Publications by authors named "Hernán Dopazo"

34 Publications

Metagenomic analysis of gut microbiota in non-treated plaque psoriasis patients stratified by disease severity: development of a new Psoriasis-Microbiome Index.

Sci Rep 2020 07 29;10(1):12754. Epub 2020 Jul 29.

Laboratorio de Genómica Computacional, Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina.

Psoriasis is an immune-mediated skin disorder. Imbalance of gut microbial populations has been implicated in many diseases. We aimed to investigate whether there were differences in gut microbiota in psoriasis patients vs non-psoriasis controls and between psoriasis severity groups. 55 psoriasis patients and 27 controls were included. V3-V4 regions of the 16S rRNA gene of fecal samples were analyzed using Illumina MiSeq. Bioinformatic analysis was performed. We found changes in gut microbiome composition depending on their psoriasis status as determined by weighted unifrac (p < 0.05), in particular an increase in Firmicutes and depletion of Bacteroidetes in psoriasis patients. Additionally, the Faecalibacterium and Blautia genus were higher in psoriasis patients while Bacteroides and Paraprevotella in non-psoriasis controls (p < 0.05, LDA score > 2). Moderate-to-severe psoriasis patients had lower biodiversity than mild psoriatic patients (p = 0.049). No differences for beta-diversity were found. We developed a Psoriasis-Microbiota Index (PMI), which discriminated among psoriasis patients and controls with sensitivity: 0.78 and specificity: 0.79. Furthermore, we performed a meta-analysis with published data to validate this index. We demonstrated gut dysbiosis in psoriasis patients, suggesting a role in psoriasis pathophysiology. Furthermore, we developed a PMI with the potential to discriminate between psoriasis patients and controls across different populations, which could be used as a biomarker in the clinical practice.
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http://dx.doi.org/10.1038/s41598-020-69537-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391695PMC
July 2020

Fine-scale genomic analyses of admixed individuals reveal unrecognized genetic ancestry components in Argentina.

PLoS One 2020 16;15(7):e0233808. Epub 2020 Jul 16.

Departamento de Ecología, Genética y Evolución, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.

Similarly to other populations across the Americas, Argentinean populations trace back their genetic ancestry into African, European and Native American ancestors, reflecting a complex demographic history with multiple migration and admixture events in pre- and post-colonial times. However, little is known about the sub-continental origins of these three main ancestries. We present new high-throughput genotyping data for 87 admixed individuals across Argentina. This data was combined to previously published data for admixed individuals in the region and then compared to different reference panels specifically built to perform population structure analyses at a sub-continental level. Concerning the Native American ancestry, we could identify four Native American components segregating in modern Argentinean populations. Three of them are also found in modern South American populations and are specifically represented in Central Andes, Central Chile/Patagonia, and Subtropical and Tropical Forests geographic areas. The fourth component might be specific to the Central Western region of Argentina, and it is not well represented in any genomic data from the literature. As for the European and African ancestries, we confirmed previous results about origins from Southern Europe, Western and Central Western Africa, and we provide evidences for the presence of Northern European and Eastern African ancestries.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233808PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365470PMC
September 2020

A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis.

Hepatol Commun 2018 Sep 5;2(9):1030-1036. Epub 2018 Sep 5.

Institute of Medical Research A. Lanari University of Buenos Aires Buenos Aires Argentina.

We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator () gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5' and 3' untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes. 2018;0:0-0).
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http://dx.doi.org/10.1002/hep4.1235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128235PMC
September 2018

Genetic variation in long noncoding RNAs and the risk of nonalcoholic fatty liver disease.

Oncotarget 2017 Apr;8(14):22917-22926

Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires, National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.

