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Rafael Sanjuán

Publications and source records attributed to Rafael Sanjuán.

At least 19 recordsLinked to original sources
PubMed2007

The cost of replication fidelity in human immunodeficiency virus type 1.

Mutation rates should be governed by at least three evolutionary factors: the need for beneficial mutations, the benefit of minimizing the mutational load and the cost of replication fidelity. RNA viruses show high mutation rates compared with DNA micro-organisms, and recent findings suggest that the cost of fidelity might play a role in the evolution of increased mutation rates. Here, by analysing previously published data from HIV-1 reverse transcriptase in vitro assays, we show a trade-off between enzymatic accuracy and the maximum rate of polymerization, thus providing a biochemical basis for the fitness cost of fidelity in HIV-1. This trade-off seems to be related to inefficient extension of mispairs, which increases fidelity at the expense of the polymerization rate. Since in RNA viruses fast replication is critical for survival, this could impose a high cost of fidelity and favour the evolution of high mutation rates.

DNA, Viral↗
PubMed2006

Topology testing of phylogenies using least squares methods.

BACKGROUND: The least squares (LS) method for constructing confidence sets of trees is closely related to LS tree building methods, in which the goodness of fit of the distances measured on the tree (patristic distances) to the observed distances between taxa is the criterion used for selecting the best topology. The generalized LS (GLS) method for topology testing is often frustrated by the computational difficulties in calculating the covariance matrix and its inverse, which in practice requires approximations. The weighted LS (WLS) allows for a more efficient albeit approximate calculation of the test statistic by ignoring the covariances between the distances. RESULTS: The goal of this paper is to assess the applicability of the LS approach for constructing confidence sets of trees. We show that the approximations inherent to the WLS method did not affect negatively the accuracy and reliability of the test both in the analysis of biological sequences and DNA-DNA hybridization data (for which character-based testing methods cannot be used). On the other hand, we report several problems for the GLS method, at least for the available implementation. For many data sets of biological sequences, the GLS statistic could not be calculated. For some data sets for which it could, the GLS method included all the possible trees in the confidence set despite a strong phylogenetic signal in the data. Finally, contrary to WLS, for simulated sequences GLS showed undercoverage (frequent non-inclusion of the true tree in the confidence set). CONCLUSION: The WLS method provides a computationally efficient approximation to the GLS useful especially in exploratory analyses of confidence sets of trees, when assessing the phylogenetic signal in the data, and when other methods are not available.

Animals↗
PubMed2006

Epistasis correlates to genomic complexity.

Whether systematic genetic interactions (epistasis) occur at the genomic scale remains a challenging topic in evolutionary biology. Epistasis should make a significant contribution to variation in complex traits and influence the evolution of genetic systems as sex, diploidy, dominance, or the contamination of genomes with deleterious mutations. We have collected data from widely different organisms and quantified epistasis in a common, per-generation scale. Simpler genomes, such as those of RNA viruses, display antagonistic epistasis (mutations have smaller effects together than expected); bacterial microorganisms do not apparently deviate from independent effects, whereas in multicellular eukaryotes, a transition toward synergistic epistasis occurs (mutations have larger effects together than expected). We propose that antagonistic epistasis might be a property of compact genomes with few nonpleiotropic biological functions, whereas in complex genomes, synergism might emerge from mutational robustness.

Animals↗
PubMed2006

In silico predicted robustness of viroid RNA secondary structures. II. Interaction between mutation pairs.

Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. Most of the 29 described viroid species fold into a rodlike or quasi-rodlike structure, whereas a few of them fold as highly branched structures. In a previous study, we used RNA thermodynamic secondary structure prediction algorithms to compare the mutational robustness of all viroid species. Here we used the same approach to explore the sign and strength of epistasis among pairs of random mutations. We found that antagonistic interactions were more abundant than synergistic ones. However, despite their lower frequency, synergistic interactions tended to be more intense. Mutational robustness and the intensity of epistasis were correlated such that viroid species with large average mutational effects showed stronger antagonistic epistasis, whereas viroids with mild average mutational effects showed weaker antagonistic interactions. The strength of antagonistic epistasis decreased with genome complexity as a consequence of the gained robustness of duplicated genomes. In good agreement with our previous finding of an evolutionary trend toward increased robustness, we now found a trend toward reduced antagonistic epistasis.

Base Pairing↗
PubMed2006

Intravenous N-acetylcysteine for preventing contrast-induced nephropathy: a randomised trial.

