Biology subjects

Maddamsetti, R.

Publications and source records attributed to Maddamsetti, R..

23 records · Page 2Linked to original sources

bioRxiv2020

Genomic and phenotypic evolution of Escherichia coli in a novel citrate-only resource environment

Evolutionary innovations allow populations to colonize new, previously inaccessible ecological niches. We previously reported that aerobic growth on citrate (Cit+) evolved in a population of Escherichia coli during adaptation to a minimal glucose medium containing citrate (DM25). Cit+ can grow in citrate-only medium (DM0), which is a novel environment for E. coli. To study adaptation to this new niche, we evolved one set of Cit+ populations for 2,500 generations in DM0 and a control set in DM25. We identified numerous parallel mutations, many mediated by transposable elements. Several lineages evolved multi-copy amplifications containing the maeA gene, constituting up to [~]15% of the genome. We also found substantial cell death in ancestral and evolved clones. Our results demonstrate the importance of copy-number variation and transposable elements in the refinement of the Cit+ trait. However, the observed mortality suggests a persistent evolutionary mismatch between E. coli physiology and a citrate-only environment.

evolutionary biology↗

bioRxiv2019

Proteome-scale discovery of protein interactions with residue-level resolution using sequence coevolution

The majority of protein interactions in most organisms are unknown, and experimental methods for determining protein interactions can yield divergent results. Here we use an orthogonal, purely computational method based on sequence coevolution to discover protein interactions at large scale. In the model organism Escherichia coli, 53% of protein pairs in the proteome are eligible for our method given currently available sequenced genomes. When assaying the entire cell envelope proteome, which is understudied due to experimental challenges, we found 620 likely interactions and their predicted structures, increasing the space of known interactions by 529. Our results show that genomic sequencing data can be used to predict and resolve protein interactions to atomic resolution at large scale. Predictions and code are freely available at https://marks.hms.harvard.edu/ecolicomplex and https://github.com/debbiemarkslab/EVcouplings

bioinformatics↗

bioRxiv2018

Genome-wide discovery of epistatic loci affecting antibiotic resistance using evolutionary couplings

The analysis of whole genome sequencing data should, in theory, allow the discovery of interdependent loci that cause antibiotic resistance. In practice, however, identifying this epistasis remains a challenge as the vast number of possible interactions erodes statistical power. To solve this problem, we extend a method that has been successfully used to identify epistatic residues in proteins to infer genomic loci that are strongly coupled and associated with antibiotic resistance. Our method reduces the number of tests required for an epistatic genome-wide association study and increases the likelihood of identifying causal epistasis. We discovered 38 loci and 250 epistatic pairs that influence the dose needed to inhibit growth for five different antibiotics in 1,102 isolates of Neisseria gonorrhoeae that were confirmed in an independent dataset of 495 isolates. Many known resistance-affecting loci were recovered; however, the majority of loci occurred in unreported genes, including murE which was associated with cefixime. About half of the novel epistasis we report involved at least one locus previously associated with antibiotic resistance, including interactions between gyrA and parC associated with ciprofloxacin. Still, many combinations involved unreported loci and genes. Our work provides a systematic identification of epistasis pairs affecting antibiotic resistance in N. gonorrhoeae and a generalizable method for epistatic genome-wide association studies.

genomics↗

bioRxiv2018

Viral gain-of-function experiments uncover residues under diversifying selection in nature

Viral gain-of-function mutations are commonly observed in the laboratory; however, it is unknown whether those mutations also evolve in nature. We identify two key residues in the host recognition protein of bacteriophage {lambda} that are necessary to exploit a new receptor; both residues repeatedly evolved among homologs from environmental samples. Our results provide evidence for widespread host-shift evolution in nature and a proof of concept for integrating experiments with genomic epidemiology.

evolutionary biology↗

bioRxiv2017

Analysis of bacterial genomes from an evolution experiment with horizontal gene transfer shows that recombination can sometimes overwhelm selection

We analyzed genomes from an experiment in which Escherichia coli K-12 Hfr donors were periodically introduced into 12 evolving populations of E. coli B. Previous work showed that recombination did not increase adaptation, despite increasing variation relative to asexual controls. The effects of recombination were highly variable: one lineage was mostly derived from the donors, while another acquired almost no donor DNA. In most lineages, some regions showed repeated introgression and others almost none. Regions with high introgression tended to be near the donors origin of transfer sites. To determine whether introgressed alleles imposed a genetic load, we extended the experiment for 200 generations without recombination and sequenced whole-population samples. Beneficial alleles in the recipient populations were occasionally driven extinct by maladaptive donor-derived alleles. On balance, our analyses indicate that the plasmid-mediated recombination was sufficiently frequent to drive donor alleles to fixation without providing much, if any, selective advantage.

evolutionary biology↗