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1.  Quantifying the similarity of monotonic trajectories in rough and smooth fitness landscapes 
Molecular bioSystems  2013;9(7):1627-1631.
When selection is strong and mutations are rare, evolution can be thought of as an uphill trajectory in a rugged fitness landscape. In this context the fitness landscape is a directed acyclic graph in which nodes are genotypes and edges lead from lower to higher fitness genotypes that differ by a single mutation. Because the space of genotypes is vastly multi-dimensional, classification of fitness landscapes is challenging. Many proposed summary characteristics of fitness landscapes attempt to quantify biologically relevant and intuitive notions such as roughness or peak accessibility in alternative ways. Here we explore, in different types of landscapes, the behavior of the recently introduced mean path divergence which quantifies the degree of similarity among evolutionary trajectories with the same endpoints. We find that monotonic trajectories in empirical and model fitness landscapes are significantly more constrained, with low median path divergence, than those in purely additive landscapes. By contrast, transcription factor sequence specificity (aptamer binding affinity) landscapes are markedly smoother and allow substantial variability in monotonic paths that can be greater than that in fully additive landscapes. We propose that the smoothness of the specificity landscapes is a consequence of the simple dependence of the transcription factor binding affinity on the aptamer sequence in contrast to the complex sequence-fitness mapping in folding landscapes.
doi:10.1039/c3mb25553k
PMCID: PMC4325993  PMID: 23460358
2.  Computational methods for Gene Orthology inference 
Briefings in Bioinformatics  2011;12(5):379-391.
Accurate inference of orthologous genes is a pre-requisite for most comparative genomics studies, and is also important for functional annotation of new genomes. Identification of orthologous gene sets typically involves phylogenetic tree analysis, heuristic algorithms based on sequence conservation, synteny analysis, or some combination of these approaches. The most direct tree-based methods typically rely on the comparison of an individual gene tree with a species tree. Once the two trees are accurately constructed, orthologs are straightforwardly identified by the definition of orthology as those homologs that are related by speciation, rather than gene duplication, at their most recent point of origin. Although ideal for the purpose of orthology identification in principle, phylogenetic trees are computationally expensive to construct for large numbers of genes and genomes, and they often contain errors, especially at large evolutionary distances. Moreover, in many organisms, in particular prokaryotes and viruses, evolution does not appear to have followed a simple ‘tree-like’ mode, which makes conventional tree reconciliation inapplicable. Other, heuristic methods identify probable orthologs as the closest homologous pairs or groups of genes in a set of organisms. These approaches are faster and easier to automate than tree-based methods, with efficient implementations provided by graph-theoretical algorithms enabling comparisons of thousands of genomes. Comparisons of these two approaches show that, despite conceptual differences, they produce similar sets of orthologs, especially at short evolutionary distances. Synteny also can aid in identification of orthologs. Often, tree-based, sequence similarity- and synteny-based approaches can be combined into flexible hybrid methods.
doi:10.1093/bib/bbr030
PMCID: PMC3178053  PMID: 21690100
homolog; ortholog; paralog; xenolog; orthologous groups; tree reconciliation; comparative genomics
3.  Estimation of prokaryotic supergenome size and composition from gene frequency distributions 
BMC Genomics  2014;15(Suppl 6):S14.
Background
Because prokaryotic genomes experience a rapid flux of genes, selection may act at a higher level than an individual genome. We explore a quantitative model of the distributed genome whereby groups of genomes evolve by acquiring genes from a fixed reservoir which we denote as supergenome. Previous attempts to understand the nature of the supergenome treated genomes as random, independent collections of genes and assumed that the supergenome consists of a small number of homogeneous sub-reservoirs. Here we explore the consequences of relaxing both assumptions.
Results
We surveyed several methods for estimating the size and composition of the supergenome. The methods assumed that genomes were either random, independent samples of the supergenome or that they evolved from a common ancestor along a known tree via stochastic sampling from the reservoir. The reservoir was assumed to be either a collection of homogeneous sub-reservoirs or alternatively composed of genes with Gamma distributed gain probabilities. Empirical gene frequencies were used to either compute the likelihood of the data directly or first to reconstruct the history of gene gains and then compute the likelihood of the reconstructed numbers of gains.
Conclusions
Supergenome size estimates using the empirical gene frequencies directly are not robust with respect to the choice of the model. By contrast, using the gene frequencies and the phylogenetic tree to reconstruct multiple gene gains produces reliable estimates of the supergenome size and indicates that a homogeneous supergenome is more consistent with the data than a supergenome with Gamma distributed gain probabilities.
doi:10.1186/1471-2164-15-S6-S14
PMCID: PMC4240607  PMID: 25572821
supergenome; genome evolution; gene frequency distribution; ancestral reconstruction
4.  Small Proteins Can No Longer Be Ignored 
Annual review of biochemistry  2014;83:753-777.