BACKGROUND: Studies evaluating the role of N-acetylcysteine in patients undergoing coronary angiography have yielded inconsistent data. Less is known about patients with normal renal function at baseline. METHODS: Prospective, double-blind, placebo-controlled trial to determine the benefits of intravenous N-acetylcysteine as an adjunct to hydration in this kind of population. Patients were randomly assigned to receive either N-acetylcysteine (600 mg twice daily) or placebo, in addition to 0.45% intravenous saline. The primary end point was development of contrast-induced nephropathy, defined as an acute increase in the serum creatinine concentration > or = 0.5 mg/dl and/or > 25% increase above baseline level at 48 h after contrast dosing. RESULTS: A total of 216 patients were studied: N-acetylcysteine = 107 and placebo = 109. Treatment groups were similar with respect to baseline clinical characteristics. Overall incidence of contrast-induced nephropathy was 10.2%, 10.3% in the N-acetylcysteine group and 10.1% in the placebo group. Furthermore, no significant differences were observed when considering the non-diabetic population, although there was a trend towards a protective effect of N-acetylcysteine in the subgroup of 47 patients with both hypertension and diabetes. There were no significant changes in serum urea nitrogen concentrations. The incidence of in-hospital adverse clinical events was low: no patient with contrast-induced nephropathy required dialysis, the median Coronary Unit stay was 4.5 vs. 4 days, and the mortality rate was 2.8% vs. 4.6% in the N-acetylcysteine and placebo groups, respectively (p=NS). CONCLUSIONS: The prophylactic administration of intravenous N-acetylcysteine provides no additional benefit to saline hydration in high-risk coronary patients with normal renal function.

Acetylcysteine↗
PubMed2006

The effect of co- and superinfection on the adaptive dynamics of vesicular stomatitis virus.

In many infectious diseases, hosts are often simultaneously infected with several genotypes of the same pathogen. Much theoretical work has been done on modelling multiple infection dynamics, but empirical evidences are relatively scarce. Previous studies have demonstrated that coinfection allows faster adaptation than single infection in RNA viruses. Here, we use experimental populations of the vesicular stomatitis Indiana virus derived from an infectious cDNA, to show that superinfection dynamics promotes faster adaptation than single infection. In addition, we have analysed two different periodicities of multiple infection, daily and separated 5 days in time. Daily multiple infections allow higher fitness increases than multiple infections taking place every 5 days. We propose that the effect of superinfection on fitness is mainly influenced by the time elapsed between the first and the second infection, since shorter time intervals offer more opportunities to competition between resident and invading populations.

Animals↗
PubMed2006

In silico predicted robustness of viroids RNA secondary structures. I. The effect of single mutations.

Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. Despite this genomic simplicity, they are able of inducing devastating symptoms in susceptible plants. Most of the 29 described viroid species fold into a rodlike or quasi-rodlike structure, whereas a few of them fold as branched structures. The shape of these RNA structures is perhaps one of the most characteristic properties of viroids and sometimes is considered their only phenotype. Here we use RNA thermodynamic secondary structure prediction algorithms to compare the mutational robustness of all viroid species. After characterizing the statistical properties of the distribution of mutational effects on structure stability and the wideness of neutral neighborhood for each viroid species, we show an evolutionary trend toward increased structural robustness during viroid radiation, giving support to the adaptive value of robustness. Differences in robustness among the 2 viroid families can be explained by the larger fragility of branched structures compared with the rodlike ones. We also show that genomic redundancy can contribute to the robustness of these simple RNA genomes.

Algorithms↗
PubMed2006

Mechanisms of genetic robustness in RNA viruses.

Two key features of RNA viruses are their compacted genomes and their high mutation rate. Accordingly, deleterious mutations are common and have an enormous impact on viral fitness. In their multicellular hosts, robustness can be achieved by genomic redundancy, including gene duplication, diploidy, alternative metabolic pathways and biochemical buffering mechanisms. However, here we review evidence suggesting that during RNA virus evolution, alternative robustness mechanisms may have been selected. After briefly describing how genetic robustness can be quantified, we discuss mechanisms of intrinsic robustness arising as consequences of RNA-genome architecture, replication peculiarities and quasi-species population dynamics. These intrinsic robustness mechanisms operate efficiently at the population level, despite the mutational sensitivity shown by individual genomes. Finally, we discuss the possibility that viruses might exploit cellular buffering mechanisms for their own benefit, producing a sort of extrinsic robustness.

Evolution, Molecular↗
PubMed2006

Quantifying antagonistic epistasis in a multifunctional RNA secondary structure of the Rous sarcoma virus.

Recent studies have suggested that antagonistic epistasis (i.e. mutations having smaller effects in combination than alone) may be common among RNA viruses, in contrast to other biological systems. Here, by re-analysing previously published data from a random viral library, selection and epistasis coefficients were estimated in the U5-IR stem and loop of the Rous sarcoma virus, a region that adopts a conserved secondary structure and is involved in various essential steps of viral infection. The estimated mutational fitness effects are extremely high and genetic interactions are antagonistic on average. This pattern might be representative of RNA virus genomes, which show high compaction and frequent secondary structures. The implications for RNA virus adaptability are explored.