The human transcriptome comprises a myriad of non protein-coding RNA species, including long noncoding RNAs (lncRNAs), which have a remarkable role in transcriptional and epigenetic regulation. We hypothesized that variants in lncRNAs influence the susceptibility to nonalcoholic fatty liver disease (NAFLD). Using next generation sequencing, we performed a survey of genetic variation associated with randomly selected lncRNA-genomic regions located within both experimentally validated and computationally predicted regulatory elements. We used a two-stage (exploratory, n = 96 and replication, n = 390) case-control approach that included well-characterized patients with NAFLD diagnosed by liver biopsy. We sequenced > 263 megabase pairs at quality score > Q17, in a total of 2,027,565 reads, including 170 lncRNA-genomic regions. In the sequencing analysis and the validated dataset, we found that the rs2829145 A/G located in a lncRNA (lnc-JAM2-6) was associated with NAFLD and the disease severity. Prediction of regulatory elements in lnc-JAM2-6 showed potential sequence-specific binding motifs of oncogenes MAFK and JUND, and the transcription factor CEBPB that is involved in inflammatory response. The A-allele was significantly associated with NAFLD as disease trait (p = 0.0081) and the disease severity (NASH-nonalcoholic steatohepatitis vs controls: OR 2.36 [95% CI: 1.54-3.62], p = 0.000078). The A-allele carriers also have significantly higher body mass index and glucose-related traits compared with homozygous GG. Hence, our results suggest that variation in lncRNAs contributes to NAFLD severity, while pointing toward the complexity of the genetic component of NAFLD, which involves still unexplored regulatory regions of the genome.
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http://dx.doi.org/10.18632/oncotarget.15286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410273PMC
April 2017

Mitochondrial genome architecture in non-alcoholic fatty liver disease.

J Pathol 2016 12 18;240(4):437-449. Epub 2016 Oct 18.

Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.

Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the 'missing heritability' of NAFLD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4803DOI Listing
December 2016

Transcriptome modulation during host shift is driven by secondary metabolites in desert Drosophila.

Mol Ecol 2016 09 6;25(18):4534-50. Epub 2016 Sep 6.

IEGEBA-CONICET, UNiversidad de Buenos Aires, FAcultad de Ciencias Exactas y Naturales, Intendente Güiraldes 2160, Ciudad Universitaria (C1428 EHA), CABA, Argentina.

High-throughput transcriptome studies are breaking new ground to investigate the responses that organisms deploy in alternative environments. Nevertheless, much remains to be understood about the genetic basis of host plant adaptation. Here, we investigate genome-wide expression in the fly Drosophila buzzatii raised in different conditions. This species uses decaying tissues of cactus of the genus Opuntia as primary rearing substrate and secondarily, the necrotic tissues of the columnar cactus Trichocereus terscheckii. The latter constitutes a harmful host, rich in mescaline and other related phenylethylamine alkaloids. We assessed the transcriptomic responses of larvae reared in Opuntia sulphurea and T. terscheckii, with and without the addition of alkaloids extracted from the latter. Whole-genome expression profiles were massively modulated by the rearing environment, mainly by the presence of T. terscheckii alkaloids. Differentially expressed genes were mainly related to detoxification, oxidation-reduction and stress response; however, we also found genes involved in development and neurobiological processes. In conclusion, our study contributes new data onto the role of transcriptional plasticity in response to alternative rearing environments.
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http://dx.doi.org/10.1111/mec.13785DOI Listing
September 2016

Selective constraints on protamine 2 in primates and rodents.

BMC Evol Biol 2016 Jan 22;16:21. Epub 2016 Jan 22.

Reproductive Ecology and Biology Group, Museo Nacional de Ciencias Naturales (CSIC), c/Jose Gutierrez Abascal 2, 28006, Madrid, Spain.

Background: Protamines are sperm nuclear proteins with a crucial role in chromatin condensation. Their function is strongly linked to sperm head morphology and male fertility. Protamines appear to be affected by a complex pattern of selective constraints. Previous studies showed that sexual selection affects protamine coding sequence and expression in rodents. Here we analyze selective constraints and post-copulatory sexual selection acting on protamine 2 (Prm2) gene sequences of 53 species of primates and rodents. We focused on possible differences in selective constraints between these two clades and on the two functional domains of PRM2 (cleaved- and mature-PRM2). We also assessed if and how changes in Prm2 coding sequence may affect sperm head dimensions.