Small proteins, here defined as proteins of 50 amino acids or less in the absence of processing, have traditionally been overlooked due to challenges in their annotation and biochemical detection. In the past several years however, increasing numbers of small proteins have been identified either through the realization that mutations in “intergenic” regions actually are within unannotated small protein genes, or through the discovery that some small, regulatory RNAs (sRNAs) encode small proteins. These insights together with comparative sequence analysis indicate that tens if not hundreds of small proteins are synthesized in a given organism. This review will summarize what has been learned about the functions of several of these bacterial small proteins, most of which act at the membrane, illustrating the astonishing range of processes in which the small proteins act and pointing to several general conclusions. Important questions for future studies of these overlooked proteins also will be discussed.
doi:10.1146/annurev-biochem-070611-102400
PMCID: PMC4166647  PMID: 24606146
membrane; cell division; sporulation; transport; signal transduction; sprotein
5.  Genomes in turmoil: quantification of genome dynamics in prokaryote supergenomes 
BMC Biology  2014;12(1):66.
Background
Genomes of bacteria and archaea (collectively, prokaryotes) appear to exist in incessant flux, expanding via horizontal gene transfer and gene duplication, and contracting via gene loss. However, the actual rates of genome dynamics and relative contributions of different types of event across the diversity of prokaryotes are largely unknown, as are the sizes of microbial supergenomes, i.e. pools of genes that are accessible to the given microbial species.
Results
We performed a comprehensive analysis of the genome dynamics in 35 groups (34 bacterial and one archaeal) of closely related microbial genomes using a phylogenetic birth-and-death maximum likelihood model to quantify the rates of gene family gain and loss, as well as expansion and reduction. The results show that loss of gene families dominates the evolution of prokaryotes, occurring at approximately three times the rate of gain. The rates of gene family expansion and reduction are typically seven and twenty times less than the gain and loss rates, respectively. Thus, the prevailing mode of evolution in bacteria and archaea is genome contraction, which is partially compensated by the gain of new gene families via horizontal gene transfer. However, the rates of gene family gain, loss, expansion and reduction vary within wide ranges, with the most stable genomes showing rates about 25 times lower than the most dynamic genomes. For many groups, the supergenome estimated from the fraction of repetitive gene family gains includes about tenfold more gene families than the typical genome in the group although some groups appear to have vast, ‘open’ supergenomes.
Conclusions
Reconstruction of evolution for groups of closely related bacteria and archaea reveals an extremely rapid and highly variable flux of genes in evolving microbial genomes, demonstrates that extensive gene loss and horizontal gene transfer leading to innovation are the two dominant evolutionary processes, and yields robust estimates of the supergenome size.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-014-0066-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-014-0066-4
PMCID: PMC4166000  PMID: 25141959
6.  Dark matter in archaeal genomes: a rich source of novel mobile elements, defense systems and secretory complexes 
Extremophiles  2014;18(5):877-893.
Microbial genomes encompass a sizable fraction of poorly characterized, narrowly spread fast-evolving genes. Using sensitive methods for sequences comparison and protein structure prediction, we performed a detailed comparative analysis of clusters of such genes, which we denote “dark matter islands”, in archaeal genomes. The dark matter islands comprise up to 20 % of archaeal genomes and show remarkable heterogeneity and diversity. Nevertheless, three classes of entities are common in these genomic loci: (a) integrated viral genomes and other mobile elements; (b) defense systems, and (c) secretory and other membrane-associated systems. The dark matter islands in the genome of thermophiles and mesophiles show similar general trends of gene content, but thermophiles are substantially enriched in predicted membrane proteins whereas mesophiles have a greater proportion of recognizable mobile elements. Based on this analysis, we predict the existence of several novel groups of viruses and mobile elements, previously unnoticed variants of CRISPR-Cas immune systems, and new secretory systems that might be involved in stress response, intermicrobial conflicts and biogenesis of novel, uncharacterized membrane structures.
Electronic supplementary material
The online version of this article (doi:10.1007/s00792-014-0672-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s00792-014-0672-7
PMCID: PMC4158269  PMID: 25113822
Archaeal genomes; ORFans; Genomic islands; Integration; Viruses; Defense
7.  Pseudo-chaotic oscillations in CRISPR-virus coevolution predicted by bifurcation analysis 
Biology Direct  2014;9:13.
Background
The CRISPR-Cas systems of adaptive antivirus immunity are present in most archaea and many bacteria, and provide resistance to specific viruses or plasmids by inserting fragments of foreign DNA into the host genome and then utilizing transcripts of these spacers to inactivate the cognate foreign genome. The recent development of powerful genome engineering tools on the basis of CRISPR-Cas has sharply increased the interest in the diversity and evolution of these systems. Comparative genomic data indicate that during evolution of prokaryotes CRISPR-Cas loci are lost and acquired via horizontal gene transfer at high rates. Mathematical modeling and initial experimental studies of CRISPR-carrying microbes and viruses reveal complex coevolutionary dynamics.