Avian Sarcoma Viruses↗
PubMed2006

[Prognostic value of serum creatinine in non-ST-elevation acute coronary syndrome].

INTRODUCTION AND OBJECTIVES: Cardiovascular disease is the main cause of death in patients with kidney failure. Moreover, the presence of impaired renal function is an important prognostic factor in patients with heart disease, and is a determinant of outcome during follow-up. The main aim was to investigate the relationship between kidney failure at admission and one-year mortality in patients with non-ST-elevation acute coronary syndrome. PATIENTS AND METHOD: We studied 1029 consecutive patients admitted to our institution. The serum creatinine level and glomerular filtration rate were determined at admission, and classical risk factors and biochemical markers were assessed. The primary endpoint was all-cause mortality at one year. RESULTS: Patients who died were older, more frequently had a history of diabetes or coronary artery disease, were more likely to have heart failure at admission, had higher troponin-I, myoglobin and creatinine levels, and were less likely to have dyslipidemia or to be a smoker. Multivariate analysis showed that the independent predictors of all-cause mortality at one year were age, diabetes, troponin-I level, Killip class > 1, male gender, creatinine level, and glomerular filtration rate. There was a linear correlation between increased risk and creatinine level. CONCLUSIONS: Creatinine level at admission is one of the most important covariates in early prognostic stratification in these patients. A high serum creatinine level (or a low glomerular filtration rate) increases the probability of death due to all causes. The serum creatinine level is, moreover, an inexpensive, easy-to-use, and widely available prognostic marker.

Acute Disease↗
PubMed2005

The cost of replication fidelity in an RNA virus.

It is often argued that high mutation rates are advantageous for RNA viruses, because they confer elevated rates of adaptation. However, there is no direct evidence showing a positive correlation between mutation and adaptation rates among RNA viruses. Moreover, theoretical work does not argue in favor of this prediction. We used a series of vesicular stomatitis virus clones harboring single amino acid substitutions in the RNA polymerase to demonstrate that changes inducing enhanced fidelity paid a fitness cost, but that there was no positive correlation between mutation an adaptation rates. We demonstrate that the observed mutation rate in vesicular stomatitis virus can be explained by a trade-off between replication rate and replication fidelity.

Adaptation, Biological↗
PubMed2005

Epistasis and the adaptability of an RNA virus.

We have explored the patterns of fitness recovery in the vesicular stomatitis RNA virus. We show that, in our experimental setting, reversions to the wild-type genotype were rare and fitness recovery was at least partially driven by compensatory mutations. We compared compensatory adaptation for genotypes carrying (1) mutations with varying deleterious fitness effects, (2) one or two deleterious mutations, and (3) pairs of mutations showing differences in the strength and sign of epistasis. In all cases, we found that the rate of fitness recovery and the proportion of reversions were positively affected by population size. Additionally, we observed that mutations with large fitness effect were always compensated faster than mutations with small fitness effect. Similarly, compensatory evolution was faster for genotypes carrying a single deleterious mutation than for those carrying pairs of mutations. Finally, for genotypes carrying two deleterious mutations, we found evidence of a negative correlation between the epistastic effect and the rate of compensatory evolution.

Adaptation, Biological↗
PubMed2005

RNA viruses as complex adaptive systems.

RNA viruses have high mutation rates and so their populations exist as dynamic and complex mutant distributions. It has been consistently observed that when challenged with a new environment, viral populations adapt following hyperbolic-like kinetics: adaptation is initially very rapid, but then slows down as fitness reaches an asymptotic value. These adaptive dynamics have been explained in terms of populations moving towards the top of peaks on rugged fitness landscapes. Fitness fluctuations of varying magnitude are observed during adaptation. Often the presence of fluctuations in the evolution of physical systems indicates some form of self-organization, or where many components of the system are simultaneously involved. Here we analyze data from several in vitro evolution experiments carried out with vesicular stomatitis virus (VSV) looking for the signature of criticality and scaling. Long-range fitness correlations have been detected during the adaptive process. We also found that the magnitude of fitness fluctuations, far from being trivial, conform to a Weibull probability distribution function, suggesting that viral adaptation belongs to a broad category of phenomena previously documented in other fields and related with emergence.

Biological Evolution↗
PubMed2005

Mode of selection and experimental evolution of antiviral drugs resistance in vesicular stomatitis virus.

