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‣ Comparative Genomics of Trace Element Dependence in Biology*

Zhang, Yan; Gladyshev, Vadim N.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Biological trace elements are needed in small quantities but are used by all living organisms. A growing list of trace element-dependent proteins and trace element utilization pathways highlights the importance of these elements for life. In this minireview, we focus on recent advances in comparative genomics of trace elements and explore the evolutionary dynamics of the dependence of user proteins on these elements. Many zinc protein families evolved representatives that lack this metal, whereas selenocysteine in proteins is dynamically exchanged with cysteine. Several other elements, such as molybdenum and nickel, have a limited number of user protein families, but they are strictly dependent on these metals. Comparative genomics of trace elements provides a foundation for investigating the fundamental properties, functions, and evolutionary dynamics of trace element dependence in biology.

‣ Genome Biology of the Cyclostomes and Insights into the Evolutionary Biology of Vertebrate Genomes

Smith, J. J.; Saha, N. R.; Amemiya, C. T.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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The jawless vertebrates (lamprey and hagfish) are the closest extant outgroups to all jawed vertebrates (gnathostomes) and can therefore provide critical insight into the evolution and basic biology of vertebrate genomes. As such, it is notable that the genomes of lamprey and hagfish posses a capacity for rearrangement that is beyond anything known from the gnathostomes. Like the jawed vertebrates, lamprey and hagfish undergo rearrangement of adaptive immune receptors. However, the receptors and the mechanisms for rearrangement that are utilized by jawless vertebrates clearly evolved independently of the gnathostome system. Unlike the jawed vertebrates, lamprey and hagfish also undergo extensive programmed rearrangements of the genome during embryonic development. By considering these fascinating genome biologies in the context of proposed (albeit contentious) phylogenetic relationships among lamprey, hagfish, and gnathostomes, we can begin to understand the evolutionary history of the vertebrate genome. Specifically, the deep shared ancestry and rapid divergence of lampreys, hagfish and gnathostomes is considered evidence that the two versions of programmed rearrangement present in lamprey and hagfish (embryonic and immune receptor) were present in an ancestral lineage that existed more than 400 million years ago and perhaps included the ancestor of the jawed vertebrates. Validating this premise will require better characterization of the genome sequence and mechanisms of rearrangement in lamprey and hagfish.

‣ Phylogenomics of Unusual Histone H2A Variants in Bdelloid Rotifers

Van Doninck, Karine; Mandigo, Morgan L.; Hur, Jae H.; Guglielmini, Julien; Milinkovitch, Michel C.; Malik, Harmit S.; Wang, Peter; Lane, William S.; Meselson, Matthew Stanley
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Rotifers of Class Bdelloidea are remarkable in having evolved for millions of years, apparently without males and meiosis. In addition, they are unusually resistant to desiccation and ionizing radiation and are able to repair hundreds of radiation-induced DNA double-strand breaks per genome with little effect on viability or reproduction. Because specific histone H2A variants are involved in DSB repair and certain meiotic processes in other eukaryotes, we investigated the histone H2A genes and proteins of two bdelloid species. Genomic libraries were built and probed to identify histone H2A genes in Adineta vaga and Philodina roseola, species representing two different bdelloid families. The expressed H2A proteins were visualized on SDS-PAGE gels and identified by tandem mass spectrometry. We find that neither the core histone H2A, present in nearly all other eukaryotes, nor the H2AX variant, a ubiquitous component of the eukaryotic DSB repair machinery, are present in bdelloid rotifers. Instead, they are replaced by unusual histone H2A variants of higher mass. In contrast, a species of rotifer belonging to the facultatively sexual, desiccation- and radiation-intolerant sister class of bdelloid rotifers, the monogononts, contains a canonical core histone H2A and appears to lack the bdelloid H2A variant genes. Applying phylogenetic tools...

