Dr. Mario A. Fares (Principal Investigator)



Contact Details:

Email: faresm@tcd.ie
Phone: +353 (0) 1 8963521

Introduction

The main aim of my research is the understanding of how novel functions and biological complexity emerge in nature. In particular, we are interested in identifying the evolutionary trajectories, at the genome and regulatory levels, to biological innovations. This aim is relevant not only to the understanding of species diversification and the emergence of complexity but also to provide key knowledge for biotechnological and biomedical developments. Many biological innovations are simply off-limits  for evolution because they involve dramatic changes to organisms that are often not tolerated by natural selection. However, under certain conditions, some molecular mechanisms can minimize the effects of innovative mutations allowing them to survive in the genome and become eventually fixed, potentially emerging as adaptive features when the environment changes. Our focus is on the characterization and use of buffering molecular mechanisms that provide robustness to mutations allowing the exploration of larger genotypic networks, and thus originating novel phenotypes. The main robustness mechanisms we study are heat-shock proteins, also known as molecular chaperones, and gene and genome duplications.

To achieve our goal, we conduct theoretical and experimental research in a diverse range of fields. In particular, we test specific evolutionary scenarios by evolving microbes under laboratory-controlled experiments and analyzing the consequences of specific evolutionary dynamics at the genome and physiological levels. A brief description of our specific interests is given below.

a) The Role of Molecular Chaperones in Regulating Mutational Robustness and Functional Innovation

 

Heat shock proteins (Hsps) belong to a largely conserved family of proteins that are ubiquitous in living organisms at all levels of complexity, from organelles to microbes and multi-cellular organisms. Hsps perform essential functions in the cell, chief among which is the folding of nascent proteins to acquire their functional conformation. Through the folding of mutated protein versions, some hsps have been suggested to buffer the destabilizing effects of mutations and, in doing so, they allow genomes to explore a wider genotypic network and access otherwise prohibited phenotypes. How do hsps regulate this mutational robustness is unknown. We are mostly interested on the role of GroEL, an essential hsp in prokaryotes and eukaryotic organelles, in regulating mutational robustness and allowing the epistatic interaction between conditionally neutral mutations and innovative destabilizing changes.

b) The Role of Gene Duplication in Functional Diversification

Gene duplication is the process by which a gene originates two identical copies, presumably performing identical functions too. Gene duplication can take place at different scales, from single nucleotides to entire genomes. While the classic theory of Susumo Ohno established that after duplication one gene copy, devoid of selection pressures, can explore novel functions alternative to the ancestral ones, evolution by gene duplication seems more complex than predicted by theory: both the genomic background in which it arises and the mechanism of duplication having significant impact on determining the functional fates of duplicates. What seems less doubtful is that major organismal diversification events are concomitant with gene and genome duplications. However, it remains undefined the mechanism through which gene duplication leads to innovations. In my group, we investigate mutational robustness mediated by gene duplication as a starting point in the re-wiring of the epistatic and regulatory relationships between genoytpes, a cause prima facie of innovations.

c) Molecular Coevolution

Coevolution is classically defined as the reciprocal natural selection between two interacting populations. From the molecular perspective, coevolution can be readily understood as the reciprocal selective constraints between two interacting molecules. Within the framework of molecular coevolution I include also epistasis because certain genomic background can facilitate previously prohibited mutations that, in turn, modify the epistatic potential of the new genomic context. We are interested in those signatures of coevolution that are the result of molecular coadaptation. For example, physically interacting proteins exercise reciprocal selection upon one another that is translated into a coadaptation process which leaves coevolution signatures in the amino acid sequences. Coevolution has many theoretical and pragmatic application, probably the most sound being the in silico identification of protein-protein physical interactions or the prediction of three-dimensional protein folds. In my group, we develop mathematical models and computational tools to identify molecular coevolution within and between protein sequences. We are particularly interested in identifying coadaptation dynamics in general, protein-protein interactions and functional shifts leading to protein functional promiscuity.

 

d) Experimental Evolution

To test many of the evolutionary hypotheses derived from theoretical analyses we frequently rely on the reconstruction of particular evolutionary scenarios in the laboratory using evolution experiments.In these evolution experiments we use microbes that we evolve for thousands of generations under specific laboratory conditions. Genome and RNA sequencing is often used in my laboratory to determine the mutational spectrum of evolved cells and to map genotypes to phenotypes. So far, we have used such evolution experiments to test the potential of GroEL and of gene and genome duplications to buffer the effects of deleterious non-lethal mutations in cells evolving under conditions of very inefficient natural selection. We are also developing methods to identify the evolutionary trajectories of microbes to adaptation to various stress conditions. These trajectories are our base from which we hope to stem a number of technological and biomedical applications.



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