Results: The domain of Prm2 that is cleaved off during binding to DNA (cleaved-Prm2) was found to be under purifying selection in both clades, whereas the domain that remains bound to DNA (mature-Prm2) was found to be positively selected in primates and under relaxed constraint in rodents. Changes in cleaved-Prm2 coding sequence are significantly correlated to sperm head width and elongation in rodents. Contrary to expectations, a significant effect of sexual selection was not found on either domain or clade.

Conclusions: Mature-PRM2 may be free to evolve under less constraint due to the existence of PRM1 as a more conserved and functionally redundant copy. The cleaved-PRM2 domain seems to play an important role in sperm head shaping. However, sexual selection on its sequence may be difficult to detect until it is identified which sperm head phenotype (shape and size) confers advantages for sperm performance in different mammalian clades.
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http://dx.doi.org/10.1186/s12862-016-0588-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724148PMC
January 2016

Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.

Am J Clin Nutr 2016 Feb 20;103(2):422-34. Epub 2016 Jan 20.

Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-Instituto de Investigaciones Medicas,

Background: Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown.

Objective: We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS.

Design: Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included.

Results: Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations.

Conclusions: In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and insulin resistance. Hence, to maintain homeostasis, the liver upregulates these enzymes, leading to changes in the amounts of amino acids released into the circulation.
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http://dx.doi.org/10.3945/ajcn.115.118695DOI Listing
February 2016

Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA Hydroxymethylation and TET Proteins.

Medicine (Baltimore) 2015 Sep;94(36):e1480

From the Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina (CJP, RS, TFG); Biomedical Genomics and Evolution Laboratory, Ecology, Genetics and Evolution Department, Faculty of Science, IEGEBA, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina (HD, CR); Department of Pathology, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina (JSM); Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina (GOC); and Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina (RS, SS).

The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained.Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n = 90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1-3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants.We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R = 0.50, P = 0.000382) and PPARGC1A-mRNA levels (R = -0.57, P = 0.04).We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4 ± 0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8 ± 0.8), means ± standard deviation, P = 0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10-1.97; P = 0.005). The p.Ile1762Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and transcriptional levels, and Type 2 diabetes.Our results suggest that 5-hmC might be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and PPARGC1A expression. Genetic diversity at TET loci suggests an "epigenetic" regulation of programmed liver-cell death and a TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program.
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http://dx.doi.org/10.1097/MD.0000000000001480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616643PMC
September 2015

Analysis of Five Gene Sets in Chimpanzees Suggests Decoupling between the Action of Selection on Protein-Coding and on Noncoding Elements.

Genome Biol Evol 2015 May 14;7(6):1490-505. Epub 2015 May 14.

Departament de Ciències Experimentals i la Salut, Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, PRBB, Barcelona, Spain

We set out to investigate potential differences and similarities between the selective forces acting upon the coding and noncoding regions of five different sets of genes defined according to functional and evolutionary criteria: 1) two reference gene sets presenting accelerated and slow rates of protein evolution (the Complement and Actin pathways); 2) a set of genes with evidence of accelerated evolution in at least one of their introns; and 3) two gene sets related to neurological function (Parkinson's and Alzheimer's diseases). To that effect, we combine human-chimpanzee divergence patterns with polymorphism data obtained from target resequencing 20 central chimpanzees, our closest relatives with largest long-term effective population size. By using the distribution of fitness effect-alpha extension of the McDonald-Kreitman test, we reproduce inferences of rates of evolution previously based only on divergence data on both coding and intronic sequences and also obtain inferences for other classes of genomic elements (untranslated regions, promoters, and conserved noncoding sequences). Our results suggest that 1) the distribution of fitness effect-alpha method successfully helps distinguishing different scenarios of accelerated divergence (adaptation or relaxed selective constraints) and 2) the adaptive history of coding and noncoding sequences within the gene sets analyzed is decoupled.
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http://dx.doi.org/10.1093/gbe/evv082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494068PMC
May 2015

Positive selection in nucleoporins challenges constraints on early expressed genes in Drosophila development.