‣ Mammalian Sleep Dynamics: How Diverse Features Arise From a Common Physiological Framework

Robinson, Peter A.; Kedziora, David J.; Abeysuriya, Romesh G.; Friston, Karl J.; Phillips, Andrew J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Mammalian sleep varies widely, ranging from frequent napping in rodents to consolidated blocks in primates and unihemispheric sleep in cetaceans. In humans, rats, mice and cats, sleep patterns are orchestrated by homeostatic and circadian drives to the sleep–wake switch, but it is not known whether this system is ubiquitous among mammals. Here, changes of just two parameters in a recent quantitative model of this switch are shown to reproduce typical sleep patterns for 17 species across 7 orders. Furthermore, the parameter variations are found to be consistent with the assumptions that homeostatic production and clearance scale as brain volume and surface area, respectively. Modeling an additional inhibitory connection between sleep-active neuronal populations on opposite sides of the brain generates unihemispheric sleep, providing a testable hypothetical mechanism for this poorly understood phenomenon. Neuromodulation of this connection alone is shown to account for the ability of fur seals to transition between bihemispheric sleep on land and unihemispheric sleep in water. Determining what aspects of mammalian sleep patterns can be explained within a single framework, and are thus universal, is essential to understanding the evolution and function of mammalian sleep. This is the first demonstration of a single model reproducing sleep patterns for multiple different species. These wide-ranging findings suggest that the core physiological mechanisms controlling sleep are common to many mammalian orders...

‣ Lamarck Ascending! A Review of Transformations of Lamarckism: From Subtle Fluids to Molecular Biology. Edited by Snait B. Gissis and Eva Jablonka, MIT Press, 2011

Haig, David Addison
Fonte: University of Michigan Libraries Publicador: University of Michigan Libraries
Tipo: Commentary or Review
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Transformations of Lamarckism is an edited volume arising from a workshop to commemorate the bicentenary of the publication of Philosophie Zoologique. The contributed chapters discuss the history of Lamarckism, present new developments in biology that could be considered to vindicate Lamarck, and argue for a revision, if not a revolution, in evolutionary theory. My review argues that twentieth and twenty-first century conceptions of Lamarckism can be considered a reaction to August Weismann’s uncompromising rejection of the inheritance of acquired characters in the late nineteenth century. Weismann rejected the inheritance of acquired characters both as a proximate mechanism of heredity and as an ultimate cause of adaptation. I argue that Weismann’s proximate claim is still valid for the kind of mechanism that he had in mind but that the inheritance of acquired characters has come to refer to many different processes, some of which undoubtedly do occur. However, processes of physiological adaptation and adaptive plasticity, even if transgenerational, do not challenge Weismann’s claim about the ultimate causes of adaptation because these processes can be understood as evolving by natural selection. Finally, I discuss some of the emotional and aesthetic reasons why many find Lamarckism an attractive alternative to hard-core neo-Darwinism.; Organismic and Evolutionary Biology

‣ Using Whole-Genome Sequence Data to Predict Quantitative Trait Phenotypes in Drosophila melanogaster

Ober, Ulrike; Stone, Eric A.; Richards, Stephen; Zhu, Dianhui; Gibbs, Richard A.; Stricker, Christian; Gianola, Daniel; Schlather, Martin; Mackay, Trudy F. C.; Simianer, Henner; Ayroles, Julien
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Predicting organismal phenotypes from genotype data is important for plant and animal breeding, medicine, and evolutionary biology. Genomic-based phenotype prediction has been applied for single-nucleotide polymorphism (SNP) genotyping platforms, but not using complete genome sequences. Here, we report genomic prediction for starvation stress resistance and startle response in Drosophila melanogaster, using ∼2.5 million SNPs determined by sequencing the Drosophila Genetic Reference Panel population of inbred lines. We constructed a genomic relationship matrix from the SNP data and used it in a genomic best linear unbiased prediction (GBLUP) model. We assessed predictive ability as the correlation between predicted genetic values and observed phenotypes by cross-validation, and found a predictive ability of 0.239±0.008 (0.230±0.012) for starvation resistance (startle response). The predictive ability of BayesB, a Bayesian method with internal SNP selection, was not greater than GBLUP. Selection of the 5% SNPs with either the highest absolute effect or variance explained did not improve predictive ability. Predictive ability decreased only when fewer than 150,000 SNPs were used to construct the genomic relationship matrix. We hypothesize that predictive power in this population stems from the SNP–based modeling of the subtle relationship structure caused by long-range linkage disequilibrium and not from population structure or SNPs in linkage disequilibrium with causal variants. We discuss the implications of these results for genomic prediction in other organisms.; Organismic and Evolutionary Biology

