ODoSE: a webserver for genome-wide calculation of adaptive divergence in prokaryotes

This is the final version of the article. Available from the publisher via the DOI in this record.Quantifying patterns of adaptive divergence between taxa is a major goal in the comparative and evolutionary study of prokaryote genomes. When applied appropriately, the McDonald-Kreitman (MK) test is a powerful test of selection based on the relative frequency of non-synonymous and synonymous substitutions between species compared to non-synonymous and synonymous polymorphisms within species. The webserver ODoSE (Ortholog Direction of Selection Engine) allows the calculation of a novel extension of the MK test, the Direction of Selection (DoS) statistic, as well as the calculation of a weighted-average Neutrality Index (NI) statistic for the entire core genome, allowing for systematic analysis of the evolutionary forces shaping core genome divergence in prokaryotes. ODoSE is hosted in a Galaxy environment, which makes it easy to use and amenable to customization and is freely available at www.odose.nl.MWJvP is funded by the Netherlands Organization for Scientific Research (NWO) via a VENI grant. TtB and MAvD are funded by the BioAssist/BRS programme of the Netherlands Bioinformatics Centre, which is supported by the Netherlands Genomics Initiative. This work is part of the programme of BiG Grid, the Dutch e-Science Grid, which is financially supported by the NWO. MV is supported by investment from the European Regional Development Fund and the European Social Fund Convergence Programme for Cornwall and the Isles of Scilly to the European Centre for the Environment and Human Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations

Degeneracy: a link between evolvability, robustness and complexity in biological systems

A full accounting of biological robustness remains elusive; both in terms of the mechanisms by which robustness is achieved and the forces that have caused robustness to grow over evolutionary time. Although its importance to topics such as ecosystem services and resilience is well recognized, the broader relationship between robustness and evolution is only starting to be fully appreciated. A renewed interest in this relationship has been prompted by evidence that mutational robustness can play a positive role in the discovery of adaptive innovations (evolvability) and evidence of an intimate relationship between robustness and complexity in biology. This paper offers a new perspective on the mechanics of evolution and the origins of complexity, robustness, and evolvability. Here we explore the hypothesis that degeneracy, a partial overlap in the functioning of multi-functional components, plays a central role in the evolution and robustness of complex forms. In support of this hypothesis, we present evidence that degeneracy is a fundamental source of robustness, it is intimately tied to multi-scaled complexity, and it establishes conditions that are necessary for system evolvability

Benchmarking ortholog identification methods using functional genomics data

BACKGROUND: The transfer of functional annotations from model organism proteins to human proteins is one of the main applications of comparative genomics. Various methods are used to analyze cross-species orthologous relationships according to an operational definition of orthology. Often the definition of orthology is incorrectly interpreted as a prediction of proteins that are functionally equivalent across species, while in fact it only defines the existence of a common ancestor for a gene in different species. However, it has been demonstrated that orthologs often reveal significant functional similarity. Therefore, the quality of the orthology prediction is an important factor in the transfer of functional annotations (and other related information). To identify protein pairs with the highest possible functional similarity, it is important to qualify ortholog identification methods. RESULTS: To measure the similarity in function of proteins from different species we used functional genomics data, such as expression data and protein interaction data. We tested several of the most popular ortholog identification methods. In general, we observed a sensitivity/selectivity trade-off: the functional similarity scores per orthologous pair of sequences become higher when the number of proteins included in the ortholog groups decreases. CONCLUSION: By combining the sensitivity and the selectivity into an overall score, we show that the InParanoid program is the best ortholog identification method in terms of identifying functionally equivalent proteins

Scaling properties of protein family phylogenies

One of the classical questions in evolutionary biology is how evolutionary processes are coupled at the gene and species level. With this motivation, we compare the topological properties (mainly the depth scaling, as a characterization of balance) of a large set of protein phylogenies with a set of species phylogenies. The comparative analysis shows that both sets of phylogenies share remarkably similar scaling behavior, suggesting the universality of branching rules and of the evolutionary processes that drive biological diversification from gene to species level. In order to explain such generality, we propose a simple model which allows us to estimate the proportion of evolvability/robustness needed to approximate the scaling behavior observed in the phylogenies, highlighting the relevance of the robustness of a biological system (species or protein) in the scaling properties of the phylogenetic trees. Thus, the rules that govern the incapability of a biological system to diversify are equally relevant both at the gene and at the species level.Comment: Replaced with final published versio

Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

The evolutionary signal in metagenome phyletic profiles predicts many gene functions

Background. The function of many genes is still not known even in model organisms. An increasing availability of microbiome DNA sequencing data provides an opportunity to infer gene function in a systematic manner. Results. We evaluated if the evolutionary signal contained in metagenome phyletic profiles (MPP) is predictive of a broad array of gene functions. The MPPs are an encoding of environmental DNA sequencing data that consists of relative abundances of gene families across metagenomes. We find that such MPPs can accurately predict 826 Gene Ontology functional categories, while drawing on human gut microbiomes, ocean metagenomes, and DNA sequences from various other engineered and natural environments. Overall, in this task, the MPPs are highly accurate, and moreover they provide coverage for a set of Gene Ontology terms largely complementary to standard phylogenetic profiles, derived from fully sequenced genomes. We also find that metagenomes approximated from taxon relative abundance obtained via 16S rRNA gene sequencing may provide surprisingly useful predictive models. Crucially, the MPPs derived from different types of environments can infer distinct, non-overlapping sets of gene functions and therefore complement each other. Consistently, simulations on > 5000 metagenomes indicate that the amount of data is not in itself critical for maximizing predictive accuracy, while the diversity of sampled environments appears to be the critical factor for obtaining robust models. Conclusions. In past work, metagenomics has provided invaluable insight into ecology of various habitats, into diversity of microbial life and also into human health and disease mechanisms. We propose that environmental DNA sequencing additionally constitutes a useful tool to predict biological roles of genes, yielding inferences out of reach for existing comparative genomics approaches

Less Can Be More: RNA-Adapters May Enhance Coding Capacity of Replicators

It is still not clear how prebiotic replicators evolved towards the complexity found in present day organisms. Within the most realistic scenario for prebiotic evolution, known as the RNA world hypothesis, such complexity has arisen from replicators consisting solely of RNA. Within contemporary life, remarkably many RNAs are involved in modifying other RNAs. In hindsight, such RNA-RNA modification might have helped in alleviating the limits of complexity posed by the information threshold for RNA-only replicators. Here we study the possible role of such self-modification in early evolution, by modeling the evolution of protocells as evolving replicators, which have the opportunity to incorporate these mechanisms as a molecular tool. Evolution is studied towards a set of 25 arbitrary ‘functional’ structures, while avoiding all other (misfolded) structures, which are considered to be toxic and increase the death-rate of a protocell. The modeled protocells contain a genotype of different RNA-sequences while their phenotype is the ensemble of secondary structures they can potentially produce from these RNA-sequences. One of the secondary structures explicitly codes for a simple sequence-modification tool. This ‘RNA-adapter’ can block certain positions on other RNA-sequences through antisense base-pairing. The altered sequence can produce an alternative secondary structure, which may or may not be functional. We show that the modifying potential of interacting RNA-sequences enables these protocells to evolve high fitness under high mutation rates. Moreover, our model shows that because of toxicity of misfolded molecules, redundant coding impedes the evolution of self-modification machinery, in effect restraining the evolvability of coding structures. Hence, high mutation rates can actually promote the evolution of complex coding structures by reducing redundant coding. Protocells can successfully use RNA-adapters to modify their genotype-phenotype mapping in order to enhance the coding capacity of their genome and fit more information on smaller sized genomes