Biology subjects

Maddamsetti, R.

Publications and source records attributed to Maddamsetti, R..

3 recordsLinked to original sources

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↗