Phylogenetic Predictions on Grids

A phylogenetic or evolutionary tree is constructed from a set of species or DNA sequences and depicts the relatedness between the sequences. Predictions of future sequences in a phylogenetic tree are important for a variety of applications including drug discovery, pharmaceutical research and disease control. In this work, we predict future DNA sequences in a phylogenetic tree using cellular automata. Cellular automata are used for modeling neighbor-dependent mutations from an ancestor to a progeny in a branch of the phylogenetic tree. Since the number of possible ways of transformations from an ancestor to a progeny is huge, we use computational grids and middleware techniques to explore the large number of cellular automata rules used for the mutations. We use the popular and recurring neighbor-based transitions or mutations to predict the progeny sequences in the phylogenetic tree. We performed predictions for three types of sequences, namely, triose phosphate isomerase, pyruvate kinase, and polyketide synthase sequences, by obtaining cellular automata rules on a grid consisting of 29 machines in 4 clusters located in 4 countries, and compared the predictions of the sequences using our method with predictions by random methods. We found that in all cases, our method gave about 40% better predictions than the random methods.

The Contribution of Rare Species to Community Phylogenetic Diversity across a Global Network of Forest Plots

Niche differentiation has been proposed as an explanation for rarity in species assemblages. To test this hypothesis requires quantifying the ecological similarity of species. This similarity can potentially be estimated by using phylogenetic relatedness. In this study, we predicted that if niche differentiation does explain the co-occurrence of rare and common species, then rare species should contribute greatly to the overall community phylogenetic diversity (PD), abundance will have phylogenetic signal, and common and rare species will be phylogenetically dissimilar. We tested these predictions by developing a novel method that integrates species rank abundance distributions with phylogenetic trees and trend analyses, to examine the relative contribution of individual species to the overall community PD. We then supplement this approach with analyses of phylogenetic signal in abundances and measures of phylogenetic similarity within and between rare and common species groups. We applied this analytical approach to 15 long-term temperate and tropical forest dynamics plots from around the world. We show that the niche differentiation hypothesis is supported in six of the nine gap-dominated forests but is rejected in the six disturbance-dominated and three gap-dominated forests. We also show that the three metrics utilized in this study each provide unique but corroborating information regarding the phylogenetic distribution of rarity in communities.

Phylogenetic analysis and molecular dating suggest that hemidactylus anamallensis is not a member of the hemidactylus radiation and has an ancient late cretaceous origin

Background of the Work: The phylogenetic position and evolution of Hemidactylus anamallensis (family Gekkonidae) has been much debated in recent times. In the past it has been variously assigned to genus Hoplodactylus (Diplodactylidae) as well as a monotypic genus `Dravidogecko' (Gekkonidae). Since 1995, this species has been assigned to Hemidactylus, but there is much disagreement between authors regarding its phylogenetic position within this genus. In a recent molecular study H. anamallensis was sister to Hemidactylus but appeared distinct from it in both mitochondrial and nuclear markers. However, this study did not include genera closely allied to Hemidactylus, thus a robust evaluation of this hypothesis was not undertaken. Methods: The objective of this study was to investigate the phylogenetic position of H. anamallensis within the gekkonid radiation. To this end, several nuclear and mitochondrial markers were sequenced from H. anamallensis, selected members of the Hemidactylus radiation and genera closely allied to Hemidactylus. These sequences in conjunction with published sequences were subjected to multiple phylogenetic analyses. Furthermore the nuclear dataset was also subjected to molecular dating analysis to ascertain the divergence between H. anamallensis and related genera. Results and Conclusion: Results showed that H. anamallensis lineage was indeed sister to Hemidactylus group but was separated from the rest of the Hemidactylus by a long branch. The divergence estimates supported a scenario wherein H. anamallensis dispersed across a marine barrier to the drifting peninsular Indian plate in the late Cretaceous whereas Hemidactylus arrived on the peninsular India after the Indian plate collided with the Eurasian plate. Based on these molecular evidence and biogeographical scenario we suggest that the genus Dravidogecko should be resurrected.

