John W Pinney’s research while affiliated with Imperial College London and other places

In times when herpesvirus genomic data were scarce, the cospeciation between these viruses and their hosts was considered to be common knowledge. However, as more herpesviral sequences were made available, tree reconciliation analyses started to reveal topological incongruences between host and viral phylogenies, indicating that other cophylogenetic events, such as intrahost speciation and host switching, likely played important roles along more than 200 million years of evolutionary history of these viruses. Tree reconciliations performed with undated phylogenies can identify topological differences, but offer insufficient information to reveal temporal incongruences between the divergence timing of host and viral species. In this study, we performed cophylogenetic analyses using time-resolved trees of herpesviruses and their hosts, based on careful molecular clock modelling. This approach enabled us to infer cophylogenetic events over time, and also integrate information on host biogeography to better understand host-virus evolutionary history. Given the increasing amount of sequence data now available, mismatches between host and viral phylogenies have become more evident, and to account for such phylogenetic differences, host switches, intrahost speciations and losses were frequently found in all tree reconciliations. For all subfamilies in Herpesviridae, under all scenarios we explored, intrahost speciation and host switching were more frequent than cospeciation, which was shown to be a rare event, restricted to contexts where topological and temporal patterns of viral and host evolution were in strict agreement.

Herpesviruses (HVs, Family: Herpesviridae) have large genomes that encode hundreds of proteins. Apart from amino acid mutations, protein domain acquisitions, duplications and losses are also common modes of evolution. HV domain repertoires differ across species, and only a core set is shared among all species, aspect that raises a question: How have HV domain repertoires diverged while keeping some similarities? To answer such question, we used profile Hidden Markov Models (HMMs) to search for domains in all possible translated open reading frames (ORFs) of fully sequenced HV genomes. With at least 274 domains being identified, we built a matrix of domain counts per species, and applied a parsimony method to reconstruct the ancestral states of these domains along the HV phylogeny. It revealed events of domain gain, duplication, and loss over more than 400 millions of years, where Alpha-, Beta-, and GammaHVs expanded and condensed their domain repertoires at distinct rates. Most of the acquired domains perform 'Modulation and Control', 'Envelope', or 'Auxiliary' functions, categories that showed high flexibility (number of domains) and redundancy (number of copies). Conversely, few gains and duplications were observed for domains involved in 'Capsid assembly and structure', and 'DNA Replication, recombination and metabolism'. Among the forty-one primordial domains encoded by Herpesviridae ancestors, twenty-eight are still found in all present-day HVs. Because of their distinct evolutionary strategies, HV domain repertoires are very specific at the subfamily, genus and species levels. Differences in domain composition may not only explain HV host range and tissue tropism, but also provide hints to the origins of HVs.

The evolution of protein-protein interactions (PPIs) is directly influenced by the evolutionary histories of the genes and the species encoding the interacting proteins. When it comes to PPIs of host-pathogen systems, the complexity of their evolution is much higher, as two independent, but biologically associated entities, are involved. In this work, an integrative approach combining phylogenetics, tree reconciliations, ancestral sequence reconstructions, and homology modelling is proposed for studying the evolution of host-pathogen PPIs. As a case study, we analysed the evolution of interactions between herpesviral glycoproteins gD/gG and the cell membrane proteins nectins. By modelling the structures of more than 12,000 ancestral states of these virus-host complexes it was found that in early times of their evolution, these proteins were unable to interact, most probably due to electrostatic incompatibilities between their interfaces. After the event of gene duplication that gave rise to a paralog of gD (known as gG), both protein lineages evolved following distinct functional constraints, with most gD reaching high binding affinities towards nectins, while gG lost such ability, most probably due to a process of neofunctionalization. Based on their favourable interaction energies (negative ΔG), it is possible to hypothesize that apart from nectins 1 and 2, some alphaherpesviruses might also use nectins 3 and 4 as cell receptors. These findings show that the proposed integrative method is suitable for modelling the evolution of host-pathogen protein interactions, and useful for raising new hypotheses that broaden our understanding about the evolutionary history of PPIs, and their molecular functioning.

Herpesviruses (HVs) have large genomes that can encode thousands of proteins. Apart from amino acid mutations, protein domain acquisitions, duplications and losses are also common modes of evolution. HV domain repertoires differ across species, and only a core set is shared among all viruses, aspect that raises a question: How have HV domain repertoires diverged while keeping some similarities? To answer such question, we used profile HMMs to search for domains in all possible translated ORFs of fully sequenced HV genomes. With at least 274 domains being identified, we built a matrix of domain counts per species, and applied a parsimony method to reconstruct the ancestral states of these domains along the HV phylogeny. It revealed events of domain gain, duplication and loss over more than 400 millions of years, where Alpha-, Beta- and Gammaherpesviruses expanded and condensed their domain repertoires at distinct rates. Most of the acquired domains perform 'Modulation and Control', 'Envelope' or 'Auxiliary' functions, categories that showed high flexibility (number of domains) and redundancy (number of copies). Conversely, few gains and duplications were observed for domains involved in 'Capsid assembly and structure', and 'DNA Replication, recombination and metabolism'. Among the 41 primordial domains encoded by herpesvirus ancestors, 28 are still found in all present-day HVs. Because of their distinct evolutionary strategies, herpesvirus domain repertoires are very specific at the subfamily, genus and species levels. Differences in domain composition may not just explain HV host range and tissue tropism, but also provide hints to the origins of herpesviruses.

