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1.  Widespread Positive Selection in Synonymous Sites of Mammalian Genes 
Molecular biology and evolution  2007;24(8):1821-1831.
Evolution of protein sequences is largely governed by purifying selection, with a small fraction of proteins evolving under positive selection. The evolution at synonymous positions in protein-coding genes is not nearly as well understood, with the extent and types of selection remaining, largely, unclear. A statistical test to identify purifying and positive selection at synonymous sites in protein-coding genes was developed. The method compares the rate of evolution at synonymous sites (Ks) to that in intron sequences of the same gene after sampling the aligned intron sequences to mimic the statistical properties of coding sequences. We detected purifying selection at synonymous sites in ∼28% of the 1,562 analyzed orthologous genes from mouse and rat, and positive selection in ∼12% of the genes. Thus, the fraction of genes with readily detectable positive selection at synonymous sites is much greater than the fraction of genes with comparable positive selection at nonsynonymous sites, i.e., at the level of the protein sequence. Unlike other genes, the genes with positive selection at synonymous sites showed no correlation between Ks and the rate of evolution in nonsynonymous sites (Ka), indicating that evolution of synonymous sites under positive selection is decoupled from protein evolution. The genes with purifying selection at synonymous sites showed significant anticorrelation between Ks and expression level and breadth, indicating that highly expressed genes evolve slowly. The genes with positive selection at synonymous sites showed the opposite trend, i.e., highly expressed genes had, on average, higher Ks. For the genes with positive selection at synonymous sites, a significantly lower mRNA stability is predicted compared to the genes with negative selection. Thus, mRNA destabilization could be an important factor driving positive selection in nonsynonymous sites, probably, through regulation of expression at the level of mRNA degradation and, possibly, also translation rate. So, unexpectedly, we found that positive selection at synonymous sites of mammalian genes is substantially more common than positive selection at the level of protein sequences. Positive selection at synonymous sites might act through mRNA destabilization affecting mRNA levels and translation.
PMCID: PMC2632937  PMID: 17522087
synonymous sites; nonsynonymous sites; positive selection; purifying selection; introns
2.  Orthologs of the small RPB8 subunit of the eukaryotic RNA polymerases are conserved in hyperthermophilic Crenarchaeota and "Korarchaeota" 
Biology Direct  2007;2:38.
Although most of the key components of the transcription apparatus, and in particular, RNA polymerase (RNAP) subunits, are conserved between archaea and eukaryotes, no archaeal homologs of the small RPB8 subunit of eukaryotic RNAP have been detected. We report that orthologs of RPB8 are encoded in all sequenced genomes of hyperthermophilic Crenarchaeota and a recently sequenced "korarchaeal" genome, but not in Euryarchaeota or the mesophilic crenarchaeon Cenarchaeum symbiosum. These findings suggest that all 12 core subunits of eukaryotic RNAPs were already present in the last common ancestor of the extant archaea.
This article was reviewed by Purificacion Lopez-Garcia and Chris Ponting.
PMCID: PMC2234397  PMID: 18081935
3.  Clusters of orthologous genes for 41 archaeal genomes and implications for evolutionary genomics of archaea 
Biology Direct  2007;2:33.
An evolutionary classification of genes from sequenced genomes that distinguishes between orthologs and paralogs is indispensable for genome annotation and evolutionary reconstruction. Shortly after multiple genome sequences of bacteria, archaea, and unicellular eukaryotes became available, an attempt on such a classification was implemented in Clusters of Orthologous Groups of proteins (COGs). Rapid accumulation of genome sequences creates opportunities for refining COGs but also represents a challenge because of error amplification. One of the practical strategies involves construction of refined COGs for phylogenetically compact subsets of genomes.