Genome Biol Evol 2013 ;5(11):2231-41

Departamento de Ecología, Genética y Evolución-IEGEBA (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.

Developmental conservation among related species is a common generalization known as von Baer's third law and implies that early stages of development are the most refractory to change. The "hourglass model" is an alternative view that proposes that middle stages are the most constrained during development. To investigate this issue, we undertook a genomic approach and provide insights into how natural selection operates on genes expressed during the first 24 h of Drosophila ontogeny in the six species of the melanogaster group for which whole genome sequences are available. Having studied the rate of evolution of more than 2,000 developmental genes, our results showed differential selective pressures at different moments of embryogenesis. In many Drosophila species, early zygotic genes evolved slower than maternal genes indicating that mid-embryogenesis is the stage most refractory to evolutionary change. Interestingly, positively selected genes were found in all embryonic stages even during the period with the highest developmental constraint, emphasizing that positive selection and negative selection are not mutually exclusive as it is often mistakenly considered. Among the fastest evolving genes, we identified a network of nucleoporins (Nups) as part of the maternal transcriptome. Specifically, the acceleration of Nups was driven by positive selection only in the more recently diverged species. Because many Nups are involved in hybrid incompatibilities between species of the Drosophila melanogaster subgroup, our results link rapid evolution of early developmental genes with reproductive isolation. In summary, our study revealed that even within functional groups of genes evolving under strong negative selection many positively selected genes could be recognized. Understanding these exceptions to the broad evolutionary conservation of early expressed developmental genes can shed light into relevant processes driving the evolution of species divergence.
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http://dx.doi.org/10.1093/gbe/evt156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845637PMC
October 2014

Neutral theory predicts the relative abundance and diversity of genetic elements in a broad array of eukaryotic genomes.

PLoS One 2013 14;8(6):e63915. Epub 2013 Jun 14.

Evolutionary Genomics Laboratory, Bioinformatics and Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.

It is universally true in ecological communities, terrestrial or aquatic, temperate or tropical, that some species are very abundant, others are moderately common, and the majority are rare. Likewise, eukaryotic genomes also contain classes or "species" of genetic elements that vary greatly in abundance: DNA transposons, retrotransposons, satellite sequences, simple repeats and their less abundant functional sequences such as RNA or genes. Are the patterns of relative species abundance and diversity similar among ecological communities and genomes? Previous dynamical models of genomic diversity have focused on the selective forces shaping the abundance and diversity of transposable elements (TEs). However, ideally, models of genome dynamics should consider not only TEs, but also the diversity of all genetic classes or "species" populating eukaryotic genomes. Here, in an analysis of the diversity and abundance of genetic elements in >500 eukaryotic chromosomes, we show that the patterns are consistent with a neutral hypothesis of genome assembly in virtually all chromosomes tested. The distributions of relative abundance of genetic elements are quite precisely predicted by the dynamics of an ecological model for which the principle of functional equivalence is the main assumption. We hypothesize that at large temporal scales an overarching neutral or nearly neutral process governs the evolution of abundance and diversity of genetic elements in eukaryotic genomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063915PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683013PMC
January 2014

Evolutionary Genomics of Genes Involved in Olfactory Behavior in the Drosophila melanogaster Species Group.

Evol Bioinform Online 2012 9;8:89-104. Epub 2012 Jan 9.

Departamento de Ecología, Genética y Evolución; Facultad de Ciencias Exactas y Naturales; Universidad de Buenos Aires; Buenos Aires; Argentina.