‣ Mutation Induced Extinction in Finite Populations: Lethal Mutagenesis and Lethal Isolation

Wylie, Christopher Scott; Shakhnovich, Eugene Isaacovitch
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate “semi-conservatively,” e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N). However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (τ) in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how τ scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i) features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii) is based on the biophysics of protein folding. More specifically...

‣ Effects of Epistasis and Pleiotropy on Fitness Landscapes

Østman, Bjørn
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 12/04/2013 Português
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The factors that influence genetic architecture shape the structure of the fitness landscape, and therefore play a large role in the evolutionary dynamics. Here the NK model is used to investigate how epistasis and pleiotropy -- key components of genetic architecture -- affect the structure of the fitness landscape, and how they affect the ability of evolving populations to adapt despite the difficulty of crossing valleys present in rugged landscapes. Populations are seen to make use of epistatic interactions and pleiotropy to attain higher fitness, and are not inhibited by the fact that valleys have to be crossed to reach peaks of higher fitness.; Comment: 10 pages, 6 figures. To appear in "Origin of Life and Evolutionary Mechanisms" (P. Pontarotti, ed.). Evolutionary Biology: 16th Meeting 2012, Springer-Verlag

‣ A new formulation of protein evolutionary models that account for structural constraints

Bordner, Andrew J.; Mittelmann, Hans D.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
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Despite the importance of a thermodynamically stable structure with a conserved fold for protein function, almost all evolutionary models neglect site-site correlations that arise from physical interactions between neighboring amino acid sites. This is mainly due to the difficulty in formulating a computationally tractable model since rate matrices can no longer be used. Here we introduce a general framework, based on factor graphs, for constructing probabilistic models of protein evolution with site interdependence. Conveniently, efficient approximate inference algorithms, like Belief Propagation, can be used to calculate likelihoods for these models. We fit an amino acid substitution model of this type that accounts for both solvent accessibility and site-site correlations. Comparisons of the new model with rate matrix models and a model accounting only for solvent accessibility demonstrate that it better fits the sequence data. We also examine evolution within a family of homohexameric enzymes and find that site-site correlations between most contacting subunits contribute to a higher likelihood. In addition, we show that the new substitution model has a similar mathematical form to the one introduced in (Rodrigue et al. 2005), although with different parameter interpretations and values. We also perform a statistical analysis of the effects of amino acids at neighboring sites on substitution probabilities and find a significant perturbation of most probabilities...

‣ Mathematical Structure of Evolutionary Theory

Ao, P.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 15/03/2004 Português
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Here we postulate three laws which form a mathematical framework to capture the essence of Darwinian evolutionary dynamics. The second law is most quantitative and is explicitly expressed by a unique form of stochastic differential equation. A precise definition of Wright's adaptive landscape is given and a new and consistent interpretation of Fisher's fundamental theorem of natural selection is provided. Based on a recently discovered theorem the generality of the proposed laws is illustrated by an explicit demonstration of their equivalence to a general conventional non-equilibrium dynamics formulation. The proposed laws provide a coherence framework to discuss several current evolutionary problems, such as speciation and stability, and gives a firm base for the application of statistical physics tools in Darwinian dynamics.; Comment: 10 pages

‣ Metabolic Rate Calibrates the Molecular Clock: Reconciling Molecular and Fossil Estimates of Evolutionary Divergence

