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PubMed1999

Evolution by small steps and rugged landscapes in the RNA virus phi6.

Fisher's geometric model of adaptive evolution argues that adaptive evolution should generally result from the substitution of many mutations of small effect because advantageous mutations of small effect should be more common than those of large effect. However, evidence for both evolution by small steps and for Fisher's model has been mixed. Here we report supporting results from a new experimental test of the model. We subjected the bacteriophage phi6 to intensified genetic drift in small populations and caused viral fitness to decline through the accumulation of a deleterious mutation. We then propagated the mutated virus at a range of larger population sizes and allowed fitness to recover by natural selection. Although fitness declined in one large step, it was usually recovered in smaller steps. More importantly, step size during recovery was smaller with decreasing size of the recovery population. These results confirm Fisher's main prediction that advantageous mutations of small effect should be more common. We also show that the advantageous mutations of small effect are compensatory mutations whose advantage is conditional (epistatic) on the presence of the deleterious mutation, in which case the adaptive landscape of phi6 is likely to be very rugged.

Bacteriophage phi 6↗
PubMed1995

Does the time course of bubble evolution explain decompression sickness risk?

A probabilistic model of decompression sickness (DCS) risk based on linear-exponential (LE) kinetics has given the best fit of the human air and nitrox DCS database. To test the hypothesis that its success may be due to the formation of a gas phase during decompression, we developed a physiologically based bubble evolution model using a numerical solution of a partial differential equation system. Because of the computational intensity of this method, it could not be used to fully explore our hypothesis. Consequently, we compared the solution with that of a computationally simpler approximation that was previously published by Van Liew and found the two approaches gave similar results. Using the simpler model, assuming bubble densities of 1 and 1,000 bubbles/cm3, we found a tissue time constant of at least 80 min (equivalent to perfusion of 1/80 ml.g-1.min-1) was required to achieve a delay in bubble dissolution comparable to the prolonged risk of DCS predicted by the LE model. We suggest that the persistence of single bubbles in a uniformly perfused homogeneous tissue alone is unlikely to explain persistent DCS risk.

Blood Flow Velocity↗
PubMed2000

Microstructural evolution of lipid aggregates in nucleating model and human biles visualized by cryogenic transmission electron microscopy.

Obtaining reliable information on the physical state and ultrastructure of bile is difficult because of its mixed aqueous-lipid composition and thermodynamic metastability. We have used time-lapse cryogenic transmission electron microscopy (cryo-TEM) combined with video-enhanced light microscopy (VELM) to study microstructural evolution in nucleating bile. A well-characterized model bile and gallbladder biles from cholesterol and pigment gallstone patients were studied sequentially during cholesterol nucleation and precipitation. In model bile, cholesterol crystallization was preceded by the appearance of the following distinct microstructures: spheroidal micelles (3-5 nm), discoidal membrane patches (50-150 nm) often in multiple layers (2-10), discs (50-100 nm), and unilamellar (50-200 nm) and larger multilamellar vesicles (MLVs). The membrane patches and discs appeared to be short-lived intermediates in a micelle-to-vesicle transition. Vesicular structures formed by growth and closure of patches as well as by budding off from vesicles with fewer bilayers. MLVs became more abundant, uniform, and concentric as a function of time. In native bile, all the above microstructures, except discoidal membrane patches, were observed. However, native MLVs were more uniform and concentric from the beginning. When cholesterol crystals appeared by light microscopy, MLVs were always detected by cryo-TEM. Edges of early cholesterol crystals were lined up with micelles and MLVs in a way suggesting an active role in feeding crystal growth from these microstructures. These findings, for the first time documented by cryo-TEM in human bile, provide a microstructural framework that can serve as a basis for investigation of specific factors that influence biliary cholesterol nucleation and crystal formation.

Bile↗
PubMed1996

Computer simulation of transposable element evolution: random template and strict master models.

It has been proposed that the most extensively studied mammalian retrotransposons replicate by some form of a master template model. This conclusion has been drawn largely from DNA sequence analysis and is based on phylogenetic tree topology, the presence and ordering of shared variants, the degree of divergence between elements within a subfamily, and the shape of the distribution of pairwise differences between elements. To investigate how robust these parameters are as predictors of the model of transposition, computer simulations of the two most extreme transposition models, the Random Template Model and the Strict Master Model, were carried out. A prototype of a computer simulator for studying retrotransposition is presented. The simulator is a versatile digital workbench that maintains DNA sequence data and allows manipulation of a range of factors including reverse transcriptase and in situ mutation rates, transposition template, and transposition rate. All parameters previously used as predictors of the model of transposition were markedly different for the two extreme models when evaluated using large sample sizes of sequences from experiments simulating up to 15 million years of evolution.