New Archaeal Clusters of Orthologous Genes (arCOGs) were constructed for 41 archaeal genomes (13 Crenarchaeota, 27 Euryarchaeota and one Nanoarchaeon) using an improved procedure that employs a similarity tree between smaller, group-specific clusters, semi-automatically partitions orthology domains in multidomain proteins, and uses profile searches for identification of remote orthologs. The annotation of arCOGs is a consensus between three assignments based on the COGs, the CDD database, and the annotations of homologs in the NR database. The 7538 arCOGs, on average, cover ~88% of the genes in a genome compared to a ~76% coverage in COGs. The finer granularity of ortholog identification in the arCOGs is apparent from the fact that 4538 arCOGs correspond to 2362 COGs; ~40% of the arCOGs are new. The archaeal gene core (protein-coding genes found in all 41 genome) consists of 166 arCOGs. The arCOGs were used to reconstruct gene loss and gene gain events during archaeal evolution and gene sets of ancestral forms. The Last Archaeal Common Ancestor (LACA) is conservatively estimated to possess 996 genes compared to 1245 and 1335 genes for the last common ancestors of Crenarchaeota and Euryarchaeota, respectively. It is inferred that LACA was a chemoautotrophic hyperthermophile that, in addition to the core archaeal functions, encoded more idiosyncratic systems, e.g., the CASS systems of antivirus defense and some toxin-antitoxin systems.
The arCOGs provide a convenient, flexible framework for functional annotation of archaeal genomes, comparative genomics and evolutionary reconstructions. Genomic reconstructions suggest that the last common ancestor of archaea might have been (nearly) as advanced as the modern archaeal hyperthermophiles. ArCOGs and related information are available at: .
This article was reviewed by Peer Bork, Patrick Forterre, and Purificacion Lopez-Garcia.
PMCID: PMC2222616  PMID: 18042280
4.  Evolution of the genetic code: partial optimization of a random code for robustness to translation error in a rugged fitness landscape 
Biology Direct  2007;2:24.
The standard genetic code table has a distinctly non-random structure, with similar amino acids often encoded by codons series that differ by a single nucleotide substitution, typically, in the third or the first position of the codon. It has been repeatedly argued that this structure of the code results from selective optimization for robustness to translation errors such that translational misreading has the minimal adverse effect. Indeed, it has been shown in several studies that the standard code is more robust than a substantial majority of random codes. However, it remains unclear how much evolution the standard code underwent, what is the level of optimization, and what is the likely starting point.
We explored possible evolutionary trajectories of the genetic code within a limited domain of the vast space of possible codes. Only those codes were analyzed for robustness to translation error that possess the same block structure and the same degree of degeneracy as the standard code. This choice of a small part of the vast space of possible codes is based on the notion that the block structure of the standard code is a consequence of the structure of the complex between the cognate tRNA and the codon in mRNA where the third base of the codon plays a minimum role as a specificity determinant. Within this part of the fitness landscape, a simple evolutionary algorithm, with elementary evolutionary steps comprising swaps of four-codon or two-codon series, was employed to investigate the optimization of codes for the maximum attainable robustness. The properties of the standard code were compared to the properties of four sets of codes, namely, purely random codes, random codes that are more robust than the standard code, and two sets of codes that resulted from optimization of the first two sets. The comparison of these sets of codes with the standard code and its locally optimized version showed that, on average, optimization of random codes yielded evolutionary trajectories that converged at the same level of robustness to translation errors as the optimization path of the standard code; however, the standard code required considerably fewer steps to reach that level than an average random code. When evolution starts from random codes whose fitness is comparable to that of the standard code, they typically reach much higher level of optimization than the standard code, i.e., the standard code is much closer to its local minimum (fitness peak) than most of the random codes with similar levels of robustness. Thus, the standard genetic code appears to be a point on an evolutionary trajectory from a random point (code) about half the way to the summit of the local peak. The fitness landscape of code evolution appears to be extremely rugged, containing numerous peaks with a broad distribution of heights, and the standard code is relatively unremarkable, being located on the slope of a moderate-height peak.
The standard code appears to be the result of partial optimization of a random code for robustness to errors of translation. The reason the code is not fully optimized could be the trade-off between the beneficial effect of increasing robustness to translation errors and the deleterious effect of codon series reassignment that becomes increasingly severe with growing complexity of the evolving system. Thus, evolution of the code can be represented as a combination of adaptation and frozen accident.
This article was reviewed by David Ardell, Allan Drummond (nominated by Laura Landweber), and Rob Knight.
Open Peer Review
This article was reviewed by David Ardell, Allan Drummond (nominated by Laura Landweber), and Rob Knight.