Gillooly, James F.; Allen, Andrew P.; West, Geoffrey B.; Brown, James H.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 22/04/2004 Português
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Observations that rates of molecular evolution vary widely within and among lineages have cast doubts upon the existence of a single molecular clock. Differences in the timing of evolutionary events estimated from genetic and fossil evidence have raised further questions about the existence of molecular clocks and their use. Here we present a model of nucleotide substitution that combines new theory on metabolic rate with the now classic neutral theory of molecular evolution. The model quantitatively predicts rate heterogeneity, and reconciles differences in molecular- and fossil-estimated dates of evolutionary events. Model predictions are supported by extensive data from mitochondrial and nuclear genomes. By accounting for the effects of body size and temperature on metabolic rate, a single molecular clock explains heterogeneity in rates of nucleotide substitution in different genes, taxa, and thermal environments. This model suggests that there is indeed a general molecular clock, as originally proposed by Zuckerkandl and Pauling, but that it ticks at a constant substitution rate per unit mass-specific metabolic energy rather than per unit time. More generally, the model suggests that body size and temperature combine to control the overall rate of evolution through their effects on metabolism.

‣ Unifying Evolutionary and Network Dynamics

Swarup, Samarth; Gasser, Les
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 13/04/2007 Português
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Many important real-world networks manifest "small-world" properties such as scale-free degree distributions, small diameters, and clustering. The most common model of growth for these networks is "preferential attachment", where nodes acquire new links with probability proportional to the number of links they already have. We show that preferential attachment is a special case of the process of molecular evolution. We present a new single-parameter model of network growth that unifies varieties of preferential attachment with the quasispecies equation (which models molecular evolution), and also with the Erdos-Renyi random graph model. We suggest some properties of evolutionary models that might be applied to the study of networks. We also derive the form of the degree distribution resulting from our algorithm, and we show through simulations that the process also models aspects of network growth. The unification allows mathematical machinery developed for evolutionary dynamics to be applied in the study of network dynamics, and vice versa.; Comment: 11 pages, 12 figures, Accepted for publication in Physical Review E

‣ Evolutionary Placement of Short Sequence Reads

Berger, S. A.; Stamatakis, A.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 15/11/2009 Português
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We present an Evolutionary Placement Algorithm (EPA) for the rapid assignment of sequence fragments (short reads) to branches of a given phylogenetic tree under the Maximum Likelihood (ML) model. The accuracy of the algorithm is evaluated on several real-world data sets and compared to placement by pair-wise sequence comparison, using edit distances and BLAST. We test two versions of the placement algorithm, one slow and more accurate where branch length optimization is conducted for each short read insertion and a faster version where the branch lengths are approximated at the insertion position. For the slow version, additional heuristic techniques are explored that almost yield the same run time as the fast version, with only a small loss of accuracy. When those additional heuristics are employed the run time of the more accurate algorithm is comparable to that of a simple BLAST search for data sets with a high number of short query sequences. Moreover, the accuracy of the Evolutionary Placement Algorithm is significantly higher, in particular when the taxon sampling of the reference topology is sparse or inadequate. Our algorithm, which has been integrated into RAxML, therefore provides an equally fast but more accurate alternative to BLAST for phylogeny-aware analysis of short-read sequence data.

‣ Identifiability of the unrooted species tree topology under the coalescent model with time-reversible substitution processes, site-specific rate variation, and invariable sites

Chifman, Julia; Kubatko, Laura
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
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The inference of the evolutionary history of a collection of organisms is a problem of fundamental importance in evolutionary biology. The abundance of DNA sequence data arising from genome sequencing projects has led to significant challenges in the inference of these phylogenetic relationships. Among these challenges is the inference of the evolutionary history of a collection of species based on sequence information from several distinct genes sampled throughout the genome. It is widely accepted that each individual gene has its own phylogeny, which may not agree with the species tree. Many possible causes of this gene tree incongruence are known. The best studied is incomplete lineage sorting, which is commonly modeled by the coalescent process. Numerous methods based on the coalescent process have been proposed for estimation of the phylogenetic species tree given DNA sequence data. However, use of these methods assumes that the phylogenetic species tree can be identified from DNA sequence data at the leaves of the tree, although this has not been formally established. We prove that the unrooted topology of the n-leaf phylogenetic species tree is generically identifiable given observed data at the leaves of the tree that are assumed to have arisen from the coalescent process under a time-reversible substitution process with the possibility of site-specific rate variation modeled by the discrete gamma distribution and a proportion of invariable sites.

