Prochlorococcus cyanobacteria are extremely abundant in the oceans, as are the viruses that infect them. How hosts and viruses coexist in nature remains unclear, although the presence of both susceptible and resistant cells may allow this coexistence. Combined whole-genome sequencing and PCR screening technology now enables us to investigate the effect of resistance on genome evolution and the genomic mechanisms behind the long-term coexistence of Prochlorococcus and their viruses. Here we present a genome analysis of 77 substrains selected for resistance to ten viruses, revealing mutations primarily in non-conserved, horizontally transferred genes that localize to a single hypervariable genomic island. Mutations affected viral attachment to the cell surface and imposed a fitness cost to the host, manifested by significantly lower growth rates or a previously unknown mechanism of more rapid infection by other viruses. The mutant genes are generally uncommon in nature yet some carry polymorphisms matching those found experimentally. These data are empirical evidence indicating that viral-attachment genes are preferentially located in genomic islands and that viruses are a selective pressure enhancing the diversity of both island genes and island gene content. This diversity emerges as a genomic mechanism that reduces the effective host population size for infection by a given virus, thus facilitating long-term coexistence between viruses and their hosts in nature.
Many bacteria, including the model bacterium Escherichia coli can survive for years within spent media, following resource exhaustion. We carried out evolutionary experiments, followed by whole genome sequencing of hundreds of evolved clones to study the dynamics by which E. coli adapts during the first 4 months of survival under resource exhaustion. Our results reveal that bacteria evolving under resource exhaustion are subject to intense selection, manifesting in rapid mutation accumulation, enrichment in functional mutation categories and extremely convergent adaptation. In the most striking example of convergent adaptation, we found that across five independent populations adaptation to conditions of resource exhaustion occurs through mutations to the three same specific positions of the RNA polymerase core enzyme. Mutations to these three sites are strongly antagonistically pleiotropic, in that they sharply reduce exponential growth rates in fresh media. Such antagonistically pleiotropic mutations, combined with the accumulation of additional mutations, severely reduce the ability of bacteria surviving under resource exhaustion to grow exponentially in fresh media. We further demonstrate that the three positions at which these resource exhaustion mutations occur are conserved for the ancestral E. coli allele, across bacterial phyla, with the exception of nonculturable bacteria that carry the resource exhaustion allele at one of these positions, at very high frequencies. Finally, our results demonstrate that adaptation to resource exhaustion is not limited by mutational input and that bacteria are able to rapidly adapt under resource exhaustion in a temporally precise manner through allele frequency fluctuations.
Phages are extremely abundant in the oceans, influencing the population dynamics, diversity and evolution of their hosts. Here we assessed the diversity and phylogenetic relationships among T7-like cyanophages using DNA polymerase (replication), major capsid (structural) and photosynthesis psbA (host-derived) genes from isolated phages. DNA polymerase and major capsid phylogeny divided them into two discrete clades with no evidence for gene exchange between clades. Clade A phages primarily infect Synechococcus while clade B phages infect either Synechococcus or Prochlorococcus. The major capsid gene of one of the phages from clade B carries a putative intron. Nearly all clade B phages encode psbA whereas clade A phages do not. This suggests an ancient separation between cyanophages from these two clades, with the acquisition or loss of psbA occurring around the time of their divergence. A mix and match of clustering patterns was found for the replication and structural genes within each major clade, even among phages infecting different host genera. This is suggestive of numerous gene exchanges within each major clade and indicates that core phage functions have not coevolved with specific hosts. In contrast, clustering of phage psbA broadly tracks that of the host genus. These findings suggest that T7-like cyanophages evolve through clade-limited gene exchanges and that different genes are subjected to vastly different selection pressures.
The evolution of antibiotic-resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria’s capacity to evolve resistance may debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many suggest leveraging phages’ ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that in vitro, λtrn, a phage trained for 28 d, suppressed bacteria ∼1,000-fold for three to eight times longer than its untrained ancestor. Prolonged suppression was due to a delay in the evolution of resistance caused by several factors. Mutations that confer resistance to λtrn are ∼100× less common, and while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to λtrn. Mutations that confer resistance to λtrn are more costly than mutations for untrained phage resistance. Furthermore, when resistance does evolve, λtrn is better able to suppress these forms of resistance. One way that λtrn improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This transfer of information from the host genome is an unexpected but highly efficient mode of training phage. Lastly, we found that many other independently trained λ phages were able to suppress bacterial populations, supporting the important role training could play during phage therapeutic development.
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