Comparative systems biology

Tens of thousands of microbial genomes are being sequenced each year, enabling the application of comparative genomics and evolutionary biology to unravel biological mechanisms. I have made extensive use of computational tools such as constraints based modeling, to identify patterns in the evolution and structure-function relationships of metabolic phenotypes across thousands of bacterial strains. I showed that the large genomic and phenotypic diversity observed across bacterial species has developed through a regular clock-like phenotypic divergence over hundreds of millions of years (poster). I am further using comparative modeling to understand how metabolic architectures constrain microbial physiology, their evolutionary trajectories and potential for innovation (poster).

Probabilistic metabolic modeling

Accurate genome annotations beyond model microbial species is a high research priority. To address annotation uncertainty in non-model species I developed GLOBUS (Global Biochemical Reconstruction Using Sampling) -a principled probabilistic framework for the genome-wide annotation of metabolic genes. GLOBUS combines information about sequence homology with gene-gene functional correlations to assign correct probabilities to the annotation of biochemical functions to candidate genes. This method offers the ability to reconcile inconsistent annotations and has proven most useful for assigning functions to genes with very low similarity to known enzymes. This tool was succesfully applied in the discovery of enzymatic gene functions in the model bacterial species B. subtilis; currently, GLOBUS is being used to support the reconstruction and modeling of metabolism across multiple microbial species of biomedical interest.

Systems biology of pathogens

The rise of antimicrobial resistance is a pressing public health challenge. In-depth understanding of the metabolism and potential interactions of pathogenic microorganisms holds great importance in the identification of new therapeutic interventions. An illustration of this potential is the reconstruction and comprehensive systems analysis of the first genome-scale reconstruction of P. falciparum metabolism. The model enabled the investigation of the parasite’s metabolic properties in an integrated fashion and provides a unique platform for the interpretation of transcriptomics, metabolomics, and other data. Metabolic simulations led to the identification of 40 new drug targets that may open new avenues for malaria treatment.

Mechanisms of molecular evolution

Sample logotype

Evolution occurs at multiple levels of biological organization, therefore a complete understanding of how life evolves requires an account of the relationship between genetic changes and their phenotypic impact. One interesting question in this area is what sets the rate of protein evolution (also known as the molecular clock). While it is well known that expression levels are a major determinant of evolutionary rates, the reasons behind this correlation are widely debated. I investigated this problem using experiments and comparative analyses. The analysis showed that there is a minor contribution of misfolding toxicity, compared to gratuitous protein expression, in determining the fitness costs of mutations in highly expressed proteins. As new experimental methods are developed, and data are collected across different organisms, the biological constrains behind these associations will continue to become clear.

2018 Germán Plata
Template design by Andreas Viklund