‣ Bridging physiological and evolutionary time scales in a gene regulatory network

Marchand, Gwenaëlle; Huynh-Thu, Vân Anh; Kane, Nolan; Arribat, Sandrine; Varès, Didier; Rengel, David; Balzergue, Sandrine; Rieseberg, Loren; Vincourt, Patrick; Geurts, Pierre; Vignes, Matthieu; Langlade, Nicolas B.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
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Gene regulatory networks (GRN) govern phenotypic adaptations and reflect the trade-offs between physiological responses and evolutionary adaptation that act at different time scales. To identify patterns of molecular function and genetic diversity in GRNs, we studied the drought response of the common sunflower, Helianthus annuus, and how the underlying GRN is related to its evolution. We examined the responses of 32,423 expressed sequences to drought and to abscisic acid and selected 145 co-expressed transcripts. We characterized their regulatory relationships in nine kinetic studies based on different hormones. From this, we inferred a GRN by meta-analyses of a Gaussian graphical model and a random forest algorithm and studied the genetic differentiation among populations (FST) at nodes. We identified two main hubs in the network that transport nitrate in guard cells. This suggests that nitrate transport is a critical aspect of sunflower physiological response to drought. We observed that differentiation of the network genes in elite sunflower cultivars is correlated with their position and connectivity. This systems biology approach combined molecular data at different time scales and identified important physiological processes. At the evolutionary level...

‣ A Preliminary Study of Threonine Deaminase Duplication in Solanaceae

Huang, Jie
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Tese de Doutorado
Publicado em //2013 Português
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One of the most important questions in evolutionary biology is how new genes and new functions arise and evolve. Among the theories addressing this question, gene duplication is one of the most popular. Previous study has shown that two threonine deaminase (TD) gene copies exist in Solanum lycopersicum, and these two copies have very different functions and low sequence similarities. The primary objective of this study was to widen our understanding of this gene duplication and the subsequent evolutionary processes affecting the duplicate copies by first collecting additional TD sequences from related species, building a gene tree, and inferring the point of gene duplication. The evolutionary processes acting on this gene were then analyzed using the program PAML. Results indicate that 1) The TD duplication probably occurred in before the split of the Solanoideae from the Nicotianoidea; and 2) there is strong evidence for positive selection on one of the TD copies after gene duplication, while for the other TD copy, only weak evidence for positive selection was found; and 3) adaptive improvement of the copy with new function probably spanned a period of at least 25 million years.

; Thesis

‣ Gene expression in developing fibres of Upland cotton (Gossypium hirsutum L.) was massively altered by domestication;

Flagel, Lex
Fonte: BIOMED CENTRAL LTD Publicador: BIOMED CENTRAL LTD
Publicado em //2010 Português
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Background: Understanding the evolutionary genetics of modern crop phenotypes has a dual relevance to evolutionary biology and crop improvement. Modern upland cotton (Gossypium hirsutum L.) was developed following thousands of years of artificial selection from a wild form, G. hirsutum var. yucatanense, which bears a shorter, sparser, layer of single-celled, ovular trichomes ('fibre'). In order to gain an insight into the nature of the developmental genetic transformations that accompanied domestication and crop improvement, we studied the transcriptomes of cotton fibres from wild and domesticated accessions over a developmental time course. Results: Fibre cells were harvested between 2 and 25 days post-anthesis and encompassed the primary and secondary wall synthesis stages. Using amplified messenger RNA and a custom microarray platform designed to interrogate expression for 40,430 genes, we determined global patterns of expression during fibre development. The fibre transcriptome of domesticated cotton is far more dynamic than that of wild cotton, with over twice as many genes being differentially expressed during development (12,626 versus 5273). Remarkably, a total of 9465 genes were diagnosed as differentially expressed between wild and domesticated fibres when summed across five key developmental time points. Human selection during the initial domestication and subsequent crop improvement has resulted in a biased upregulation of components of the transcriptional network that are important for agronomically advanced fibre...