Results
We performed a bifurcation analysis of models of coevolution of viruses and microbial host that possess CRISPR-Cas hereditary adaptive immunity systems. The analyzed Malthusian and logistic models display complex, and in particular, quasi-chaotic oscillation regimes that have not been previously observed experimentally or in agent-based models of the CRISPR-mediated immunity. The key factors for the appearance of the quasi-chaotic oscillations are the non-linear dependence of the host immunity on the virus load and the partitioning of the hosts into the immune and susceptible populations, so that the system consists of three components.
Conclusions
Bifurcation analysis of CRISPR-host coevolution model predicts complex regimes including quasi-chaotic oscillations. The quasi-chaotic regimes of virus-host coevolution are likely to be biologically relevant given the evolutionary instability of the CRISPR-Cas loci revealed by comparative genomics. The results of this analysis might have implications beyond the CRISPR-Cas systems, i.e. could describe the behavior of any adaptive immunity system with a heritable component, be it genetic or epigenetic. These predictions are experimentally testable.
Reviewers’ reports
This manuscript was reviewed by Sandor Pongor, Sergei Maslov and Marek Kimmel. For the complete reports, go to the Reviewers’ Reports section.
doi:10.1186/1745-6150-9-13
PMCID: PMC4096434  PMID: 24986220
8.  Universal Pacemaker of Genome Evolution in Animals and Fungi and Variation of Evolutionary Rates in Diverse Organisms 
Genome Biology and Evolution  2014;6(6):1268-1278.
Gene evolution is traditionally considered within the framework of the molecular clock (MC) model whereby each gene is characterized by an approximately constant rate of evolution. Recent comparative analysis of numerous phylogenies of prokaryotic genes has shown that a different model of evolution, denoted the Universal PaceMaker (UPM), which postulates conservation of relative, rather than absolute evolutionary rates, yields a better fit to the phylogenetic data. Here, we show that the UPM model is a better fit than the MC for genome wide sets of phylogenetic trees from six species of Drosophila and nine species of yeast, with extremely high statistical significance. Unlike the prokaryotic phylogenies that include distant organisms and multiple horizontal gene transfers, these are simple data sets that cover groups of closely related organisms and consist of gene trees with the same topology as the species tree. The results indicate that both lineage-specific and gene-specific rates are important in genome evolution but the lineage-specific contribution is greater. Similar to the MC, the gene evolution rates under the UPM are strongly overdispersed, approximately 2-fold compared with the expectation from sampling error alone. However, we show that neither Drosophila nor yeast genes form distinct clusters in the tree space. Thus, the gene-specific deviations from the UPM, although substantial, are uncorrelated and most likely depend on selective factors that are largely unique to individual genes. Thus, the UPM appears to be a key feature of genome evolution across the history of cellular life.
doi:10.1093/gbe/evu091
PMCID: PMC4079209  PMID: 24812293
molecular clock; genome evolution; phylogenetic trees; relative evolution rates
9.  Genome reduction as the dominant mode of evolution 
Bioessays  2013;35(9):829-837.
A common belief is that evolution generally proceeds towards greater complexity at both the organismal and the genomic level, numerous examples of reductive evolution of parasites and symbionts notwithstanding. However, recent evolutionary reconstructions challenge this notion. Two notable examples are the reconstruction of the complex archaeal ancestor and the intron-rich ancestor of eukaryotes. In both cases, evolution in most of the lineages was apparently dominated by extensive loss of genes and introns, respectively. These and many other cases of reductive evolution are consistent with a general model composed of two distinct evolutionary phases: the short, explosive, innovation phase that leads to an abrupt increase in genome complexity, followed by a much longer reductive phase, which encompasses either a neutral ratchet of genetic material loss or adaptive genome streamlining. Quantitatively, the evolution of genomes appears to be dominated by reduction and simplification, punctuated by episodes of complexification.
doi:10.1002/bies.201300037
PMCID: PMC3840695  PMID: 23801028
ancestral reconstruction; archaea; genome complexification; genome reduction; horizontal gene transfer; orthologs
10.  GENOME-WIDE COMPARATIVE ANALYSIS OF PHYLOGENETIC TREES: THE PROKARYOTIC FOREST OF LIFE 
Methods in molecular biology (Clifton, N.J.)  2012;856:10.1007/978-1-61779-585-5_3.