Animals↗
PubMed1999

On the importance of a methyl group in beta-lactamase evolution: free energy profiles and molecular modeling.

beta-Lactam antibiotics are generally thought to inhibit their target enzymes, the bacterial cell wall-synthesizing DD-peptidases, because of their resemblance to D-alanyl-D-alanine peptides. Although a favorable conformation of the latter does structurally resemble the beta-lactams with respect to backbone conformation, a significant difference is the presence of a D-methyl substituent on the penultimate alanine residue of the cell wall peptide. A classical beta-lactam antibiotic has a hydrogen in the corresponding position. In the process of evolution of a beta-lactamase from a DD-peptidase, it seems likely that this D-methyl group would be selected against, to ensure that the former enzyme would hydrolyze beta-lactams rather than peptides. In this paper, the effect of the penultimate D-alanine residue (as opposed to a glycine residue) has been examined in peptide substrates of a present-day DD-peptidase and a beta-lactamase. The peptides N-(phenylacetyl)-D-alanyl-D-phenylalanine and N-(phenylacetyl)glycyl-D-phenylalanine were used as a test pair against the DD-peptidase of Streptomyces R61 and the structurally very similar class C beta-lactamase of Enterobacter cloacae P99. The kinetics of turnover of both of these substrates were determined for both enzymes. To quantify the partitioning of the acyl-enzyme intermediate, the aminolysis by D-phenylalanine of a cognate pair of depsipeptides was also studied. Thus, free energy-reaction coordinate diagrams were constructed for turnover of both peptides by both enzymes. Comparison of these profiles showed that the D-methyl group is preferred over hydrogen by the DD-peptidase at all stages of catalysis (acyl-enzyme and acylation and deacylation transition states), whereas the beta-lactamase selects against the D-methyl group only at the peptide acylation transition state. A process of evolution by uniform dissociation of the methyl group by the beta-lactamase has apparently occurred. These results were explored structurally by computational models of the acylation tetrahedral intermediates. A methyl group pocket on the DD-peptidase, less favorable on the beta-lactamase, was identified. The interaction of the leaving group, the terminal D-alanine residue, with the two enzymes was interesting, since it seemed that different positively charged active site residues were directly associated with the carboxylate, Lys 315 in the beta-lactamase and Arg 285 (rather than His 298) in the case of the DD-peptidase. The problems posed by larger substituents on the penultimate residue of the peptide, and in particular by the heterocyclic substituent present in a bicyclic beta-lactam, were analyzed. Qualitative and quantitative analysis of the models support the proposed importance of the penultimate D-alanine in beta-lactamase evolution.

Carboxypeptidases↗
PubMed2003

Scaling law in sizes of protein sequence families: from super-families to orphan genes.

It has been observed that the size of protein sequence families is unevenly distributed, with few super families with a large number of members and many "orphan" proteins that do not belong to any family. Here it is shown that the distribution of sizes of protein families in different databases and classifications (Protomap, Prodom, Cog) follows a power-law behavior with similar scaling exponents, which is characteristic of self-organizing systems. Since large databases are used in this study, a more detailed analysis of the data than in previous studies was possible. Hence, it is shown that the size distribution is governed by two exponents, different for the super families and the orphan proteins. A simple model of protein evolution is proposed, in which proteins are dynamically generated and clustered into families. The model yields a scaling behavior very similar to the distribution observed in the actual sequence databases, including the two distinct regimes for the large and small families, and thus suggests that the existence of "super families" of proteins and "orphan" proteins are two manifestations of the same evolutionary process.

Algorithms↗
PubMed2006

Rapid evolution of reproductive proteins in abalone and Drosophila.

Observations from different taxa, including plants, protozoa, insects and mammals, indicate that proteins involved in reproduction evolve rapidly. Several models of adaptive evolution have been proposed to explain this phenomenon, such as sexual conflict, sexual selection, self versus non-self recognition and pathogen resistance. Here we discuss the potential role of sexual conflict in the rapid evolution of reproductive genes in two different animal systems, abalone (Haliotis) and Drosophila. In abalone, we reveal how specific interacting sperm-egg proteins were identified and discuss this identification in the light of models for rapid protein evolution and speciation. For Drosophila, we describe the genomic approaches taken to identify male accessory gland proteins and female reproductive tract proteins. Patterns of protein evolution from both abalone and Drosophila support the predicted patterns of rapid protein evolution driven by sexual conflict. We stress however that other selective pressures may contribute to the rapid evolution that is observed. We conclude that the key to distinguishing between sexual conflict and other mechanisms of protein evolution will be an integration of genetic, experimental and theoretical data.