Phylogenetic relationships and classification of thiolases and thiolase-like proteins of Mycobacterium tuberculosis and Mycobacterium smegmatis

Thiolases are enzymes involved in lipid metabolism. Thiolases remove the acetyl-CoA moiety from 3-ketoacyl-CoAs in the degradative reaction. They can also catalyze the reverse Claisen condensation reaction, which is the first step of biosynthetic processes such as the biosynthesis of sterols and ketone bodies. In human, six distinct thiolases have been identified. Each of these thiolases is different from the other with respect to sequence, oligomeric state, substrate specificity and subcellular localization. Four sequence fingerprints, identifying catalytic loops of thiolases, have been described. In this study genome searches of two mycobacterial species (Mycobacterium tuberculosis and Mycobacterium smegmatis), were carried out, using the six human thiolase sequences as queries. Eight and thirteen different thiolase sequences were identified in M. tuberculosis and M. smegmatis, respectively. In addition, thiolase-like proteins (one encoded in the Mtb and two in the Msm genome) were found. The purpose of this study is to classify these mostly uncharacterized thiolases and thiolase-like proteins. Several other sequences obtained by searches of genome databases of bacteria, mammals and the parasitic protist family of the Trypanosomatidae were included in the analysis. Thiolase-like proteins were also found in the trypanosomatid genomes, but not in those of mammals. In order to study the phylogenetic relationships at a high confidence level, additional thiolase sequences were included such that a total of 130 thiolases and thiolase-like protein sequences were used for the multiple sequence alignment. The resulting phylogenetic tree identifies 12 classes of sequences, each possessing a characteristic set of sequence fingerprints for the catalytic loops. From this analysis it is now possible to assign the mycobacterial thiolases to corresponding homologues in other kingdoms of life. The results of this bioinformatics analysis also show interesting differences between the distributions of M. tuberculosis and M. smegmatis thiolases over the 12 different classes. (C) 2014 Elsevier Ltd. All rights reserved.

An island called India: phylogenetic patterns across multiple taxonomic groups reveal endemic radiations

Island systems from around the world have provided fascinating opportunities for studies pertaining to various evolutionary processes. One recurring feature of isolated islands is the presence of endemic radiations. In this regard, the Indian subcontinent is an interesting entity given it has been an island during much of its history following separation from Madagascar and currently is isolated from much of Eurasia by the Himalayas in the north and the Indian Ocean in the south. Not surprisingly, recent molecular studies on a number of endemic taxa from India have reported endemic radiations. These studies suggest that the uniqueness of Indian biota is not just due to its diverse origin, but also due to evolution in isolation. The isolation of India has generated some peculiarities typically seen on oceanic islands. However, these patterns might be confined to, groups with low dispersal ability.

Structure-Based Phylogenetic Analysis of the Lipocalin Superfamily

Lipocalins constitute a superfamily of extracellular proteins that are found in all three kingdoms of life. Although very divergent in their sequences and functions, they show remarkable similarity in 3-D structures. Lipocalins bind and transport small hydrophobic molecules. Earlier sequence-based phylogenetic studies of lipocalins highlighted that they have a long evolutionary history. However the molecular and structural basis of their functional diversity is not completely understood. The main objective of the present study is to understand functional diversity of the lipocalins using a structure-based phylogenetic approach. The present study with 39 protein domains from the lipocalin superfamily suggests that the clusters of lipocalins obtained by structure-based phylogeny correspond well with the functional diversity. The detailed analysis on each of the clusters and sub-clusters reveals that the 39 lipocalin domains cluster based on their mode of ligand binding though the clustering was performed on the basis of gross domain structure. The outliers in the phylogenetic tree are often from single member families. Also structure-based phylogenetic approach has provided pointers to assign putative function for the domains of unknown function in lipocalin family. The approach employed in the present study can be used in the future for the functional identification of new lipocalin proteins and may be extended to other protein families where members show poor sequence similarity but high structural similarity.

An addition to the endemic Indian radiation of Eutropis: Phylogenetic position of Eutropis dissimilis Hallowell (Squamata: Scincidae)

Skinks of the genus Eutropis represent one of the most widespread and speciose lizard groups in tropical Asia. Numerous recent studies have utilized a variety of genes and methods to reconstruct the phylogeny of these lizards, however these studies have not resolved the placement of one of the widely distributed Eutropis Fitzinger, E. dissimilis. We have sequenced a specimen of E. dissimilis from the type locality and our result suggests that it is part of the Indian radiation of Eutropis and not related to African Trachylepis Fitzinger or Southeast Asian Dasia Gray as previously suggested. Furthermore, we report that the sequence of E. dissimilis used in an earlier study of the once cosmopolitan genus `Mabuya' may have been erroneously identified and appears to be a sequence of E. novemcarinata. We also demonstrate that the evolution of a clear lower eyelid, which was considered a synapomorphy for the sister genus Trachylepis, has arisen multiple times in Eutropis.