Genome-wide comparison of phylogenetic trees is becoming an increasingly common approach in evolutionary genomics, and a variety of approaches for such comparison have been developed. In this article we present several methods for comparative analysis of large numbers of phylogenetic trees. To compare phylogenetic trees taking into account the bootstrap support for each internal branch, the Boot-Split Distance (BSD) method is introduced as an extension of the previously developed Split Distance (SD) method for tree comparison. The BSD method implements the straightforward idea that comparison of phylogenetic trees can be made more robust by treating tree splits differentially depending on the bootstrap support. Approaches are also introduced for detecting tree-like and net-like evolutionary trends in the phylogenetic Forest of Life (FOL), i.e., the entirety of the phylogenetic trees for conserved genes of prokaryotes. The principal method employed for this purpose includes mapping quartets of species onto trees to calculate the support of each quartet topology and so to quantify the tree and net contributions to the distances between species. We describe the applications methods used to analyze the FOL and the results obtained with these methods. These results support the concept of the Tree of Life (TOL) as a central evolutionary trend in the FOL as opposed to the traditional view of the TOL as a ‘species tree’.
doi:10.1007/978-1-61779-585-5_3
PMCID: PMC3842619  PMID: 22399455
Forest of life; tree of life; phylogenomic methods; tree comparison; map of quartets
11.  Evolutionary Dynamics of the Prokaryotic Adaptive Immunity System CRISPR-Cas in an Explicit Ecological Context 
Journal of Bacteriology  2013;195(17):3834-3844.
A stochastic, agent-based mathematical model of the coevolution of the archaeal and bacterial adaptive immunity system, CRISPR-Cas, and lytic viruses shows that CRISPR-Cas immunity can stabilize the virus-host coexistence rather than leading to the extinction of the virus. In the model, CRISPR-Cas immunity does not specifically promote viral diversity, presumably because the selection pressure on each single proto-spacer is too weak. However, the overall virus diversity in the presence of CRISPR-Cas grows due to the increase of the host and, accordingly, the virus population size. Above a threshold value of total viral diversity, which is proportional to the viral mutation rate and population size, the CRISPR-Cas system becomes ineffective and is lost due to the associated fitness cost. Our previous modeling study has suggested that the ubiquity of CRISPR-Cas in hyperthermophiles, which contrasts its comparative low prevalence in mesophiles, is due to lower rates of mutation fixation in thermal habitats. The present findings offer a complementary, simpler perspective on this contrast through the larger population sizes of mesophiles compared to hyperthermophiles, because of which CRISPR-Cas can become ineffective in mesophiles. The efficacy of CRISPR-Cas sharply increases with the number of proto-spacers per viral genome, potentially explaining the low information content of the proto-spacer-associated motif (PAM) that is required for spacer acquisition by CRISPR-Cas because a higher specificity would restrict the number of spacers available to CRISPR-Cas, thus hampering immunity. The very existence of the PAM might reflect the tradeoff between the requirement of diverse spacers for efficient immunity and avoidance of autoimmunity.
doi:10.1128/JB.00412-13
PMCID: PMC3754601  PMID: 23794616
13.  Stability along with Extreme Variability in Core Genome Evolution 
Genome Biology and Evolution  2013;5(7):1393-1402.
The shape of the distribution of evolutionary distances between orthologous genes in pairs of closely related genomes is universal throughout the entire range of cellular life forms. The near invariance of this distribution across billions of years of evolution can be accounted for by the Universal Pace Maker (UPM) model of genome evolution that yields a significantly better fit to the phylogenetic data than the Molecular Clock (MC) model. Unlike the MC, the UPM model does not assume constant gene-specific evolutionary rates but rather postulates that, in each evolving lineage, the evolutionary rates of all genes change (approximately) in unison although the pacemakers of different lineages are not necessarily synchronized. Here, we dissect the nearly constant evolutionary rate distribution by comparing the genome-wide relative rates of evolution of individual genes in pairs or triplets of closely related genomes from diverse bacterial and archaeal taxa. We show that, although the gene-specific relative rate is an important feature of genome evolution that explains more than half of the variance of the evolutionary distances, the ranges of relative rate variability are extremely broad even for universal genes. Because of this high variance, the gene-specific rate is a poor predictor of the conservation rank for any gene in any particular lineage.
doi:10.1093/gbe/evt098
PMCID: PMC3730350  PMID: 23821522
evolutionary rate; universal genes; molecular clock; universal pacemaker of genome evolution
14.  Insights into archaeal evolution and symbiosis from the genomes of a nanoarchaeon and its inferred crenarchaeal host from Obsidian Pool, Yellowstone National Park 
Biology Direct  2013;8:9.
Background
A single cultured marine organism, Nanoarchaeum equitans, represents the Nanoarchaeota branch of symbiotic Archaea, with a highly reduced genome and unusual features such as multiple split genes.