Animals↗
PubMed1996

Modeling marrow damage from response data: evolution from radiation biology to benzene toxicity.

Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between 5 and 30 days. Mortality data from 27 experiments with 851 dose-response groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals: 12,827 mice, 2925 rats, 1676 sheep, 829 swine, 479 dogs, and 204 burros. Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is critical to hematopoietic recovery does not resemble stemlike cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD50 and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in fitting of model coefficients.

Animals↗
PubMed1996

Widespread use of the glu-tRNAGln transamidation pathway among bacteria. A member of the alpha purple bacteria lacks glutaminyl-trna synthetase.

The expression of the Rhizobium meliloti glutamyl-tRNA synthetase gene in Escherichia coli under the control of a trc promoter results in a toxic effect upon isopropyl-beta-D-thiogalactopyranoside induction, which is probably caused by a misacylation activity. To further investigate this unexpected result, we looked at the pathway of Gln-tRNAGln formation in R. meliloti. No glutaminyl-tRNA synthetase activity has been found in R. meliloti crude extract, but we detected a specific aminotransferase activity that changes Glu-tRNAGln to Gln-tRNAGln. Our results show that R. meliloti, a member of the alpha-subdivision of the purple bacteria, is the first Gram-negative bacteria reported to use a transamidation pathway for Gln-tRNAGln synthesis. A phylogenetic analysis of the contemporary glutamyl-tRNA synthetase and glutaminyl-tRNA synthetase amino acid sequences reveals that a close evolutionary relationship exists between R. meliloti and yeast mitochondrial glutamyl-tRNA synthetases, which is consistent with an origin of mitochondria in the alpha-subdivision of Gram-negative purple bacteria. A 256-amino acid open reading frame closely related to bacterial glutamyl-tRNA synthetases, which probably originates from a glutamyl-tRNA synthetase gene duplication, was found in the 4-min region of the E. coli chromosome. We suggest that this open reading frame is a relic of an ancient transamidation pathway that occurred in an E. coli ancestor before the horizontal transfer of a eukaryotic glutaminyl-tRNA synthetase (Lamour, V., Quevillon, S., Diriong, S., N'Guyen, V. C., Lipinski, M., and Mirande, M.(1994) Proc. Natl. Acad. Sci. U. S. A. 91, 8670-8674) and that it favored its stable acquisition. From these observations, a revisited model for the evolution of the contemporary glutamyl-tRNA synthetases and glutaminyl-tRNA synthetases that differs from the generally accepted model for the evolution of aminoacyl-tRNA synthetases is proposed.

Amino Acid Sequence↗
PubMed2000

[Genetic evolution under vaccine pressure: the Bordetella pertussis model].

A possible genetic selective pressure related to the long-term use of vaccines has been the object of recent theoretical thought and publications. For more than thirty years, an effective vaccine has been in use against whooping cough on a wide scale basis in several countries. Thus, the Bordetella pertussis model may contribute to the analysis of an evolutionary risk linked to the vaccine. To maintain and improve the control of whooping cough, better vaccination coverage must be achieved in countries where prevalence is low. In countries where high vaccination coverage has been achieved over a long period, a trend toward the resurgence of the disease has been observed. Efforts are therefore now being directed toward primary vaccination and boosters. These two targets require new vaccines with fewer side effects. Outbreaks in highly vaccinated populations have been reported, raising the issues of vaccine efficacy, of the long-term effect of vaccines on the transmission of the disease, and of genetic selective pressure. Time trend modifications of circulating strains related to vaccination practices and vaccine types have been observed and are compatible with a selective pressure of the vaccine on related pathogens. However, evidence for a causal relation is lacking. In order to monitor and understand the various effects the vaccine may be having on the effectiveness of immunisation against whooping cough, further surveillance is needed, integrating a standardised characterisation of circulating strains and vaccines by way of a space-time sampling model.

Biological Evolution↗
PubMed2005

The evolution of mutation rate in finite asexual populations.