Previous comparative genomic studies of genes involved in olfactory behavior in Drosophila focused only on particular gene families such as odorant receptor and/or odorant binding proteins. However, olfactory behavior has a complex genetic architecture that is orchestrated by many interacting genes. In this paper, we present a comparative genomic study of olfactory behavior in Drosophila including an extended set of genes known to affect olfactory behavior. We took advantage of the recent burst of whole genome sequences and the development of powerful statistical tools to analyze genomic data and test evolutionary and functional hypotheses of olfactory genes in the six species of the Drosophila melanogaster species group for which whole genome sequences are available. Our study reveals widespread purifying selection and limited incidence of positive selection on olfactory genes. We show that the pace of evolution of olfactory genes is mostly independent of the life cycle stage, and of the number of life cycle stages, in which they participate in olfaction. However, we detected a relationship between evolutionary rates and the position that the gene products occupy in the olfactory system, genes occupying central positions tend to be more constrained than peripheral genes. Finally, we demonstrate that specialization to one host does not seem to be associated with bursts of adaptive evolution in olfactory genes in D. sechellia and D. erecta, the two specialists species analyzed, but rather different lineages have idiosyncratic evolutionary histories in which both historical and ecological factors have been involved.
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http://dx.doi.org/10.4137/EBO.S8484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273929PMC
August 2012

Sexual selection halts the relaxation of protamine 2 among rodents.

PLoS One 2011 21;6(12):e29247. Epub 2011 Dec 21.

Reproductive Ecology and Biology Group, Museo Nacional de Ciencias Naturales (CSIC), Madrid, Spain.

Sexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029247PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244444PMC
May 2012

Discovery of an ebolavirus-like filovirus in europe.

PLoS Pathog 2011 Oct 20;7(10):e1002304. Epub 2011 Oct 20.

National Center of Microbiology, (ISCIII), Madrid, Spain.

Filoviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genetically distinct filovirus, provisionally named Lloviu virus, after the site of detection, Cueva del Lloviu, in Spain.
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http://dx.doi.org/10.1371/journal.ppat.1002304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197594PMC
October 2011

Evolution of the biosynthesis of di-myo-inositol phosphate, a marker of adaptation to hot marine environments.

Environ Microbiol 2012 Mar 26;14(3):691-701. Epub 2011 Oct 26.

Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República-EAN, Apartado 127, 2780-157 Oeiras, Portugal.

The synthesis of di-myo-inositol phosphate (DIP), a common compatible solute in hyperthermophiles, involves the consecutive actions of inositol-1-phosphate cytidylyltransferase (IPCT) and di-myo-inositol phosphate phosphate synthase (DIPPS). In most cases, both activities are present in a single gene product, but separate genes are also found in a few organisms. Genes for IPCT and DIPPS were found in the genomes of 33 organisms, all with thermophilic/hyperthermophilic lifestyles. Phylogeny of IPCT/DIPPS revealed an incongruent topology with 16S RNA phylogeny, thus suggesting horizontal gene transfer. The phylogenetic tree of the DIPPS domain was rooted by using phosphatidylinositol phosphate synthase sequences as out-group. The root locates at the separation of genomes with fused and split genes. We propose that the gene encoding DIPPS was recruited from the biosynthesis of phosphatidylinositol. The last DIP-synthesizing ancestor harboured separated genes for IPCT and DIPPS and this architecture was maintained in a crenarchaeal lineage, and transferred by horizontal gene transfer to hyperthermophilic marine Thermotoga species. It is plausible that the driving force for the assembly of those two genes in the early ancestor is related to the acquired advantage of DIP producers to cope with high temperature. This work corroborates the view that Archaea were the first hyperthermophilic organisms.
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http://dx.doi.org/10.1111/j.1462-2920.2011.02621.xDOI Listing
March 2012

Genome-wide heterogeneity of nucleotide substitution model fit.

Genome Biol Evol 2011 7;3:896-908. Epub 2011 Aug 7.

Department of Biochemistry, Genetics, and Immunology, University of Vigo, Vigo, Spain.