Results
The first terrestrial hyperthermophilic member of the Nanoarchaeota was collected from Obsidian Pool, a thermal feature in Yellowstone National Park, separated by single cell isolation, and sequenced together with its putative host, a Sulfolobales archaeon. Both the new Nanoarchaeota (Nst1) and N. equitans lack most biosynthetic capabilities, and phylogenetic analysis of ribosomal RNA and protein sequences indicates that the two form a deep-branching archaeal lineage. However, the Nst1 genome is more than 20% larger, and encodes a complete gluconeogenesis pathway as well as the full complement of archaeal flagellum proteins. With a larger genome, a smaller repertoire of split protein encoding genes and no split non-contiguous tRNAs, Nst1 appears to have experienced less severe genome reduction than N. equitans. These findings imply that, rather than representing ancestral characters, the extremely compact genomes and multiple split genes of Nanoarchaeota are derived characters associated with their symbiotic or parasitic lifestyle. The inferred host of Nst1 is potentially autotrophic, with a streamlined genome and simplified central and energetic metabolism as compared to other Sulfolobales.
Conclusions
Comparison of the N. equitans and Nst1 genomes suggests that the marine and terrestrial lineages of Nanoarchaeota share a common ancestor that was already a symbiont of another archaeon. The two distinct Nanoarchaeota-host genomic data sets offer novel insights into the evolution of archaeal symbiosis and parasitism, enabling further studies of the cellular and molecular mechanisms of these relationships.
Reviewers
This article was reviewed by Patrick Forterre, Bettina Siebers (nominated by Michael Galperin) and Purification Lopez-Garcia
doi:10.1186/1745-6150-8-9
PMCID: PMC3655853  PMID: 23607440
Archaea evolution; Single cell genomics; Symbiosis; Hyperthermophiles; Split genes
15.  Seeing the Tree of Life behind the phylogenetic forest 
BMC Biology  2013;11:46.
doi:10.1186/1741-7007-11-46
PMCID: PMC3626908  PMID: 23587361
16.  Comparative genomics of defense systems in archaea and bacteria 
Nucleic Acids Research  2013;41(8):4360-4377.
Our knowledge of prokaryotic defense systems has vastly expanded as the result of comparative genomic analysis, followed by experimental validation. This expansion is both quantitative, including the discovery of diverse new examples of known types of defense systems, such as restriction-modification or toxin-antitoxin systems, and qualitative, including the discovery of fundamentally new defense mechanisms, such as the CRISPR-Cas immunity system. Large-scale statistical analysis reveals that the distribution of different defense systems in bacterial and archaeal taxa is non-uniform, with four groups of organisms distinguishable with respect to the overall abundance and the balance between specific types of defense systems. The genes encoding defense system components in bacterial and archaea typically cluster in defense islands. In addition to genes encoding known defense systems, these islands contain numerous uncharacterized genes, which are candidates for new types of defense systems. The tight association of the genes encoding immunity systems and dormancy- or cell death-inducing defense systems in prokaryotic genomes suggests that these two major types of defense are functionally coupled, providing for effective protection at the population level.
doi:10.1093/nar/gkt157
PMCID: PMC3632139  PMID: 23470997
17.  The Vast, Conserved Mammalian lincRNome 
PLoS Computational Biology  2013;9(2):e1002917.
We compare the sets of experimentally validated long intergenic non-coding (linc)RNAs from human and mouse and apply a maximum likelihood approach to estimate the total number of lincRNA genes as well as the size of the conserved part of the lincRNome. Under the assumption that the sets of experimentally validated lincRNAs are random samples of the lincRNomes of the corresponding species, we estimate the total lincRNome size at approximately 40,000 to 50,000 species, at least twice the number of protein-coding genes. We further estimate that the fraction of the human and mouse euchromatic genomes encoding lincRNAs is more than twofold greater than the fraction of protein-coding sequences. Although the sequences of most lincRNAs are much less strongly conserved than protein sequences, the extent of orthology between the lincRNomes is unexpectedly high, with 60 to 70% of the lincRNA genes shared between human and mouse. The orthologous mammalian lincRNAs can be predicted to perform equivalent functions; accordingly, it appears likely that thousands of evolutionarily conserved functional roles of lincRNAs remain to be characterized.
Author Summary
Genome analysis of humans and other mammals reveals a surprisingly small number of protein-coding genes, only slightly over 20,000 (although the diversity of actual proteins is substantially augmented by alternative transcription and alternative splicing). Recent analysis of the mammalian genomes and transcriptomes, in particular, using the RNAseq technology, shows that, in addition to protein-coding genes, mammalian genomes encode many long non-coding RNAs. For some of these transcripts, various regulatory functions have been demonstrated, but on the whole the repertoire of long non-coding RNAs remains poorly characterized. We compared the identified long intergenic non-coding (linc)RNAs from human and mouse, and employed a specially developed statistical technique to estimate the size and evolutionary conservation of the human and mouse lincRNomes. The estimates show that there are at least twice as many human and mouse lincRNAs than there are protein-coding genes. Moreover, about two third of the lincRNA genes appear to be conserved between human and mouse, implying thousands of conserved but still uncharacterized functions.
doi:10.1371/journal.pcbi.1002917
PMCID: PMC3585383  PMID: 23468607
18.  Gene Frequency Distributions Reject a Neutral Model of Genome Evolution 
Genome Biology and Evolution  2013;5(1):233-242.