In this article, we model analytically the evolution of mutation rate in asexual organisms. Three selective forces are present. First, everything else being equal, individuals with higher mutation rate have a larger fitness, thanks to the energy and time saved by not replicating DNA accurately. Second, as a flip side, the genome of these individuals is replicated with errors that may negatively affect fitness. Third, and conversely, replication errors have a potential benefit if beneficial mutations are to be generated. Our model describes the fate of modifiers of mutation rate under the three forces and allows us to predict the long-term evolutionary trajectory of mutation rate. We obtain three major results. First, in asexuals, the needs for both adaptation and genome preservation are not evolutionary forces that can stabilize mutation rate at an intermediate optimum. When adaptation has a significant role, it primarily destabilizes mutation rate and yields the emergence of strong-effect mutators. Second, in contrast to what is usually believed, the appearance of modifiers with large mutation rate is more likely when the fitness cost of each deleterious mutation is weak, because the cost of replication errors is then paid after a delay. Third, in small populations, and even if adaptations are needed, mutation rate is always blocked at the minimum attainable level, because the rate of adaptation is too slow to play a significant role. Only populations whose size is above a critical mass see their mutation rate affected by the need for adaptation.

Adaptation, Physiological↗
PubMed2006

Understanding linguistic evolution by visualizing the emergence of topographic mappings.

We show how cultural selection for learnability during the process of linguistic evolution can be visualized using a simple iterated learning model. Computational models of linguistic evolution typically focus on the nature of, and conditions for, stable states. We take a novel approach and focus on understanding the process of linguistic evolution itself. What kind of evolutionary system is this process? Using visualization techniques, we explore the nature of replicators in linguistic evolution, and argue that replicators correspond to local regions of regularity in the mapping between meaning and signals. Based on this argument, we draw parallels between phenomena observed in the model and linguistic phenomena observed across languages. We then go on to identify issues of replication and selection as key points of divergence in the parallels between the processes of linguistic evolution and biological evolution.

Artificial Intelligence↗
PubMed2002

On the selection and evolution of regulatory DNA motifs.

The mutation and selection of regulatory DNA sequences are presented as an ideal model system of molecular evolution where genotype, phenotype, and fitness can be explicitly and independently characterized. In this theoretical study, we construct an explicit model for the evolution of regulatory sequences, making use of the known biophysics of the binding of regulatory proteins to DNA sequences, under the assumption that fitness of a sequence depends only on its binding affinity to the regulatory protein. The model is confined to the mean field (i.e., infinite population size) limit. Using realistic values for all parameters, we determine the minimum fitness advantage needed to maintain a binding sequence, demonstrating explicitly the "error threshold" below which a binding sequence cannot survive the accumulated effect of mutation over long time. The commonly observed "fuzziness" in binding motifs arises naturally as a consequence of the balance between selection and mutation in our model. In addition, we devise a simple model for the evolution of multiple binding sequences in a given regulatory region. We find the number of evolutionarily stable binding sequences to increase in a step-like fashion with increasing fitness advantage, if multiple regulatory proteins can synergistically enhance gene transcription. We discuss possible experimental approaches to resolve open questions raised by our study.

Binding Sites↗
PubMed1997

The B12-dependent ribonucleotide reductase from the archaebacterium Thermoplasma acidophila: an evolutionary solution to the ribonucleotide reductase conundrum.

A coenzyme B12-dependent ribonucleotide reductase was purified from the archaebacterium Thermoplasma acidophila and partially sequenced. Using probes derived from the sequence, the corresponding gene was cloned, completely sequenced, and expressed in Escherichia coli. The deduced amino acid sequence shows that the catalytic domain of the B12-dependent enzyme from T. acidophila, some 400 amino acids, is related by common ancestry to the diferric tyrosine radical iron(III)-dependent ribonucleotide reductase from E. coli, yeast, mammalian viruses, and man. The critical cysteine residues in the catalytic domain that participate in the thiyl radical-dependent reaction have been conserved even though the cofactor that generates the radical is not. Evolutionary bridges created by the T. acidophila sequence and that of a B12-dependent reductase from Mycobacterium tuberculosis establish homology between the Fe-dependent enzymes and the catalytic domain of the Lactobacillus leichmannii B12-dependent enzyme as well. These bridges are confirmed by a predicted secondary structure for the Lactobacillus enzyme. Sequence similarities show that the N-terminal domain of the T. acidophila ribonucleotide reductase is also homologous to the anaerobic ribonucleotide reductase from E. coli, which uses neither B12 nor Fe cofactors. A predicted secondary structure of the N-terminal domain suggests that it is predominantly helical, as is the domain in the aerobic E. coli enzyme depending on Fe, extending the homologous family of proteins to include anaerobic ribonucleotide reductases, B12 ribonucleotide reductases, and Fe-dependent aerobic ribonucleotide reductases. A model for the evolution of the ribonucleotide reductase family is presented; in this model, the thiyl radical-based reaction mechanism is conserved, but the cofactor is chosen to best adapt the host organism to its environment. This analysis illustrates how secondary structure predictions can assist evolutionary analyses, each important in "post-genomic" biochemistry.