At a genomic scale, the patterns that have shaped molecular evolution are believed to be largely heterogeneous. Consequently, comparative analyses should use appropriate probabilistic substitution models that capture the main features under which different genomic regions have evolved. While efforts have concentrated in the development and understanding of model selection techniques, no descriptions of overall relative substitution model fit at the genome level have been reported. Here, we provide a characterization of best-fit substitution models across three genomic data sets including coding regions from mammals, vertebrates, and Drosophila (24,000 alignments). According to the Akaike Information Criterion (AIC), 82 of 88 models considered were selected as best-fit models at least in one occasion, although with very different frequencies. Most parameter estimates also varied broadly among genes. Patterns found for vertebrates and Drosophila were quite similar and often more complex than those found in mammals. Phylogenetic trees derived from models in the 95% confidence interval set showed much less variance and were significantly closer to the tree estimated under the best-fit model than trees derived from models outside this interval. Although alternative criteria selected simpler models than the AIC, they suggested similar patterns. All together our results show that at a genomic scale, different gene alignments for the same set of taxa are best explained by a large variety of different substitution models and that model choice has implications on different parameter estimates including the inferred phylogenetic trees. After taking into account the differences related to sample size, our results suggest a noticeable diversity in the underlying evolutionary process. All together, we conclude that the use of model selection techniques is important to obtain consistent phylogenetic estimates from real data at a genomic scale.
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http://dx.doi.org/10.1093/gbe/evr080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175760PMC
January 2012

SUS1 introns are required for efficient mRNA nuclear export in yeast.

Nucleic Acids Res 2011 Oct 12;39(19):8599-611. Epub 2011 Jul 12.

Centro de Investigación Príncipe Felipe, Gene Expression coupled to RNA Transport Laboratory, Av Saler 16. E-46012, Valencia, Spain.

Efficient coupling between mRNA synthesis and export is essential for gene expression. Sus1/ENY2, a component of the SAGA and TREX-2 complexes, is involved in both transcription and mRNA export. While most yeast genes lack introns, we previously reported that yeast SUS1 bears two. Here we show that this feature is evolutionarily conserved and critical for Sus1 function. We determine that while SUS1 splicing is inefficient, it responds to cellular conditions, and intronic mutations either promoting or blocking splicing lead to defects in mRNA export and cell growth. Consistent with this, we find that an intron-less SUS1 only partially rescues sus1Δ phenotypes. Remarkably, splicing of each SUS1 intron is also affected by the presence of the other and by SUS1 exonic sequences. Moreover, by following SUS1 RNA and protein levels we establish that nonsense-mediated decay (NMD) pathway and the splicing factor Mud2 both play a role in SUS1 expression. Our data (and those of the accompanying work by Hossain et al.) provide evidence of the involvement of splicing, translation, and decay in the regulation of early events in mRNP biogenesis; and imply the additional requirement for a balance in splicing isoforms from a single gene.
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http://dx.doi.org/10.1093/nar/gkr496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201862PMC
October 2011

Phylemon 2.0: a suite of web-tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing.

Nucleic Acids Res 2011 Jul 6;39(Web Server issue):W470-4. Epub 2011 Jun 6.

Evolutionary Genomics Lab, Bioinformatics and Genomics Department, Centro de Investigación Príncipe Felipe, Autopista del Saler, 16-3, 46013 Valencia, Spain.

Phylemon 2.0 is a new release of the suite of web tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing. It has been designed as a response to the increasing demand of molecular sequence analyses for experts and non-expert users. Phylemon 2.0 has several unique features that differentiates it from other similar web resources: (i) it offers an integrated environment that enables evolutionary analyses, format conversion, file storage and edition of results; (ii) it suggests further analyses, thereby guiding the users through the web server; and (iii) it allows users to design and save phylogenetic pipelines to be used over multiple genes (phylogenomics). Altogether, Phylemon 2.0 integrates a suite of 30 tools covering sequence alignment reconstruction and trimming; tree reconstruction, visualization and manipulation; and evolutionary hypotheses testing.
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http://dx.doi.org/10.1093/nar/gkr408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125789PMC
July 2011

Role of tomato BRANCHED1-like genes in the control of shoot branching.