Evolution of prokaryotes involves extensive loss and gain of genes, which lead to substantial differences in the gene repertoires even among closely related organisms. Through a wide range of phylogenetic depths, gene frequency distributions in prokaryotic pangenomes bear a characteristic, asymmetrical U-shape, with a core of (nearly) universal genes, a “shell” of moderately common genes, and a “cloud” of rare genes. We employ mathematical modeling to investigate evolutionary processes that might underlie this universal pattern. Gene frequency distributions for almost 400 groups of 10 bacterial or archaeal species each over a broad range of evolutionary distances were fit to steady-state, infinite allele models based on the distribution of gene replacement rates and the phylogenetic tree relating the species in each group. The fits of the theoretical frequency distributions to the empirical ones yield model parameters and estimates of the goodness of fit. Using the Akaike Information Criterion, we show that the neutral model of genome evolution, with the same replacement rate for all genes, can be confidently rejected. Of the three tested models with purifying selection, the one in which the distribution of replacement rates is derived from a stochastic population model with additive per-gene fitness yields the best fits to the data. The selection strength estimated from the fits declines with evolutionary divergence while staying well outside the neutral regime. These findings indicate that, unlike some other universal distributions of genomic variables, for example, the distribution of paralogous gene family membership, the gene frequency distribution is substantially affected by selection.
doi:10.1093/gbe/evt002
PMCID: PMC3595032  PMID: 23315380
gene frequency distribution; steady genome model; goodness of fit; evolution mechanisms
19.  The Ecoresponsive Genome of Daphnia pulex 
Science (New York, N.Y.)  2011;331(6017):555-561.
We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 Mb and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than 1/3 of Daphnia’s genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The co-expansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes – including many additional loci within sequenced regions that are otherwise devoid of annotations – are the most responsive genes to ecological challenges.
doi:10.1126/science.1197761
PMCID: PMC3529199  PMID: 21292972
20.  Updated clusters of orthologous genes for Archaea: a complex ancestor of the Archaea and the byways of horizontal gene transfer 
Biology Direct  2012;7:46.
Background
Collections of Clusters of Orthologous Genes (COGs) provide indispensable tools for comparative genomic analysis, evolutionary reconstruction and functional annotation of new genomes. Initially, COGs were made for all complete genomes of cellular life forms that were available at the time. However, with the accumulation of thousands of complete genomes, construction of a comprehensive COG set has become extremely computationally demanding and prone to error propagation, necessitating the switch to taxon-specific COG collections. Previously, we reported the collection of COGs for 41 genomes of Archaea (arCOGs). Here we present a major update of the arCOGs and describe evolutionary reconstructions to reveal general trends in the evolution of Archaea.
Results
The updated version of the arCOG database incorporates 91% of the pangenome of 120 archaea (251,032 protein-coding genes altogether) into 10,335 arCOGs. Using this new set of arCOGs, we performed maximum likelihood reconstruction of the genome content of archaeal ancestral forms and gene gain and loss events in archaeal evolution. This reconstruction shows that the last Common Ancestor of the extant Archaea was an organism of greater complexity than most of the extant archaea, probably with over 2,500 protein-coding genes. The subsequent evolution of almost all archaeal lineages was apparently dominated by gene loss resulting in genome streamlining. Overall, in the evolution of Archaea as well as a representative set of bacteria that was similarly analyzed for comparison, gene losses are estimated to outnumber gene gains at least 4 to 1. Analysis of specific patterns of gene gain in Archaea shows that, although some groups, in particular Halobacteria, acquire substantially more genes than others, on the whole, gene exchange between major groups of Archaea appears to be largely random, with no major ‘highways’ of horizontal gene transfer.
Conclusions
The updated collection of arCOGs is expected to become a key resource for comparative genomics, evolutionary reconstruction and functional annotation of new archaeal genomes. Given that, in spite of the major increase in the number of genomes, the conserved core of archaeal genes appears to be stabilizing, the major evolutionary trends revealed here have a chance to stand the test of time.
Reviewers
This article was reviewed by (for complete reviews see the Reviewers’ Reports section): Dr. PLG, Prof. PF, Dr. PL (nominated by Prof. JPG).
doi:10.1186/1745-6150-7-46
PMCID: PMC3534625  PMID: 23241446
Archaea; Orthologs; Horizontal gene transfer
21.  Viral Diversity Threshold for Adaptive Immunity in Prokaryotes 
mBio  2012;3(6):e00456-12.
