Calcified dental plaque (dental calculus) preserves for millennia and entraps biomolecules from all domains of life and viruses. We report the first high-resolution taxonomic and protein functional characterization of the ancient oral microbiome and demonstrate that the oral cavity has long served as a reservoir for bacteria implicated in both local and systemic disease. We characterize: (i) the ancient oral microbiome in a diseased state, (ii) 40 opportunistic pathogens, (iii) the first evidence of ancient human-associated putative antibiotic resistance genes, (iv) a genome reconstruction of the periodontal pathogen Tannerella forsythia, (v) 239 bacterial and 43 human proteins, allowing confirmation of a long-term association between host immune factors, “red-complex” pathogens, and periodontal disease, and (vi) DNA sequences matching dietary sources. Directly datable and nearly ubiquitous, dental calculus permits the simultaneous investigation of pathogen activity, host immunity, and diet, thereby extending the direct investigation of common diseases into the human evolutionary past.
We study the evolution of cooperation in communities described in terms of graphs, such that individuals occupy the vertices and engage in single rounds of the Prisoner's Dilemma with those individuals with whom they are connected through the edges of those graphs. We find an overwhelming dominance of cooperation whenever graphs are dynamically generated through the mechanisms of growth and preferential attachment. These mechanisms lead to the appearance of direct links between hubs, which constitute sufficient conditions to sustain cooperation. We show that cooperation dominates from large population sizes down to communities with nearly 100 individuals, even when extrinsic factors set a limit on the number of interactions that each individual may engage in.
Genome-scale metabolic networks are highly robust to the elimination of enzyme-coding genes. Their structure can evolve rapidly through mutations that eliminate such genes and through horizontal gene transfer that adds new enzyme-coding genes. Using flux balance analysis we study a vast space of metabolic network genotypes and their relationship to metabolic phenotypes, the ability to sustain life in an environment defined by an available spectrum of carbon sources. Two such networks typically differ in most of their reactions and have few essential reactions in common. Our observations suggest that the robustness of the Escherichia coli metabolic network to mutations is typical of networks with the same phenotype. We also demonstrate that networks with the same phenotype form large sets that can be traversed through single mutations, and that single mutations of different genotypes with the same phenotype can yield very different novel phenotypes. This means that the evolutionary plasticity and robustness of metabolic networks facilitates the evolution of new metabolic abilities. Our approach has broad implications for the evolution of metabolic networks, for our understanding of mutational robustness, for the design of antimetabolic drugs, and for metabolic engineering.
We introduce a class of small-world networks--homogeneous small-worlds--which, in contrast with the well-known Watts-Strogatz small-worlds, exhibit a homogeneous connectivity distribution, in the sense that all nodes have the same number of connections. This feature allows the investigation of pure small-world effects, detached from any associated heterogeneity. Furthermore, we use at profit the remarkable similarity between the properties of homogeneous small worlds and the heterogeneous small-worlds of Watts-Strogatz to assess the separate roles of heterogeneity and small-world effects. We investigate the dependence on these two mechanisms of the threshold for epidemic outbreaks and also of the coevolution of cooperators and defectors under natural selection. With respect to the well-studied regular homogeneous limits, we find a subtle interplay between these mechanisms. While they both contribute to reduce the threshold for an epidemic outburst, they exhibit opposite behavior in the evolution of cooperation, such that the overall results mask the true nature of their individual contribution to this process.
BackgroundA metabolic genotype comprises all chemical reactions an organism can catalyze via enzymes encoded in its genome. A genotype is viable in a given environment if it is capable of producing all biomass components the organism needs to survive and reproduce. Previous work has focused on the properties of individual genotypes while little is known about how genome-scale metabolic networks with a given function can vary in their reaction content.ResultsWe here characterize spaces of such genotypes. Specifically, we study metabolic genotypes whose phenotype is viability in minimal chemical environments that differ in their sole carbon sources. We show that regardless of the number of reactions in a metabolic genotype, the genotypes of a given phenotype typically form vast, connected, and unstructured sets -- genotype networks -- that nearly span the whole of genotype space. The robustness of metabolic phenotypes to random reaction removal in such spaces has a narrow distribution with a high mean. Different carbon sources differ in the number of metabolic genotypes in their genotype network; this number decreases as a genotype is required to be viable on increasing numbers of carbon sources, but much less than if metabolic reactions were used independently across different chemical environments.ConclusionsOur work shows that phenotype-preserving genotype networks have generic organizational properties and that these properties are insensitive to the number of reactions in metabolic genotypes.
Intravenous administration could become a delivery route of choice for prophylactic and curative gene therapies on condition that genes cross the capillary barrier and reach target tissues without being degraded. We investigated the kinetics and process of transgene delivery through mouse lung capillaries following DNA complexation with linear polyethylenimine (L-PEI) and intravenous injection. Using digoxin-labeled DNA we followed the cellular localization of DNA at different times after injection and correlated these findings with cell markers and transgene expression. At 2 h after injection some DNA was still localized on the interior of the capillary lumen, but other complexes had already crossed the barrier and resulted in gene expression. At 24 h after injection most
SummaryThe demarcation of operational taxonomic units (OTUs) from complex sequence data sets is a key step in contemporary studies of microbial ecology. However, as biologically motivated 'optimal' OTUbinning algorithms remain elusive, many conceptually distinct approaches continue to be used. Using a global data set of 887 870 bacterial 16S rRNA gene sequences, we objectively quantified biases introduced by several widely employed sequence clustering algorithms. We found that OTU-binning methods often provided surprisingly non-equivalent partitions of identical data sets, notably when clustering to the same nominal similarity thresholds; and we quantified the resulting impact on ecological data description for a well-defined human skin microbiome data set. We observed that some methods were very robust to varying clustering thresholds, while others were found to be highly susceptible even to slight threshold variations. Moreover, we comprehensively quantified the impact of the choice of 16S rRNA gene subregion, as well as of data set scope and context on algorithm performance. Our findings may contribute to an enhanced comparability of results across sequence-processing pipelines, and we arrive at recommendations towards higher levels of standardization in established workflows.
The metabolic genotype of an organism can change through loss and acquisition of enzyme-coding genes, while preserving its ability to survive and synthesize biomass in specific environments. This evolutionary plasticity allows pathogens to evolve resistance to antimetabolic drugs by acquiring new metabolic pathways that bypass an enzyme blocked by a drug. We here study quantitatively the extent to which individual metabolic reactions and enzymes can be bypassed. To this end, we use a recently developed computational approach to create large metabolic network ensembles that can synthesize all biomass components in a given environment but contain an otherwise random set of known biochemical reactions. Using this approach, we identify a small connected core of 124 reactions that are absolutely superessential (that is, required in all metabolic networks). Many of these reactions have been experimentally confirmed as essential in different organisms. We also report a superessentiality index for thousands of reactions. This index indicates how easily a reaction can be bypassed. We find that it correlates with the number of sequenced genomes that encode an enzyme for the reaction. Superessentiality can help choose an enzyme as a potential drug target, especially because the index is not highly sensitive to the chemical environment that a pathogen requires. Our work also shows how analyses of large network ensembles can help understand the evolution of complex and robust metabolic networks.drug resistance | drug target identification | essential reactions
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