Cospeciation has been suggested to be the main force driving the evolution of herpesviruses, with viral species co-diverging with their hosts along more than 400 million years of evolutionay history. Recent studies, however, have been challenging this assumption, showing that other co-phylogenetic events, such as intrahost speciations and host switches play a central role on their evolution. Most of these studies, however, were performed with undated phylogenies, which may mis-estimate the frequency of certain events. In this study we performed co-phylogenetic analyses using time-calibrated trees of herpesviruses and hosts. This approach allowed us to (i) perform better estimations of co-phylogenetic events over time, and (ii) integrate crucial information about continental drift and historical biogeography to better understand virus-host evolution. We observed that cospeciations were in fact relatively rare events, which took place mostly after the Late Cretaceous (~100 Millions of years ago). Host switches were particularly common among alphaherpesviruses, where at least 10 transfers were detected. Among beta- and gammaherpesviruses, transfers were less frequent, with intrahost speciation followed by loss playing a more prominent role, especially from the Early Jurassic to the Early Cretaceous, when these viral lineages underwent several intrahost speciations. Our study reinforces the evidence that cospeciations are indeed uncommon events in herpesvirus evolution. More than topological incongruences, mismatches in divergence times were the main disagreements between host and viral phylogenies. In most cases, host switches could not explain such disparities, highlighting the important role of losses and intrahost speciations in the evolution of herpesviruses.

To study virus–host protein interactions, knowledge about viral and host protein architectures and repertoires, their particular evolutionary mechanisms, and information on relevant sources of biological data is essential. The purpose of this review article is to provide a thorough overview about these aspects. Protein domains are basic units defining protein interactions, and the uniqueness of viral domain repertoires, their mode of evolution, and their roles during viral infection make viruses interesting models of study. Mutations at protein interfaces can reduce or increase their binding affinities by changing protein electrostatics and structural properties. During the course of a viral infection, both pathogen and cellular proteins are constantly competing for binding partners. Endogenous interfaces mediating intraspecific interactions—viral–viral or host–host interactions—are constantly targeted and inhibited by exogenous interfaces mediating viral–host interactions. From a biomedical perspective, blocking such interactions is the main mechanism underlying antiviral therapies. Some proteins are able to bind multiple partners, and their modes of interaction define how fast these “hub proteins” evolve. “Party hubs” have multiple interfaces; they establish simultaneous/stable (domain–domain) interactions, and tend to evolve slowly. On the other hand, “date hubs” have few interfaces; they establish transient/weak (domain–motif) interactions by means of short linear peptides (15 or fewer residues), and can evolve faster. Viral infections are mediated by several protein–protein interactions (PPIs), which can be represented as networks (protein interaction networks, PINs), with proteins being depicted as nodes, and their interactions as edges. It has been suggested that viral proteins tend to establish interactions with more central and highly connected host proteins. In an evolutionary arms race, viral and host proteins are constantly changing their interface residues, either to evade or to optimize their binding capabilities. Apart from gaining and losing interactions via rewiring mechanisms, virus–host PINs also evolve via gene duplication (paralogy); conservation (orthology); horizontal gene transfer (HGT) (xenology); and molecular mimicry (convergence). The last sections of this review focus on PPI experimental approaches and their limitations, and provide an overview of sources of biomolecular data for studying virus–host protein interactions.

Despite several recent advances in the automated generation of draft metabolic reconstructions, the manual curation of these networks to produce high quality genome-scale metabolic models remains a labour-intensive and challenging task. We present PathwayBooster, an open-source software tool to support the manual comparison and curation of metabolic models. It combines gene annotations from GenBank files and other sources with information retrieved from the metabolic databases BRENDA and KEGG to produce a set of pathway diagrams and reports summarising the evidence for the presence of a reaction in a given organism’s metabolic network. By comparing multiple sources of evidence within a common framework, PathwayBooster assists the curator in the identification of likely false positive (misannotated enzyme) and false negative (pathway hole) reactions. Reaction evidence may be taken from alternative annotations of the same genome and/or a set of closely related organisms. By integrating and visualising evidence from multiple sources, PathwayBooster reduces the manual effort required in the curation of a metabolic model. The software is available online at http://www.theosysbio.bio.ic.ac.uk/resources/pathwaybooster/.

The molecular reaction networks that coordinate the response of an organism to changing environmental conditions are central for survival and reproduction. Escherchia coli employs an accurate and flexible signalling system that is capable of processing ambient nitrogen availability rapidly and with high accuracy. Carefully orchestrated post-translational modifications of PII and the glutamine synthetase allow E. coli to trace nitrogen availability in a continuous, decidedly non-digital fashion. We measure the dynamic proteomic and metabolomic responses to trace the analog computations, and use an information theoretical framework to characterize the information capacity of E. coli’s nitrogen sensing network: we find that this system can transmit up to 9bits of information about the nitrogen state. This allows cells to respond rapidly and accurately even to small differences in metabolite concentrations.