PMCID: PMC2211284  PMID: 17956616
5.  Patterns of intron gain and conservation in eukaryotic genes 
The presence of introns in protein-coding genes is a universal feature of eukaryotic genome organization, and the genes of multicellular eukaryotes, typically, contain multiple introns, a substantial fraction of which share position in distant taxa, such as plants and animals. Depending on the methods and data sets used, researchers have reached opposite conclusions on the causes of the high fraction of shared introns in orthologous genes from distant eukaryotes. Some studies conclude that shared intron positions reflect, almost entirely, a remarkable evolutionary conservation, whereas others attribute it to parallel gain of introns. To resolve these contradictions, it is crucial to analyze the evolution of introns by using a model that minimally relies on arbitrary assumptions.
We developed a probabilistic model of evolution that allows for variability of intron gain and loss rates over branches of the phylogenetic tree, individual genes, and individual sites. Applying this model to an extended set of conserved eukaryotic genes, we find that parallel gain, on average, accounts for only ~8% of the shared intron positions. However, the distribution of parallel gains over the phylogenetic tree of eukaryotes is highly non-uniform. There are, practically, no parallel gains in closely related lineages, whereas for distant lineages, such as animals and plants, parallel gains appear to contribute up to 20% of the shared intron positions. In accord with these findings, we estimated that ancestral introns have a high probability to be retained in extant genomes, and conversely, that a substantial fraction of extant introns have retained their positions since the early stages of eukaryotic evolution. In addition, the density of sites that are available for intron insertion is estimated to be, approximately, one in seven basepairs.
We obtained robust estimates of the contribution of parallel gain to the observed sharing of intron positions between eukaryotic species separated by different evolutionary distances. The results indicate that, although the contribution of parallel gains varies across the phylogenetic tree, the high level of intron position sharing is due, primarily, to evolutionary conservation. Accordingly, numerous introns appear to persist in the same position over hundreds of millions of years of evolution. This is compatible with recent observations of a negative correlation between the rate of intron gain and coding sequence evolution rate of a gene, suggesting that at least some of the introns are functionally relevant.
PMCID: PMC2151770  PMID: 17935625
6.  Deinococcus geothermalis: The Pool of Extreme Radiation Resistance Genes Shrinks 
PLoS ONE  2007;2(9):e955.
Bacteria of the genus Deinococcus are extremely resistant to ionizing radiation (IR), ultraviolet light (UV) and desiccation. The mesophile Deinococcus radiodurans was the first member of this group whose genome was completely sequenced. Analysis of the genome sequence of D. radiodurans, however, failed to identify unique DNA repair systems. To further delineate the genes underlying the resistance phenotypes, we report the whole-genome sequence of a second Deinococcus species, the thermophile Deinococcus geothermalis, which at its optimal growth temperature is as resistant to IR, UV and desiccation as D. radiodurans, and a comparative analysis of the two Deinococcus genomes. Many D. radiodurans genes previously implicated in resistance, but for which no sensitive phenotype was observed upon disruption, are absent in D. geothermalis. In contrast, most D. radiodurans genes whose mutants displayed a radiation-sensitive phenotype in D. radiodurans are conserved in D. geothermalis. Supporting the existence of a Deinococcus radiation response regulon, a common palindromic DNA motif was identified in a conserved set of genes associated with resistance, and a dedicated transcriptional regulator was predicted. We present the case that these two species evolved essentially the same diverse set of gene families, and that the extreme stress-resistance phenotypes of the Deinococcus lineage emerged progressively by amassing cell-cleaning systems from different sources, but not by acquisition of novel DNA repair systems. Our reconstruction of the genomic evolution of the Deinococcus-Thermus phylum indicates that the corresponding set of enzymes proliferated mainly in the common ancestor of Deinococcus. Results of the comparative analysis weaken the arguments for a role of higher-order chromosome alignment structures in resistance; more clearly define and substantially revise downward the number of uncharacterized genes that might participate in DNA repair and contribute to resistance; and strengthen the case for a role in survival of systems involved in manganese and iron homeostasis.
PMCID: PMC1978522  PMID: 17895995
7.  The Biological Big Bang model for the major transitions in evolution 
Biology Direct  2007;2:21.
