Selection Maintains Protein Interactome Resilience in the Long-Term Evolution Experiment with Escherichia coli

Grant

2022

PLoS Genet

Self Cite

A general method to infer both positive and purifying selection during the real-time evolution of hypermutator pathogens would be broadly useful. To this end, we introduce a simple test to infer mode of selection (STIMS) from metagenomic time series of evolving microbial populations. We test STIMS on metagenomic data generated by simulations of bacterial evolution, and on metagenomic data spanning 62,750 generations of Lenski’s long-term evolution experiment with Escherichia coli (LTEE). This benchmarking shows that STIMS detects positive selection in both nonmutator and hypermutator populations, and purifying selection in hypermutator populations. Using STIMS, we find strong evidence of ongoing positive selection on key regulators of the E. coli gene regulatory network, even in some hypermutator populations. STIMS also detects positive selection on regulatory genes in hypermutator populations of Pseudomonas aeruginosa that adapted to subinhibitory concentrations of colistin–an antibiotic of last resort–for just twenty-six days of laboratory evolution. Our results show that the fine-tuning of gene regulatory networks is a general mechanism for rapid and ongoing adaptation. The simplicity of STIMS, together with its intuitive visual interpretation, make it a useful test for positive and purifying selection in metagenomic data sets that track microbial evolution in real-time.

Section: Introductionsupporting

confidence: 85%

Discovery of positive and purifying selection in metagenomic time series of hypermutator microbial populations

Grant

2022

PLoS Genet

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“…Our work also complements recent findings of purifying selection affecting protein evolution [24] and protein-protein-interaction network evolution in the LTEE [25].…”

Section: Introductionsupporting

confidence: 83%

“…That finding suggests that aerobic-specific genes may have transitioned from positive selection to purifying selection in those LTEE populations [21]. Our work also complements recent findings of purifying selection affecting protein evolution [24] and protein-protein-interaction network evolution in the LTEE [25].…”

Section: Introductionsupporting

confidence: 82%

“…Additionally, one of the six nonmutator populations, Ara+1 shows a marginally significant depletion of mutations at these loci (onetailed bootstrap: p < 0.05). Ara+1 evolved a insertion-sequence hypermutator phenotype early in its evolutionary history [30][31][32], so it is plausible that signatures of purifying selection can be seen in Ara+1 [25], even though it did not evolve an elevated point-mutation rate [31].…”

Section: Control 2: Detecting Purifying Selection In the Lteementioning

confidence: 99%

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Discovery of positive and purifying selection in metagenomic time series of hypermutator microbial populations

Grant

2020

Preprint

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We introduce a simple test to infer mode of selection (STIMS) in metagenomic time series of evolving asexual populations. STIMS compares the tempo of molecular evolution for a gene set of interest against a null distribution that is bootstrapped on random gene sets. We test STIMS on metagenomic data spanning 62,750 generations of Lenski's long-term evolution experiment with E. coli (LTEE). Our method successfully recovers signals of purifying selection and positive selection on gold standard sets of genes. We then use STIMS to study the evolution of genetic modules in the LTEE. We find strong evidence of ongoing positive selection on key regulators of the E. coli gene regulatory network. Key regulatory genes show evidence of positive selection over the entire time series, even in some hypermutator populations. By contrast, we found no signal of selection on the genetic modules that show the strongest transcriptional responses to changes in growth conditions. In addition, the cis-regulatory regions of key regulators are evolving faster than the cis-regulatory regions of their downstream regulatory targets. These results indicate that one mechanistic cause for ongoing fitness gains in the LTEE is ongoing finetuning of the gene regulatory network.

“…Using STIMS, we found evidence of purifying selection on aerobic-specific and anaerobic-specific genes (Grant, Maddamsetti, et al 2021) and essential genes (Maddamsetti and Grant 2022) in the LTEE. In addition, we found evidence of purifying selection on protein interactome resilience (Maddamsetti 2021a), and purifying selection on genes encoding highly expressed and highly interacting proteins (Maddamsetti 2021b), using different methods.…”

Section: Introductionmentioning

confidence: 97%

Idiosyncratic purifying selection on metabolic enzymes in the long-term evolution experiment withEscherichia coli

2021

Preprint

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Bacteria, Archaea, and Eukarya all share a common set of metabolic reactions. This implies that the function and topology of central metabolism has been evolving under purifying selection over deep time. Central metabolism may similarly evolve under purifying selection during longterm evolution experiments, although it is unclear how long such experiments would have to run (decades, centuries, millennia) before signs of purifying selection on metabolism appear. I hypothesized that central and superessential metabolic enzymes would show evidence of purifying selection in the long-term evolution experiment with Escherichia coli (LTEE), in which 12 initially identical bacterial populations have been evolving in the laboratory for more than 30 years and 60,000 bacterial generations. I also hypothesized that enzymes that specialize on single substrates would show stronger evidence of purifying selection in the LTEE than generalist enzymes that catalyze multiple reactions. I tested these hypotheses by analyzing metagenomic time series covering 60,000 generations of the LTEE. I find mixed support for these hypotheses: patterns of purifying selection on metabolic enzymes, at least after 60,000 generations of experimental evolution, are largely idiosyncratic and population-specific.Significance StatementPurifying selection conserves organismal function over evolutionary time. I looked for evidence of purifying selection on metabolic enzymes in an ongoing long-term evolution experiment with E. coli. While some populations show signs of purifying selection, the overall pattern is inconsistent. To explain this finding, I propose that each population’s metabolism is evolving in a molecular game of Jenga. In this conceptual model, loss-of-function mutations degrade costly, redundant, and inessential metabolic functions, after which purifying selection begins to dominate. The threshold at which purifying selection activates depends on the idiosyncratic trajectory of lost redundancies in each population.