Areas of interest: Molecular evolution, Antimicrobial resistance, Bacterial adaptation

My long-term goal is to understand the relationship between genotypes and phenotypes in a meaningful context. To do this, I use a diverse range of high-throughput mutagenesis approaches to dissect the effect of mutations on molecular function and structure – such findings are particularly useful for addressing the following three key areas (summarized below).

1. Delineating the mutational effects on multiple RNA conformations

How do mutations affect RNA functions, especially those that are structurally dynamic? I recently showed in a dynamic self-splicing intron that mutations affecting the formation of multiple conformational states can be delineated effectively using deep mutational scanning (DMS). This approach has allowed the quantification of the mutational effects in a combinatorial manner, and critically, the construction of a fitness landscape for the self-splicing intron.

Keywords: Fitness landscape, genotype-phenotype relationships, deep mutational scanning, RNA, self-splicing intron

Key paper:

2. Improving weak secondary functions that mediate the emergence of novel phenotypes

Some enzymes are promiscuous; i.e. they are able to carry out secondary reactions in addition to the one they evolved to catalyze. How evolvable are these promiscuous enzymes, and to what extent do they affect organismal fitness? I have demonstrated in the past that enzyme promiscuity is important for bacterial adaptation to new environments. For some cofactor-dependent enzymes with weak promiscuous activities, a single substitution is sufficient to improve the secondary activities to near wildtype levels and to confer growth advantages to the bacterial host under selective conditions. On the whole, protein promiscuity appears to underpin many different metabolic and cellular innovations.

Keywords: Protein promiscuity, secondary functions, metabolic plasticity, PLP-dependent enzymes

Key papers:

3. Modulating metabolic networks for bacterial adaptation

When bacteria are subjected to changing (and possibly adverse) environments, they often adapt by re-wiring their transcriptional and metabolic networks. I have investigated how mutations in some transcriptional regulators and toxin/antitoxin systems can modulate the molecular networks, which in turn affect the biofilm formation process in bacteria.

Keywords: Biofilm, transcriptional regulator, transcriptional networks, metabolic networks, toxin/antitoxin systems

Key papers:

For a complete list of my publications, see my record on Google Scholar, ORCID, and PubMed