The rampant variability in codon bias existing between bacterial genomes is expected to interfere with horizontal gene transfer (HGT), a phenomenon that drives bacterial adaptation. However, delineating the constraints imposed by codon bias on functional integration of the transferred genes is complicated by multiple genomic and functional barriers controlling HGT, and by the dependence of the evolutionary outcomes of HGT on the host’s environment. Here, we designed an experimental system in which codon composition of the transferred genes is the only variable triggering fitness change of the host. We replaced E. coli’s chromosomal folA gene encoding dihydrofolate reductase, an essential enzyme that constitutes a target for trimethoprim, with combinatorial libraries of synonymous codons of folA genes from trimethoprim-sensitive Listeria grayi and trimethoprim-resistant Neisseria sicca. The resulting populations underwent selection at a range of trimethoprim concentrations, and the ensuing changes in variant frequencies were used to infer the fitness effects of the individual combinations of codons. We found that when HGT causes overstabilization of the 5’-end mRNA, the fitness contribution of mRNA folding stability dominates over that of codon optimality. The 5’-end overstabilization can also lead to mRNA accumulation outside of the polysome, thus preventing the decay of the foreign transcripts despite the codon composition-driven reduction in translation efficiency. Importantly, the fitness effects of mRNA stability or codon optimality become apparent only at sub-lethal levels of trimethoprim individually tailored for each library, emphasizing the central role of the host’s environment in shaping the codon bias compatibility of horizontally transferred genes.
The stability and dynamics of ecological communities are dictated by interaction networks typically quantified at the level of species. But how such networks are influenced by intra-species variation (ISV) is poorly understood. Here, we use ~500,000 chromosomal barcodes to track high-resolution intra-species clonal lineages of Escherichia coli invading mice gut with the increasing complexity of gut microbiome: germ-free, antibiotic-perturbed, and innate microbiota. By co-clustering the dynamics of intra-species clonal lineages and those of gut bacteria from 16S rRNA profiling, we show the emergence of complex time-dependent interactions between E. coli clones and resident gut bacteria. With a new approach, dynamic covariance mapping (DCM), we differentiate three phases of invasion in susceptible communities: 1) initial loss of community stability as E. coli enters; 2) recolonization of some gut bacteria; and 3) recovery of stability with E. coli coexisting with resident bacteria in a quasi-steady state. Comparison of the dynamics, stability and fitness from experimental replicates and different cohorts suggest that phase 1 is driven by mutations in E. coli before colonization, while phase 3 is by de novo mutations. Our results highlight the transient nature of interaction networks in microbiomes driven by the persistent coupling of ecological and evolutionary dynamics.
The rampant variability in codon bias existing between bacterial genomes is expected to interfere with horizontal gene transfer (HGT), a phenomenon that drives bacterial adaptation. However, delineating the constraints imposed by codon bias on functional integration of the transferred genes is complicated by multiple genomic and functional barriers controlling HGT, and by the dependence of the evolutionary outcomes of HGT on the environment of the host. Here, we designed an experimental system in which codon composition of the transferred genes is the only variable triggering fitness change of the host. We replaced the chromosomal folA gene from E. coli encoding dihydrofolate reductase, an essential enzyme that constitutes a target for trimethoprim, with combinatorial libraries of synonymous codons of folA genes from trimethoprim-sensitive Listeria grayi and trimethoprim-resistant Neisseria sicca. The resulting populations underwent selection at a range of trimethoprim concentrations, and the ensuing changes in variant frequencies were used to infer the fitness effects of the individual combinations of codons. We found that when HGT causes overstabilization of the 5-end mRNA, the fitness contribution of mRNA folding stability dominates over that of codon optimality. The 5-end overstabilization can also lead to mRNA accumulation outside of the polysome, thus preventing the decay of the foreign transcripts despite the codon composition-driven reduction in translation efficiency. Importantly, the fitness effects of mRNA stability or codon optimality become apparent only at sub-lethal levels of trimethoprim individually tailored for each library, emphasizing the central role of on the environment of the host in shaping the codon bias compatibility of horizontally transferred genes.
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