ABSTRACT
Bacteria and archaea face continual onslaughts of rapidly diversifying viruses and plasmids. Many prokaryotes maintain adaptive immune systems known as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (Cas). CRISPR-Cas systems are genomic sensors that serially acquire viral and plasmid DNA fragments (spacers) that are utilized to target and cleave matching viral and plasmid DNA in subsequent genomic invasions, offering critical immunological memory. Only 50% of sequenced bacteria possess CRISPR-Cas immunity, in contrast to over 90% of sequenced archaea. To probe why half of bacteria lack CRISPR-Cas immunity, we combined comparative genomics and mathematical modeling. Analysis of hundreds of diverse prokaryotic genomes shows that CRISPR-Cas systems are substantially more prevalent in thermophiles than in mesophiles. With sequenced bacteria disproportionately mesophilic and sequenced archaea mostly thermophilic, the presence of CRISPR-Cas appears to depend more on environmental temperature than on bacterial-archaeal taxonomy. Mutation rates are typically severalfold higher in mesophilic prokaryotes than in thermophilic prokaryotes. To quantitatively test whether accelerated viral mutation leads microbes to lose CRISPR-Cas systems, we developed a stochastic model of virus-CRISPR coevolution. The model competes CRISPR-Cas-positive (CRISPR-Cas+) prokaryotes against CRISPR-Cas-negative (CRISPR-Cas−) prokaryotes, continually weighing the antiviral benefits conferred by CRISPR-Cas immunity against its fitness costs. Tracking this cost-benefit analysis across parameter space reveals viral mutation rate thresholds beyond which CRISPR-Cas cannot provide sufficient immunity and is purged from host populations. These results offer a simple, testable viral diversity hypothesis to explain why mesophilic bacteria disproportionately lack CRISPR-Cas immunity. More generally, fundamental limits on the adaptability of biological sensors (Lamarckian evolution) are predicted.
IMPORTANCE
A remarkable recent discovery in microbiology is that bacteria and archaea possess systems conferring immunological memory and adaptive immunity. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (CRISPR-Cas) are genomic sensors that allow prokaryotes to acquire DNA fragments from invading viruses and plasmids. Providing immunological memory, these stored fragments destroy matching DNA in future viral and plasmid invasions. CRISPR-Cas systems also provide adaptive immunity, keeping up with mutating viruses and plasmids by continually acquiring new DNA fragments. Surprisingly, less than 50% of mesophilic bacteria, in contrast to almost 90% of thermophilic bacteria and Archaea, maintain CRISPR-Cas immunity. Using mathematical modeling, we probe this dichotomy, showing how increased viral mutation rates can explain the reduced prevalence of CRISPR-Cas systems in mesophiles. Rapidly mutating viruses outrun CRISPR-Cas immune systems, likely decreasing their prevalence in bacterial populations. Thus, viral adaptability may select against, rather than for, immune adaptability in prokaryotes.
doi:10.1128/mBio.00456-12
PMCID: PMC3517865  PMID: 23221803
22.  Universal Pacemaker of Genome Evolution 
PLoS Computational Biology  2012;8(11):e1002785.
A fundamental observation of comparative genomics is that the distribution of evolution rates across the complete sets of orthologous genes in pairs of related genomes remains virtually unchanged throughout the evolution of life, from bacteria to mammals. The most straightforward explanation for the conservation of this distribution appears to be that the relative evolution rates of all genes remain nearly constant, or in other words, that evolutionary rates of different genes are strongly correlated within each evolving genome. This correlation could be explained by a model that we denoted Universal PaceMaker (UPM) of genome evolution. The UPM model posits that the rate of evolution changes synchronously across genome-wide sets of genes in all evolving lineages. Alternatively, however, the correlation between the evolutionary rates of genes could be a simple consequence of molecular clock (MC). We sought to differentiate between the MC and UPM models by fitting thousands of phylogenetic trees for bacterial and archaeal genes to supertrees that reflect the dominant trend of vertical descent in the evolution of archaea and bacteria and that were constrained according to the two models. The goodness of fit for the UPM model was better than the fit for the MC model, with overwhelming statistical significance, although similarly to the MC, the UPM is strongly overdispersed. Thus, the results of this analysis reveal a universal, genome-wide pacemaker of evolution that could have been in operation throughout the history of life.
