Patterns of evolutionary rate variation among genes of the anthocyanin biosynthetic pathway

The anthocyanin biosynthetic pathway is responsible for the production of anthocyanin pigments in plant tissues and shares a number of enzymes with other biochemical pathways. The six core structural genes of this pathway have been cloned and characterized in two taxonomically diverse plant species (maize and snapdragon). We have recently cloned these genes for a third species, the common morning glory, Ipomoea purpurea. This additional information provides an opportunity to examine patterns of evolution among genes within a single biochemical pathway. We report here that upstream genes in the anthocyanin pathway have evolved substantially more slowly than downstream genes and suggest that this difference in evolutionary rates may be explained by upstream genes being more constrained because they participate in several different biochemical pathways. In addition, regulatory genes associated with the anthocyanin pathway tend to evolve more rapidly than the structural genes they regulate, suggesting that adaptive evolution of flower color may be mediated more by regulatory than by structural genes. Finally, for individual anthocyanin genes, we found an absence of rate heterogeneity among three major angiosperm lineages. This rate constancy contrasts with an accelerated rate of evolution of three CHS-like genes in the Ipomoea lineage, indicating that these three genes have diverged without coordinated adjustment by other pathway genes.     

Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-κB, and Wnt/β-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.     

Small-world connectivity, motif composition, and complexity of fractal neuronal connections

Connection patterns of the cerebral cortex consist of pathways linking neuronal populations across multiple levels of scale, from whole brain regions to local minicolumns. This nested interconnectivity suggests the hypothesis that cortical connections are arranged in fractal or self-similar patterns. We describe a simple procedure to generate fractal connection patterns that aim at capturing the potential self-similarity and hierarchical ordering of neuronal connections. We examine these connection patterns by calculating a broad range of structural measures, including small-world attributes and motif composition, as well as some global measures of functional connectivity, including complexity. As we vary fractal patterns by changing a critical control parameter, we find strongly correlated changes in several structural and functional measures, suggesting that they emerge together and are mutually linked. Measures obtained from some modeled fractal patterns closely resemble those of real neuroanatomical data sets, supporting the original hypothesis.     

FunMod: A Cytoscape Plugin for Identifying Functional Modules in Undirected Protein–Protein Networks

The characterization of the interacting behaviors of complex biological systems is a primary objective in protein–protein network analysis and computational biology. In this paper we present FunMod, an innovative Cytoscape version 2.8 plugin that is able to mine undirected protein–protein networks and to infer sub-networks of interacting proteins intimately correlated with relevant biological pathways. This plugin may enable the discovery of new pathways involved in diseases. In order to describe the role of each protein within the relevant biological pathways, FunMod computes and scores three topological features of the identified sub-networks. By integrating the results from biological pathway clustering and topological network analysis, FunMod proved to be useful for the data interpretation and the generation of new hypotheses in two case studies.     

Predicting allosteric communication in myosin via a pathway of conserved residues

We present a computational method that predicts a pathway of residues that mediate protein allosteric communication. The pathway is predicted using only a combination of distance constraints between contiguous residues and evolutionary data. We applied this analysis to find pathways of conserved residues connecting the myosin ATP binding site to the lever arm. These pathway residues may mediate the allosteric communication that couples ATP hydrolysis to the lever arm recovery stroke. Having examined pre-stroke conformations of Dictyostelium, scallop, and chicken myosin II as well as Dictyostelium myosin I, we observed a conserved pathway traversing switch II and the relay helix, which is consistent with the understood need for allosteric communication in this conformation. We also examined post-rigor and rigor conformations across several myosin species. Although initial residues of these paths are more heterogeneous, all but one of these paths traverse a consistent set of relay helix residues to reach the beginning of the lever arm. We discuss our results in the context of structural elements and reported mutational experiments, which substantiate the significance of the pre-stroke pathways. Our method provides a simple, computationally efficient means of predicting a set of residues that mediate allosteric communication. We provide a refined, downloadable application and source code (on https://simtk.org) to share this tool with the wider community (https://simtk.org/home/allopathfinder).     