Major transitions in biological evolution show the same pattern of sudden emergence of diverse forms at a new level of complexity. The relationships between major groups within an emergent new class of biological entities are hard to decipher and do not seem to fit the tree pattern that, following Darwin's original proposal, remains the dominant description of biological evolution. The cases in point include the origin of complex RNA molecules and protein folds; major groups of viruses; archaea and bacteria, and the principal lineages within each of these prokaryotic domains; eukaryotic supergroups; and animal phyla. In each of these pivotal nexuses in life's history, the principal "types" seem to appear rapidly and fully equipped with the signature features of the respective new level of biological organization. No intermediate "grades" or intermediate forms between different types are detectable. Usually, this pattern is attributed to cladogenesis compressed in time, combined with the inevitable erosion of the phylogenetic signal.
I propose that most or all major evolutionary transitions that show the "explosive" pattern of emergence of new types of biological entities correspond to a boundary between two qualitatively distinct evolutionary phases. The first, inflationary phase is characterized by extremely rapid evolution driven by various processes of genetic information exchange, such as horizontal gene transfer, recombination, fusion, fission, and spread of mobile elements. These processes give rise to a vast diversity of forms from which the main classes of entities at the new level of complexity emerge independently, through a sampling process. In the second phase, evolution dramatically slows down, the respective process of genetic information exchange tapers off, and multiple lineages of the new type of entities emerge, each of them evolving in a tree-like fashion from that point on. This biphasic model of evolution incorporates the previously developed concepts of the emergence of protein folds by recombination of small structural units and origin of viruses and cells from a pre-cellular compartmentalized pool of recombining genetic elements. The model is extended to encompass other major transitions. It is proposed that bacterial and archaeal phyla emerged independently from two distinct populations of primordial cells that, originally, possessed leaky membranes, which made the cells prone to rampant gene exchange; and that the eukaryotic supergroups emerged through distinct, secondary endosymbiotic events (as opposed to the primary, mitochondrial endosymbiosis). This biphasic model of evolution is substantially analogous to the scenario of the origin of universes in the eternal inflation version of modern cosmology. Under this model, universes like ours emerge in the infinite multiverse when the eternal process of exponential expansion, known as inflation, ceases in a particular region as a result of false vacuum decay, a first order phase transition process. The result is the nucleation of a new universe, which is traditionally denoted Big Bang, although this scenario is radically different from the Big Bang of the traditional model of an expanding universe. Hence I denote the phase transitions at the end of each inflationary epoch in the history of life Biological Big Bangs (BBB).
A Biological Big Bang (BBB) model is proposed for the major transitions in life's evolution. According to this model, each transition is a BBB such that new classes of biological entities emerge at the end of a rapid phase of evolution (inflation) that is characterized by extensive exchange of genetic information which takes distinct forms for different BBBs. The major types of new forms emerge independently, via a sampling process, from the pool of recombining entities of the preceding generation. This process is envisaged as being qualitatively different from tree-pattern cladogenesis.
This article was reviewed by William Martin, Sergei Maslov, and Leonid Mirny.
PMCID: PMC1973067  PMID: 17708768
8.  On the origin of the translation system and the genetic code in the RNA world by means of natural selection, exaptation, and subfunctionalization 
Biology Direct  2007;2:14.
The origin of the translation system is, arguably, the central and the hardest problem in the study of the origin of life, and one of the hardest in all evolutionary biology. The problem has a clear catch-22 aspect: high translation fidelity hardly can be achieved without a complex, highly evolved set of RNAs and proteins but an elaborate protein machinery could not evolve without an accurate translation system. The origin of the genetic code and whether it evolved on the basis of a stereochemical correspondence between amino acids and their cognate codons (or anticodons), through selectional optimization of the code vocabulary, as a "frozen accident" or via a combination of all these routes is another wide open problem despite extensive theoretical and experimental studies. Here we combine the results of comparative genomics of translation system components, data on interaction of amino acids with their cognate codons and anticodons, and data on catalytic activities of ribozymes to develop conceptual models for the origins of the translation system and the genetic code.