Plant J 2011 Aug 24;67(4):701-14. Epub 2011 Jun 24.

Departamento de Genética Molecular de Plantas, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.

In angiosperms, shoot branching greatly determines overall plant architecture and affects fundamental aspects of plant life. Branching patterns are determined by genetic pathways conserved widely across angiosperms. In Arabidopsis thaliana (Brassicaceae, Rosidae) BRANCHED1 (BRC1) plays a central role in this process, acting locally to arrest axillary bud growth. In tomato (Solanum lycopersicum, Solanaceae, Asteridae) we have identified two BRC1-like paralogues, SlBRC1a and SlBRC1b. These genes are expressed in arrested axillary buds and both are down-regulated upon bud activation, although SlBRC1a is transcribed at much lower levels than SlBRC1b. Alternative splicing of SlBRC1a renders two transcripts that encode two BRC1-like proteins with different C-t domains due to a 3'-terminal frameshift. The phenotype of loss-of-function lines suggests that SlBRC1b has retained the ancestral role of BRC1 in shoot branch suppression. We have isolated the BRC1a and BRC1b genes of other Solanum species and have studied their evolution rates across the lineages. These studies indicate that, after duplication of an ancestral BRC1-like gene, BRC1b genes continued to evolve under a strong purifying selection that was consistent with the conserved function of SlBRC1b in shoot branching control. In contrast, the coding sequences of Solanum BRC1a genes have evolved at a higher evolution rate. Branch-site tests indicate that this difference does not reflect relaxation but rather positive selective pressure for adaptation.
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http://dx.doi.org/10.1111/j.1365-313X.2011.04629.xDOI Listing
August 2011

Phylogenetic and in silico structural analysis of the Parkinson disease-related kinase PINK1.

Hum Mutat 2011 Apr;32(4):369-78

Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain.

Parkinson disease (PD) is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Mutations in PINK1 were shown to cause recessive familial PD, and today are proposed to be associated with the disease via mitochondrial dysfunction and oxidative damage. The PINK1 gene comprises eight exons, which encode a ubiquitously expressed 581 amino acid protein that contains an N-terminal mitochondrial targeting domain and a serine/threonine protein kinase. To better understand the relationship between PINK1 and PD we have first analyzed the evolutionary history of the gene showing its late emergence in evolution. In addition, we have modeled the three-dimensional structure of PINK1 and found some evidences that help to explain the effect of some PD-related mutations in this protein's function.
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http://dx.doi.org/10.1002/humu.21444DOI Listing
April 2011

Natural selection on functional modules, a genome-wide analysis.

PLoS Comput Biol 2011 Mar 3;7(3):e1001093. Epub 2011 Mar 3.

Evolutionary Genomics Lab, Bioinformatics & Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.
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http://dx.doi.org/10.1371/journal.pcbi.1001093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048381PMC
March 2011

Recent human evolution has shaped geographical differences in susceptibility to disease.

BMC Genomics 2011 Jan 24;12:55. Epub 2011 Jan 24.

Institute of Evolutionary Biology (UPF-CSIC), PRBB, Doctor Aiguader 88, 08003, Barcelona, Catalonia, Spain.

Background: Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.

Results: We report three main findings. First, contrary to previous results, genes associated to complex diseases present lower degrees of genetic differentiation among human populations than average genome-wide levels. Second, also contrary to previous results, the differences in replicability of disease associated-loci between Europeans and East Asians are highly correlated with genetic differentiation between these populations. Finally, highly replicated genes present increased levels of high-frequency derived alleles in European and Asian populations when compared to African populations.

Conclusions: Our findings highlight the heterogeneous nature of the genetic etiology of complex disease, confirm the importance of the recent evolutionary history of our species in current patterns of disease susceptibility and could cast doubts on the status as false positives of some associations that have failed to replicate across populations.
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http://dx.doi.org/10.1186/1471-2164-12-55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039608PMC
January 2011

Sexual selection drives weak positive selection in protamine genes and high promoter divergence, enhancing sperm competitiveness.