Author Summary
A central concept of evolution is Molecular Clock according to which each gene evolves at a characteristic, near constant rate. Numerous studies support the Molecular Clock hypothesis in principle but also show that the clock is indeed very approximate. Genome-wide comparative analysis of phylogenetic trees described here reveals a distinct, more general feature of genome evolution that we called Universal Pacemaker. Under this model, when the rate of evolution changes, the change occurs synchronously in many if not all genes in the evolving genome. In other words, the relative rates of gene evolution remain constant across long evolutionary spans: if a gene is slow relative to the rest of the genes in the given lineage, it is always slow, and if it evolves fast, it is always fast. We show here that the Universal Pacemaker model fits the available data much better than the traditional Molecular Clock model. These findings are compatible with the previously observed accelerations and decelerations of evolution in individual lineages but we show that synchronous, genome-wide change of evolutionary rates is a global feature of genome evolution that appears to pervade the entire history of life.
doi:10.1371/journal.pcbi.1002785
PMCID: PMC3510094  PMID: 23209393
23.  A Tight Link between Orthologs and Bidirectional Best Hits in Bacterial and Archaeal Genomes 
Genome Biology and Evolution  2012;4(12):1286-1294.
Orthologous relationships between genes are routinely inferred from bidirectional best hits (BBH) in pairwise genome comparisons. However, to our knowledge, it has never been quantitatively demonstrated that orthologs form BBH. To test this “BBH-orthology conjecture,” we take advantage of the operon organization of bacterial and archaeal genomes and assume that, when two genes in compared genomes are flanked by two BBH show statistically significant sequence similarity to one another, these genes are bona fide orthologs. Under this assumption, we tested whether middle genes in “syntenic orthologous gene triplets” form BBH. We found that this was the case in more than 95% of the syntenic gene triplets in all genome comparisons. A detailed examination of the exceptions to this pattern, including maximum likelihood phylogenetic tree analysis, showed that some of these deviations involved artifacts of genome annotation, whereas very small fractions represented random assignment of the best hit to one of closely related in-paralogs, paralogous displacement in situ, or even less frequent genuine violations of the BBH–orthology conjecture caused by acceleration of evolution in one of the orthologs. We conclude that, at least in prokaryotes, genes for which independent evidence of orthology is available typically form BBH and, conversely, BBH can serve as a strong indication of gene orthology.
doi:10.1093/gbe/evs100
PMCID: PMC3542571  PMID: 23160176
orthology; bidirectional best hit; genome comparison; synteny
24.  Identification of Novel Positive-Strand RNA Viruses by Metagenomic Analysis of Archaea-Dominated Yellowstone Hot Springs 
Journal of Virology  2012;86(10):5562-5573.
There are no known RNA viruses that infect Archaea. Filling this gap in our knowledge of viruses will enhance our understanding of the relationships between RNA viruses from the three domains of cellular life and, in particular, could shed light on the origin of the enormous diversity of RNA viruses infecting eukaryotes. We describe here the identification of novel RNA viral genome segments from high-temperature acidic hot springs in Yellowstone National Park in the United States. These hot springs harbor low-complexity cellular communities dominated by several species of hyperthermophilic Archaea. A viral metagenomics approach was taken to assemble segments of these RNA virus genomes from viral populations isolated directly from hot spring samples. Analysis of these RNA metagenomes demonstrated unique gene content that is not generally related to known RNA viruses of Bacteria and Eukarya. However, genes for RNA-dependent RNA polymerase (RdRp), a hallmark of positive-strand RNA viruses, were identified in two contigs. One of these contigs is approximately 5,600 nucleotides in length and encodes a polyprotein that also contains a region homologous to the capsid protein of nodaviruses, tetraviruses, and birnaviruses. Phylogenetic analyses of the RdRps encoded in these contigs indicate that the putative archaeal viruses form a unique group that is distinct from the RdRps of RNA viruses of Eukarya and Bacteria. Collectively, our findings suggest the existence of novel positive-strand RNA viruses that probably replicate in hyperthermophilic archaeal hosts and are highly divergent from RNA viruses that infect eukaryotes and even more distant from known bacterial RNA viruses. These positive-strand RNA viruses might be direct ancestors of RNA viruses of eukaryotes.
doi:10.1128/JVI.07196-11
PMCID: PMC3347303  PMID: 22379100
25.  A Maximum Likelihood Method for Reconstruction of the Evolution of Eukaryotic Gene Structure 
Spliceosomal introns are one of the principal distinctive features of eukaryotes. Nevertheless, different large-scale studies disagree about even the most basic features of their evolution. In order to come up with a more reliable reconstruction of intron evolution, we developed a model that is far more comprehensive than previous ones. This model is rich in parameters, and estimating them accurately is infeasible by straightforward likelihood maximization. Thus, we have developed an expectation-maximization algorithm that allows for efficient maximization. Here, we outline the model and describe the expectation-maximization algorithm in detail. Since the method works with intron presence–absence maps, it is expected to be instrumental for the analysis of the evolution of other binary characters as well.
doi:10.1007/978-1-59745-243-4_16
PMCID: PMC3410445  PMID: 19381540
Maximum likelihood; expectation-maximization; intron evolution; ancestral reconstruction; eukaryotic gene structure

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