Our main guide in constructing the models is the Darwinian Continuity Principle whereby a scenario for the evolution of a complex system must consist of plausible elementary steps, each conferring a distinct advantage on the evolving ensemble of genetic elements. Evolution of the translation system is envisaged to occur in a compartmentalized ensemble of replicating, co-selected RNA segments, i.e., in a RNA World containing ribozymes with versatile activities. Since evolution has no foresight, the translation system could not evolve in the RNA World as the result of selection for protein synthesis and must have been a by-product of evolution drive by selection for another function, i.e., the translation system evolved via the exaptation route. It is proposed that the evolutionary process that eventually led to the emergence of translation started with the selection for ribozymes binding abiogenic amino acids that stimulated ribozyme-catalyzed reactions. The proposed scenario for the evolution of translation consists of the following steps: binding of amino acids to a ribozyme resulting in an enhancement of its catalytic activity; evolution of the amino-acid-stimulated ribozyme into a peptide ligase (predecessor of the large ribosomal subunit) yielding, initially, a unique peptide activating the original ribozyme and, possibly, other ribozymes in the ensemble; evolution of self-charging proto-tRNAs that were selected, initially, for accumulation of amino acids, and subsequently, for delivery of amino acids to the peptide ligase; joining of the peptide ligase with a distinct RNA molecule (predecessor of the small ribosomal subunit) carrying a built-in template for more efficient, complementary binding of charged proto-tRNAs; evolution of the ability of the peptide ligase to assemble peptides using exogenous RNAs as template for complementary binding of charged proteo-tRNAs, yielding peptides with the potential to activate different ribozymes; evolution of the translocation function of the protoribosome leading to the production of increasingly longer peptides (the first proteins), i.e., the origin of translation. The specifics of the recognition of amino acids by proto-tRNAs and the origin of the genetic code depend on whether or not there is a physical affinity between amino acids and their cognate codons or anticodons, a problem that remains unresolved.
We describe a stepwise model for the origin of the translation system in the ancient RNA world such that each step confers a distinct advantage onto an ensemble of co-evolving genetic elements. Under this scenario, the primary cause for the emergence of translation was the ability of amino acids and peptides to stimulate reactions catalyzed by ribozymes. Thus, the translation system might have evolved as the result of selection for ribozymes capable of, initially, efficient amino acid binding, and subsequently, synthesis of increasingly versatile peptides. Several aspects of this scenario are amenable to experimental testing.
This article was reviewed by Rob Knight, Doron Lancet, Alexander Mankin (nominated by Arcady Mushegian), and Arcady Mushegian.
PMCID: PMC1894784  PMID: 17540026
9.  The cosmological model of eternal inflation and the transition from chance to biological evolution in the history of life 
Biology Direct  2007;2:15.
Recent developments in cosmology radically change the conception of the universe as well as the very notions of "probable" and "possible". The model of eternal inflation implies that all macroscopic histories permitted by laws of physics are repeated an infinite number of times in the infinite multiverse. In contrast to the traditional cosmological models of a single, finite universe, this worldview provides for the origin of an infinite number of complex systems by chance, even as the probability of complexity emerging in any given region of the multiverse is extremely low. This change in perspective has profound implications for the history of any phenomenon, and life on earth cannot be an exception.
Origin of life is a chicken and egg problem: for biological evolution that is governed, primarily, by natural selection, to take off, efficient systems for replication and translation are required, but even barebones cores of these systems appear to be products of extensive selection. The currently favored (partial) solution is an RNA world without proteins in which replication is catalyzed by ribozymes and which serves as the cradle for the translation system. However, the RNA world faces its own hard problems as ribozyme-catalyzed RNA replication remains a hypothesis and the selective pressures behind the origin of translation remain mysterious. Eternal inflation offers a viable alternative that is untenable in a finite universe, i.e., that a coupled system of translation and replication emerged by chance, and became the breakthrough stage from which biological evolution, centered around Darwinian selection, took off. A corollary of this hypothesis is that an RNA world, as a diverse population of replicating RNA molecules, might have never existed. In this model, the stage for Darwinian selection is set by anthropic selection of complex systems that rarely but inevitably emerge by chance in the infinite universe (multiverse).
The plausibility of different models for the origin of life on earth directly depends on the adopted cosmological scenario. In an infinite universe (multiverse), emergence of highly complex systems by chance is inevitable. Therefore, under this cosmology, an entity as complex as a coupled translation-replication system should be considered a viable breakthrough stage for the onset of biological evolution.
This article was reviewed by Eric Bapteste, David Krakauer, Sergei Maslov, and Itai Yanai.
PMCID: PMC1892545  PMID: 17540027
10.  Chance and necessity in cellular response to challenge 
PMCID: PMC1865590  PMID: 17453048

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