The possession of an antiviral resistance mutation benefits a virus when the corresponding antiviral is present. But does the resistant virus pay a fitness cost when the antiviral is absent? Would an evolutionary history of association between a genotype and a resistance mutation overcome this cost by changes compensating the harmful side-effect of resistance mutations? Are combined therapies more effective against the rise of resistant viruses or against evolutionary compensations? To explore all these questions, we took an experimental evolution approach. After selecting vesicular stomatitis virus (VSV) populations able to replicate under increasing concentrations of ribavirin and/or alpha-interferon, we evolved them for more than 100 generations under sub-inhibitory concentrations of the corresponding antivirals, allowing for evolutionary compensation. Our results show that resistance for these two antivirals was not easily achieved, being the selected populations generally less fit than the ancestrals both in presence and absence of the antivirals. Evolution in presence of sub-inhibitory concentrations of antivirals compensated for the reduction in fitness in presence of antiviral therapy.

Antiviral Agents↗
PubMed2005

Weighted least-squares likelihood ratio test for branch testing in phylogenies reconstructed from distance measures.

A variety of analytical methods is available for branch testing in distance-based phylogenies. However, these methods are rarely used, possibly because the estimation of some of their statistics, especially the covariances, is not always feasible. We show that these difficulties can be overcome if some simplifying assumptions are made, namely distance independence. The weighted least-squares likelihood ratio test (WLS-LRT) we propose is easy to perform, using only the distances and some of their associated variances. If no variances are known, the use of the Felsenstein F-test, also based on weighted least squares, is discussed. Using simulated data and a data set of 43 mammalian mitochondrial sequences we demonstrate that the WLS-LRT performs as well as the generalized least-squares test, and indeed better for a large number of taxa data set. We thus show that the assumption of independence does not negatively affect the reliability or the accuracy of the least-squares approach. The results of the WLS-LRT are no worse than the results of the bootstrap methods, such as the Felsenstein bootstrap selection probability test and the Dopazo test. We also show that WLS-LRT can be applied in instances where other analytical methods are inappropriate. This point is illustrated by analyzing the relationships between human immunodeficiency virus type 1 (HIV-1) sequences isolated from various organs of different individuals.

Animals↗
PubMed2005

Following the very initial growth of biological RNA viral clones.

Due to their extremely high genetic diversity, which is a direct consequence of high mutation rates, RNA viruses are often described as molecular quasispecies. According to this theory, RNA virus populations cannot be understood in terms of individual viral clones, as they are clouds of interconnected mutants, but this prediction has not yet been demonstrated experimentally. The goal of this study was to determine the fitness of individual clones sampled from a given RNA virus population, a necessary previous step to test the above prediction. To do so, limiting dilutions of a vesicular stomatitis virus population were employed to isolate single viral clones and their initial growth dynamics were followed, corresponding to the release of the first few hundred viral particles. This technique is useful for estimating basic fitness parameters, such as intracellular growth rate, viral yield per cell, rate at which cells are infected and time spent in cell-to-cell transmission. A combination of these parameters allows estimation of the fitness of individual clones, which seems to be determined mainly by their ability to complete infection cycles more quickly. Interestingly, fitness was systematically higher for initial clones than for their derived populations. In addition to environmental changes, such as cellular defence mechanisms, these differences are attributable to high RNA virus mutation rates.

Animals↗
PubMed2005

[Prognostic value of white blood cell count in acute myocardial infarction: long-term mortality].

INTRODUCTION AND OBJECTIVES: Although traditionally an elevated white blood cell count (WBC), an indicator of systemic inflammation, has been accepted as part of the healing response following acute myocardial infarction (AMI), it has frequently been shown to be a predictor of adverse cardiovascular events. The present study was designed to assess the association between WBC and long-term mortality in AMI patients either with ST-segment elevation (STEMI) or without ST-segment elevation (non-STEMI). Patients and method. The study included 1118 consecutive patients who were admitted with the diagnosis of AMI: 569 non-STEMI and 549 STEMI. The WBC was measured in the 24 hours following admission. Patients were divided into 3 groups: WBC1 (count, <10 x 103 cells/mL), WBC2 (count, 10-14.9 x 10(3) cells/mL), and WBC3 (count, > or =15x10(3) cells/mL). All-cause mortality was recorded during a median follow-up period of 10+/-2 months. The relationship between WBC and mortality was assessed by Cox regression analysis for both types of AMI. RESULTS: Long-term mortality during follow-up was 18.5% in non-STEMI patients and 19.9% in STEMI patients. In non-STEMI patients, the adjusted hazard ratios for those in the WBC3 and WBC2 groups compared with those in the WBC1 group were 2.07 (1.08-3.94; P=.027) and 1.61 (1.03-2.51; P=.036), respectively. The corresponding figures in STEMI patients were 2.07 (1.13-3.76; P=.017) and 2.22 (1.35-3.63; P=.002), respectively. CONCLUSIONS: WBC on admission was an independent predictor of long-term mortality in both non-STEMI and STEMI patients.

Aged↗