Historical climate‐change influences modularity and nestedness of pollination networks

The structure of species interaction networks is important for species coexistence, community stability and exposure of species to extinctions. Two widespread structures in ecological networks are modularity, i.e. weakly connected subgroups of species that are internally highly interlinked, and nestedness, i.e. specialist species that interact with a subset of those species with which generalist species also interact. Modularity and nestedness are often interpreted as evolutionary ecological structures that may have relevance for community persistence and resilience against perturbations, such as climate‐change. Therefore, historical climatic fluctuations could influence modularity and nestedness, but this possibility remains untested. This lack of research is in sharp contrast to the considerable efforts to disentangle the role of historical climate‐change and contemporary climate on species distributions, richness and community composition patterns. Here, we use a global database of pollination networks to show that historical climate‐change is at least as important as contemporary climate in shaping modularity and nestedness of pollination networks. Specifically, on the mainland we found a relatively strong negative association between Quaternary climate‐change and modularity, whereas nestedness was most prominent in areas having experienced high Quaternary climate‐change. On islands, Quaternary climate‐change had weak effects on modularity and no effects on nestedness. Hence, for both modularity and nestedness, historical climate‐change has left imprints on the network structure of mainland communities, but had comparably little effect on island communities. Our findings highlight a need to integrate historical climate fluctuations into eco‐evolutionary hypotheses of network structures, such as modularity and nestedness, and then test these against empirical data. We propose that historical climate‐change may have left imprints in the structural organisation of species interactions in an array of systems important for maintaining biological diversity.     

Does the sociality of pollinators shape the organisation of pollination networks?

A striking structural pattern of pollination networks is the presence of a few highly connected species which has implications for ecological and evolutionary processes that create and maintain diversity. To understand the structure and dynamics of pollination networks we need to know which mechanisms allow the emergence of highly connected species. We investigate whether social pollinator species are highly connected in pollination networks, and whether network structure is affected by the presence of high proportions of social pollinator species. Social insects are abundant, with long activity periods and, at the highest level of social organisation, specialised foraging castes. These three attributes are likely to increase the number of interactions of social species and, consequently, their role in pollination networks. We find that social species have, on average, more prominent network roles than solitary species, a possible mechanism being the individual‐rich colonies of social insects. However, when accounting for the shared evolutionary history of pollinators, sociality is only associated with highly interactive roles in Apidae. For apid bees, our structural equation analysis shows that the effect of sociality on species network roles is an indirect result of their high levels of interaction frequency. Despite the relative importance of sociality at a species‐level, an increasing proportion of social species in pollination networks did not affect overall network structure. Our results suggest that behavioural traits may shape patterns of interaction of individual species but not the network‐level organisation of species interactions. Instead, network structure appears to be determined by more general aspects of ecological systems such as interaction intimacy, patterns of niche overlap, and species abundance distributions.     

Rapid Pathway Evolution Facilitated by Horizontal Gene Transfers across Prokaryotic Lineages

The evolutionary history of biological pathways is of general interest, especially in this post-genomic era, because it may provide clues for understanding how complex systems encoded on genomes have been organized. To explain how pathways can evolve de novo, some noteworthy models have been proposed. However, direct reconstruction of pathway evolutionary history both on a genomic scale and at the depth of the tree of life has suffered from artificial effects in estimating the gene content of ancestral species. Recently, we developed an algorithm that effectively reconstructs gene-content evolution without these artificial effects, and we applied it to this problem. The carefully reconstructed history, which was based on the metabolic pathways of 160 prokaryotic species, confirmed that pathways have grown beyond the random acquisition of individual genes. Pathway acquisition took place quickly, probably eliminating the difficulty in holding genes during the course of the pathway evolution. This rapid evolution was due to massive horizontal gene transfers as gene groups, some of which were possibly operon transfers, which would convey existing pathways but not be able to generate novel pathways. To this end, we analyzed how these pathways originally appeared and found that the original acquisition of pathways occurred more contemporaneously than expected across different phylogenetic clades. As a possible model to explain this observation, we propose that novel pathway evolution may be facilitated by bidirectional horizontal gene transfers in prokaryotic communities. Such a model would complement existing pathway evolution models.     

Expression of phosphorylated forms of ERK, MEK, PTEN and PI3K in mouse oral development

Investigations into molecular mechanisms in vertebrates have examined which growth factors regulate many of the essential underlying cellular processes in development. Growth factors regulate cell proliferation and differentiation through diverse signaling pathways like the MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) pathway. The MEK and ERK pathway can interact with the PI3K (phosphatidylinositol-3-kinase) and PTEN (phosphatase and tensin homologues deleted on chromosome 10) signaling pathway. Interactions between these pathways during development have been extensively studied in many organs; however, the importance of these pathways in oral development is not well known. In this study, we examined the expression of the phosphorylated forms of ERK (pERK), MEK (pMEK), PTEN (pPTEN) and PI3K during mouse development from E13.5 to E16.5. We found unique and overlapping expression of these factors in the craniofacial region, with pERK and pPTEN showing opposing activation patterns in both the tooth and the tongue.