamics of gene inversion events. Specifically, we would like to figure out how frequently cells sample new orientations for their genes, and determine how long newly inverted alleles are retained before they flip back (if ever). We also plan to determine the impact of gene orientation on the development of antibiotic resistance and the evolution of virulence.
If you’d like us to mention your funding sources, please list them.
We are funded by a Bill and Melinda Gates Foundation as well as the National Institute of Health.