Evolutionary games with two timescales

We consider a two timescale model of learning by economic agents wherein active or 'ontogenetic' learning by individuals takes place on a fast scale and passive or 'phylogenetic' learning by society as a whole on a slow scale, each affecting the evolution of the other. The former is modelled by the Monte Carlo dynamics of physics, while the latter is modelled by the replicator dynamics of evolutionary biology. Various qualitative aspects of the dynamics are studied in some simple cases, both analytically and numerically, and its role as a useful modelling device is emphasized.

targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.

The Evolution of Guanylyl Cyclases as Multidomain Proteins: Conserved Features of Kinase-Cyclase Domain Fusions

Guanylyl cyclases (GCs) are enzymes that generate cyclic GMP and regulate different physiologic and developmental processes in a number of organisms. GCs possess sequence similarity to class III adenylyl cyclases (ACs) and are present as either membrane-bound receptor GCs or cytosolic soluble GCs. We sought to determine the evolution of GCs using a large-scale bioinformatic analysis and found multiple lineage-specific expansions of GC genes in the genomes of many eukaryotes. Moreover, a few GC-like proteins were identified in prokaryotes, which come fused to a number of different domains, suggesting allosteric regulation of nucleotide cyclase activity Eukaryotic receptor GCs are associated with a kinase homology domain (KHD), and phylogenetic analysis of these proteins suggest coevolution of the KHD and the associated cyclase domain as well as a conservation of the sequence and the size of the linker region between the KHD and the associated cyclase domain. Finally, we also report the existence of mimiviral proteins that contain putative active kinase domains associated with a cyclase domain, which could suggest early evolution of the fusion of these two important domains involved in signa transduction.

Genetic analysis of foot-and-mouth disease virus serotype A of Indian origin and detection of positive selection and recombination in leader protease- and capsid-coding regions

The leader protease (L-pro) and capsid-coding sequences (P1) constitute approximately 3 kb of the foot-and-mouth disease virus (FMDV). We studied the phylogenetic relationship of 46 FMDV serotype A isolates of Indian origin collected during the period 1968-2005 and also eight vaccine strains using the neighbour-joining tree and Bayesian tree methods. The viruses were categorized under three major groups - Asian, Euro-South American and European. The Indian isolates formed a distinct genetic group among the Asian isolates. The Indian isolates were further classified into different genetic subgroups (<5% divergence). Post-1995 isolates were divided into two subgroups while a few isolates which originated in the year 2005 from Andhra Pradesh formed a separate group. These isolates were closely related to the isolates of the 1970s. The FMDV isolates seem to undergo reverse mutation or onvergent evolution wherein sequences identical to the ancestors are present in the isolates in circulation. The eight vaccine strains included in the study were not related to each other and belonged to different genetic groups. Recombination was detected in the L-pro region in one isolate (A IND 20/82) and in the VP1 coding 1D region in another isolate (A RAJ 21/96). Positive selection was identified at aa positions 23 in the L-pro (P<0.05; 0.046*) and at aa 171 in the capsid protein VP1 (P<0.01; 0.003**).

Nucleotide sequence of the 3' terminal region of belladonna mottle virus-Iowa (renamed Physalis mottle virus) RNA and an analysis of the relationships of tymoviral coat proteins

The 3prime terminal 1255nt sequence of Physalis mottle virus (PhMV) genomic RNA has been determined from a set of overlapping cDNA clones. The open reading frame (ORF) at the 3prime terminus corresponds to the amino acid sequence of the coat protein (CP) determined earlier except for the absence of the dipeptide, Lys-Leu, at position 110-111. In addition, the sequence upstream of the CP gene contains the message coding for 178 amino acid residues of the C-terminus of the putative replicase protein (RP). The sequence downstream of the CP gene contains an untranslated region whose terminal 80 nucleotides can be folded into a characteristic tRNA-like structure. A phylogenetic tree constructed after aligning separately the sequence of the CP, the replicase protein (RP) and the tRNA-like structure determined in this study with the corresponding sequences of other tymoviruses shows that PhMV wrongly named belladonna mottle virus [BDMV(I)] is a separate tymovirus and not another strain of BDMV(E) as originally envisaged. The phylogenetic tree in all the three cases is identical showing that any subset of genomic sequence of sufficient length can be used for establishing evolutionary relationships among tymoviruses.

