Research Projects

Cellular consequences of genetic variation



Our group studies how cellular functions have diverged during evolution as well as how they are altered in disease. We study the molecular sources of phenotypic novelties, exploring how DNA changes are propagated through molecular structures and interaction networks to give rise to phenotypic variability.

We use post-translational modifications (PTMs) data from mass-spectrometry experiments to study the evolutionary dynamics and functional importance of post-translational regulatory networks. We aim to reconstruct the ancestral states of PTM regulatory networks in order to understand how some of the wondrous cellular functions that exist today were like in their primitive forms. For this we develop approaches to infer the history of protein modifications; the determinants of specificity for PTM regulators; and the ways protein function is controlled by PTMs.

We are also increasingly interested in understanding how these regulatory systems make decisions in present day species and how they are re-wired in the context of disease (e.g. cancer or infection). We have assembled a collection of conditional phosphoproteomic experiments (phosfate.com/) that we have used to study human kinase regulation and the space of signalling states of cells. We are now studying how genetic variation seen in cancer cells changes their signalling state with an aim to understand context dependent cellular vulnerabilities to drugs.

Beyond PTM regulatory networks we are broadly interested in studying why different individuals or species diverge in their response to drugs, other environmental perturbations or additional genetic changes. For this purpose we are developing a general propose framework to predict the molecular consequences of DNA changes (www.mutfunc.com) and using these to guide genotype-phenotype associations.

Areas of interest


Function and Evolution of Post-translational networks

In collaboration with mass-spectrometry groups we are using a growing resource of PTMs from different species to study the functional relevance and evolutionary properties of post-translational networks. Areas of interest include: the study and prediction of enzyme specificity and PTM interaction networks; using information on conditional changes of PTM abundance to study signalling specificity and functional co-regulation of PTMs; development of novel methods to prioritize functionally relevant PTMs within large-scale datasets.
Predicting regulatory regions within the HSP70 domain family by measuring the conservation of PTMs.

Studying the structural and cellular mechanisms underlying trait variation


With the recent improvements in high-throughput methodologies it is becoming feasible to perform large-scale characterisation of different individuals of the same species. Ultimately this information will allow us to better understand how the genetic variation in a population relates to the variations in phenotypes. In this area of research we are developing methods to predict phenotypic variation in different strains of S. cerevisiae and E. coli from complete genome sequences making use of the accumulated knowledge for the well characterized lab strain. We are also interested in better understanding the molecular mechanisms that underlie trait variation and disease in humans.

The group is at EMBL-EBI within the Wellcome trust Genome Campus in Cambridge, UK