‣ Mitochondrial Molecular Adaptations and Life History Strategies Coevolve in Plants

Neeraja M. Krishnan; Basuthkar J. Rao
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
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Messenger RNA secondary structure prevents mutations at functionally important sites. Mutations at exposed sites would cause micro-adaptations, niche-specialization, and therefore, can be thought to promote K-strategists. Exposing, rather than protecting, conserved sites, is also potentially adaptive because they probably promote macro-adaptive changes. This presumably fits r-strategists: their population dynamics tolerate decreased survival. We found that helix-forming tendencies are greater at evolutionary conserved sites of plant mitochondrial mRNAs than at evolutionary variable sites in a majority (73%) of species–gene combinations. K-strategists preferentially protect conserved sites in short genes, r-strategists protect them most in larger genes. This adaptive scenario resembles our earlier findings in chloroplast genes. Protection levels at various codon positions also display disparity with respect to life history strategies of the plants. Conserved site protection increases overall mRNA folding stabilities for some genes, while decreases it for some others. This contrast exists between homologous genes of r- and K- strategists. Such compensating interactions between variability, mRNA size, codon position, and secondary structure factors within r- and K-strategists are most likely...

‣ The hypothesis of basic phenotype modules

Thomas von Zelewsky
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
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The evolutionary events that allowed the rapid occurrence of metazoa are still enigmatic. The presumably oldest metazoan fossils are microscopic and occur just above 635 Ma, at the beginning of the Ediacaran period. Upon condition that the lack of macrofossils in the lower Ediacaran strata is real, the assumption of a sudden appearance of already complex, but still small animals that flourished during the first half of the Ediacaran is a reasonable option. Consequently, the emergence of the first macrofossils with metazoan affinity in mid Ediacaran strata would indicate a second leap in animal evolution. Here, these apparent leaps are explained in terms of a new concept of evolvability that is based on well definable developmental modules: A system based on blast cell-induced cell division modules has paved the way for rapid evolution to small multicellular animals. The second module, an ancestral form of segments, allowed the construction of a new sort of metameric body plans that appeared some tenth of million years later and at a larger scale. Based on this new model of basic radiations, the lower Ediacaran strata are predicted to contain a sequence of exotic embryos that is followed by an explosion of small metazoan diversity. The upper Ediacaran biota are interpreted as representatives of an evolutionary succession that culminated in a maximally evolvable and segmented ancestor with an already complex archetype body plan. Then...

‣ Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations.

Shimon Bershtein; Eugene Shakhnovich
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
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Protein stability is widely recognized as a major evolutionary constraint. However, the relation between mutation-induced perturbations of protein stability and biological fitness has remained elusive. Here we explore this relation by introducing a selected set of mostly destabilizing mutations into an essential chromosomal gene of E.coli encoding dihydrofolate reductase (DHFR) to determine how changes in protein stability, activity and abundance affect fitness. Several mutant strains showed no growth while many exhibited fitness higher than wild type. Overexpression of chaperonins (GroEL/ES) buffered the effect of mutations by rescuing the lethal phenotypes and worsening better-fit strains. Changes in stability affect fitness by mediating the abundance of active and soluble proteins; DHFR of lethal strains aggregates, while destabilized DHFR of high fitness strains remains monomeric and soluble at 30oC and forms soluble oligomers at 42oC. These results suggest an evolutionary path where mutational destabilization is counterbalanced by specific oligomerization protecting proteins from aggregation.