The Out-of-India hypothesis: What do molecules suggest?

The remarkable geological and evolutionary history of peninsular India has generated much interest in the patterns and processes that might have shaped the current distributions of its endemic biota. In this regard the Out of India hypothesis, which proposes that rafting peninsular India carried Gondwanan forms to Asia after the break-up of Gondwana super continent, has gained prominence. Here we have reviewed molecular studies undertaken on a range of taxa of supposedly Gondwanan origin to better understand the Out-of-India scenario. This re-evaluation of published molecular studies indicates that there is mounting evidence supporting Out-of-India scenario for various Asian taxa. Nevertheless, in many studies the evidence is inconclusive due to lack of information on the age of relevant nodes. Studies also indicate that not all Gondwanan forms of peninsular India dispersed out of India. Many of these ancient lineages are confined to peninsular India and therefore are relict Gondwanan lineages. Additionally for some taxa an Into India rather than Out-of-India scenario better explains their current distribution. To identify the Out-of-India component of Asian biota it is imperative that we understand the complex biogeographical history of India. To this end, we propose three oversimplified yet explicit phylogenetic predictions. These predictions can be tested through the use of molecular phylogenetic tools in conjunction with palaeontological and geological data.

Structure-Based Phylogeny as a Diagnostic for Functional Characterization of Proteins with a Cupin Fold

Background: The members of cupin superfamily exhibit large variations in their sequences, functions, organization of domains, quaternary associations and the nature of bound metal ion, despite having a conserved beta-barrel structural scaffold. Here, an attempt has been made to understand structure-function relationships among the members of this diverse superfamily and identify the principles governing functional diversity. The cupin superfamily also contains proteins for which the structures are available through world-wide structural genomics initiatives but characterized as ``hypothetical''. We have explored the feasibility of obtaining clues to functions of such proteins by means of comparative analysis with cupins of known structure and function. Methodology/Principal Findings: A 3-D structure-based phylogenetic approach was undertaken. Interestingly, a dendrogram generated solely on the basis of structural dissimilarity measure at the level of domain folds was found to cluster functionally similar members. This clustering also reflects an independent evolution of the two domains in bicupins. Close examination of structural superposition of members across various functional clusters reveals structural variations in regions that not only form the active site pocket but are also involved in interaction with another domain in the same polypeptide or in the oligomer. Conclusions/Significance: Structure-based phylogeny of cupins can influence identification of functions of proteins of yet unknown function with cupin fold. This approach can be extended to other proteins with a common fold that show high evolutionary divergence. This approach is expected to have an influence on the function annotation in structural genomics initiatives.

Structural and functional characteristics of homing endonucleases

Mobile genetic elements constitute a remarkably diverse group of nonessential selfish genes that provide no apparent function to the host. These selfish genes have been implicated in host extinction, speciation and architecture of genetic systems. Homing endonucleases, encoded by the open reading frames embedded in introns or inteins of mobile genetic elements, possess double-stranded DNA-specific endonuclease activity. They inflict sequence-specific double-strand breaks at or near the homing site in intron- or intein-less allele. Subsequently, through nonreciprocal exchange the insertion sequence (intron or intein) is transferred from an intein- or intron-containing allele to an intein- or intron-less allele. The components of host double-strand break repair pathway are thought to finish the "homing" process. Several lines of evidence suggest that homing endonucleases are capable of promoting transposition into ectopic sites within or across genomes for their survival as well as dispersal in natural populations. The occurrence of inteins at high frequencies serves as instructive models for understanding the mechanistic aspects of the process of homing and its evolution. This review focuses on genetic, biochemical, structural, and phylogenetic aspects of homing endonucleases, and their comparison with restriction endonucleases.