Amino Acid Sequence↗
PubMed1998

Image analysis of dermal collagen changes during skin aging.

OBJECTIVE: To determine progressive quantitative, directional and textural changes in dermal collagen as a function of age and sex and to estimate their evolutive trend with appropriate regression models. STUDY DESIGN: Ninety-six samples of abdominal skin from autopsy cases were analyzed. The ages ranged from 3.5 months to 86 years. Picro-Sirius-stained slides were examined by polarizing microscopy, and spatial density, directional features and texture of collagen were measured by computerized image analysis. Nonlinear regression models were built to estimate evolutive changes with respect to age. The relationship between spatial orientation of collagen bundles and age was best modeled by linear regression. RESULTS: The evolutive patterns of dermal thickness and spatial density of collagen bundles correspond to a second-order polynomial model with a progressive increase from childhood to middle age and a relatively sharp decrease after the seventh decade. The evolution of textural pattern of dermal collagen, defined by gradient analysis, depicts a sort of inverted U. Its complexity is maximum in the first year of life, decreases until the period 25-50 years and increases progressively after the sixth decade. The horizontal orientation of collagen bundles with intermingled fascicles oriented in other directions, shown by young individuals, is progressively simplified with aging. In elderly subjects, collagen bundles have a horizontal orientation. No significant sex-related differences were found. CONCLUSION: Dermal collagen changes related to aging are apparently independent of sex, at least in abdominal skin, and show characteristic curvilinear evolutive trends defined by decreased dermal thickness in the elderly, decrease in the spatial density of collagen bundles and increase in textural heterogeneity of the dermis. Progressive simplification in the orientation of collagen bundles leading to a predominant horizontal disposition followed a linear trend. These changes could contribute to providing a substantial morphologic basis to age-associated biomechanical alterations in the skin.

Abdomen↗
PubMed2005

Empirical codon substitution matrix.

BACKGROUND: Codon substitution probabilities are used in many types of molecular evolution studies such as determining Ka/Ks ratios, creating ancestral DNA sequences or aligning coding DNA. Until the recent dramatic increase in genomic data enabled construction of empirical matrices, researchers relied on parameterized models of codon evolution. Here we present the first empirical codon substitution matrix entirely built from alignments of coding sequences from vertebrate DNA and thus provide an alternative to parameterized models of codon evolution. RESULTS: A set of 17,502 alignments of orthologous sequences from five vertebrate genomes yielded 8.3 million aligned codons from which the number of substitutions between codons were counted. From this data, both a probability matrix and a matrix of similarity scores were computed. They are 64 x 64 matrices describing the substitutions between all codons. Substitutions from sense codons to stop codons are not considered, resulting in block diagonal matrices consisting of 61 x 61 entries for the sense codons and 3 x 3 entries for the stop codons. CONCLUSION: The amount of genomic data currently available allowed for the construction of an empirical codon substitution matrix. However, more sequence data is still needed to construct matrices from different subsets of DNA, specific to kingdoms, evolutionary distance or different amount of synonymous change. Codon mutation matrices have advantages for alignments up to medium evolutionary distances and for usages that require DNA such as ancestral reconstruction of DNA sequences and the calculation of Ka/Ks ratios.

Amino Acid Substitution↗
PubMed2005

Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model.

Because each change in the evolution of a cancer is predicated on the effects of previous events, a full understanding of selective changes and their effect on tumor progression can only be understood in the context of appropriate initiating events. Here, we define the effect of pRb function inactivation in prostate epithelium on both the initiation of prostate cancer and the establishment of selective pressures that lead to diminished Pten function and tumor evolution. Using genetically engineered mice, we show that inactivation of the pRb family proteins (Rb/p107/p130) induces epithelial proliferation and apoptosis and is sufficient to produce prostatic intraepithelial neoplasia (PIN) lesions. Over time, adenocarcinomas develop in all mice with no evidence of neuroendocrine tumors. Apoptosis is dependent on Pten function and not p53, unlike other epithelial cell types tested previously. Consequently, Pten hemizygosity reduces apoptosis by 50%, accelerating progression to adenocarcinomas with heterogeneous composition. Heterogeneity is associated with concurrent Pten haploinsufficiency and focal selective progression to complete Pten loss, which yields distinct tumor properties. Given that this analysis models the apparent timing of highly penetrant events in human prostate cancer, observed effects may recapitulate the natural evolution of prostate cancer development.

Adenocarcinoma↗