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The Fogg Group studies various aspects of the role of viruses in Horizontal Gene Transfer (HGT)
Viruses are the most abundant biological entities on Earth. They are responsible for widespread HGT between microbes and are a major contributor to carbon cycling in the environment. HGT plays a crucial role in bacterial evolution by providing adaptive shortcuts and access to important traits such as fitness, virulence, or antibiotic resistance. This is particularly true for the densely packed microbial communities such as marine biofilms or the human gut. The holistic impact of viruses and virus-like entities in real world settings remains poorly understood, and our research aims to address this knowledge gap. In particular, the lab specializes in the study of bacteriophages and an influential, yet greatly understudied, mechanism of HGT known as Gene Transfer Agents (GTAs).
GTAs are essentially domesticated viruses that have lost the ability to propagate themselves and instead they indiscriminately package and disseminate any DNA present in their microbial hosts, with phenomenal rates of antibiotic gene transfer observed in situ. GTAs are widespread across the microbial tree of life. They are often conserved for hundreds of millions of years, and have evolved independently on multiple occasions in diverse prokaryotes. This conservation and repeated convergent evolution demonstrates the important ecological role and strong adaptive advantage that GTAs provide to their hosts.
DNA Packaging by Viruses and Gene Transfer Agents (GTAs)
DNA Packaging by Viruses and Gene Transfer Agents (GTAs)
True viruses are essentially selfish – they use host resources to replicate their own genome and package it into a protein shell before the progeny moves on to infect a new host. GTAs, on the other hand, have no preference for the spread of their own genes and therefore any gene may be transferred by GTAs.
Our work aims to improve our understanding of the structure of the GTA DNA packaging complex in isolation and together with DNA or the broader GTA particles, how universal these structures are between evolutionary distinct GTAs, what the similarities and differences are between GTA and viral systems, how GTA specific characteristics affect overall function.
Our findings will be leveraged to develop biotechnological tools (e.g. genome editing of intractable microorganisms, delivery of potent antimicrobials, etc) or to define classifiers that allow us to effectively distinguish GTAs from prophages in silico – a key challenge in the GTA field.
Structure and features of the Rhodobacter GTA (RcGTA). RcGTAs look like typical tailed bacteriophages but differ if several important ways - 1) The DNA packaged inside does not encode the GTA but is instead non-specific fragments of any DNA in the host cell; 2) Lack of DNA specificity is likely due to the lack of a Small Terminase DNA-binding domain; 3) The capacity of the capsid is too small to contain its own genes due to its small intrinsic geometry and oblate shape; 4) low packaged DNA density, possibly due to conserved GTA amino acid residues in the Large Terminase protein.
The Impact of GTAs on Bacterial Evolution
The Impact of GTAs on Bacterial Evolution
GTAs are likely to play a pivotal role in promoting bacterial adaptability, evolution, and spread of AMR. However, despite their clear importance, an urgent knowledge gap exists regarding the specific regulatory and mechanistic frameworks that govern GTA activity. We employ a multidisciplinary approach combining genetic, molecular, structural, and evolutionary methodologies to:
Provide in-depth regulatory, mechanistic, and evolutionary knowledge of this prevalent, yet understudied, mechanism of genetic exchange
Produce empirical information that will allow for the identification and/or induction of novel GTAs in non-model organisms (e.g. in soil, marine, clinical environments)
Understand how GTAs navigate complex environments like biofilms, and to utilize GTA-derived components for biofilm disruption
Predict the impact they have on bacterial genomes and how they provide evolutionary benefits to their hosts
By generating foundational knowledge of GTA activity in the environment, this project will enable more accurate predictions and mitigation strategies for the flow of virulence and antibiotic resistance genes into clinical environments. Furthermore, mechanistic insights into GTA regulation will facilitate the rational design of targeted interventions, for example interruption of gene transfer to and from pathogens, or the engineering of microbiomes.
The Impact of Gene Transfer Agents. For a long time GTAs were thought to be niche elements only found in few marine species, however, we now know they are abundant in diverse environments and can carry out a variety of functions. Our research seeks to: 1) uncover the true prevalence of GTAs and to fully characterize GTAs from diverse species; 2) decipher precisely how GTAs are regulated at a molecular level and the environmental triggers that lead to their production; 3) define the mechanisms by which GTAs provide an evolutionary benefit. We know there is a huge cost to GTA production, i.e. cell death, but we also have evidence that GTAs can provide multiple potential benefits to recipient cells in the population.
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