Proc Biol Sci 2009 Jul 1;276(1666):2427-36. Epub 2009 Apr 1.

Reproductive Ecology and Biology Group, Museo Nacional de Ciencias Naturales (CSIC), c/José Gutiérrez Abascal 2, 28006 Madrid, Spain.

Phenotypic adaptations may be the result of changes in gene structure or gene regulation, but little is known about the evolution of gene expression. In addition, it is unclear whether the same selective forces may operate at both levels simultaneously. Reproductive proteins evolve rapidly, but the underlying selective forces promoting such rapid changes are still a matter of debate. In particular, the role of sexual selection in driving positive selection among reproductive proteins remains controversial, whereas its potential influence on changes in promoter regions has not been explored. Protamines are responsible for maintaining DNA in a compacted form in chromosomes in sperm and the available evidence suggests that they evolve rapidly. Because protamines condense DNA within the sperm nucleus, they influence sperm head shape. Here, we examine the influence of sperm competition upon protamine 1 and protamine 2 genes and their promoters, by comparing closely related species of Mus that differ in relative testes size, a reliable indicator of levels of sperm competition. We find evidence of positive selection in the protamine 2 gene in the species with the highest inferred levels of sperm competition. In addition, sperm competition levels across all species are strongly associated with high divergence in protamine 2 promoters that, in turn, are associated with sperm swimming speed. We suggest that changes in protamine 2 promoters are likely to enhance sperm swimming speed by making sperm heads more hydrodynamic. Such phenotypic changes are adaptive because sperm swimming speed may be a major determinant of fertilization success under sperm competition. Thus, when species have diverged recently, few changes in gene-coding sequences are found, while high divergence in promoters seems to be associated with the intensity of sexual selection.
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http://dx.doi.org/10.1098/rspb.2009.0257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690471PMC
July 2009

Use of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.

Hum Mutat 2008 Jan;29(1):198-204

Structural Genomics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.

Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.
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http://dx.doi.org/10.1002/humu.20628DOI Listing
January 2008

Identification of conserved domains in the promoter regions of nitric oxide synthase 2: implications for the species-specific transcription and evolutionary differences.

BMC Genomics 2007 Aug 8;8:271. Epub 2007 Aug 8.

Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid, Spain.

Background: The majority of the genes involved in the inflammatory response are highly conserved in mammals. These genes are not significantly expressed under normal conditions and are mainly regulated at the transcription and prost-transcriptional level. Transcription from the promoters of these genes is very dependent on NF-kappaB activation, which integrates the response to diverse extracellular stresses. However, in spite of the high conservation of the pattern of promoter regulation in kappaB-regulated genes, there is inter-species diversity in some genes. One example is nitric oxide synthase 2 (NOS-2), which exhibits a species-specific pattern of expression in response to infection or pro-inflammatory challenge.

Results: We have conducted a comparative genomic analysis of NOS-2 with different bioinformatic approaches. This analysis shows that in the NOS-2 gene promoter the position and the evolutionary divergence of some conserved regions are different in rodents and non-rodent mammals, and in particular in primates. Two not previously described distal regions in rodents that are similar to the unique upstream region responsible of the NF-kappaB activation of NOS-2 in humans are fragmented and translocated to different locations in the rodent promoters. The rodent sequences moreover lack the functional kappaB sites and IFN-gamma response sites present in the homologous human, rhesus monkey and chimpanzee regions. The absence of kappaB binding in these regions was confirmed by electrophoretic mobility shift assays.

Conclusion: The data presented reveal divergence between rodents and other mammals in the location and functionality of conserved regions of the NOS-2 promoter containing NF-kappaB and IFN-gamma response elements.
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http://dx.doi.org/10.1186/1471-2164-8-271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1973084PMC
August 2007

The human phylome.

Genome Biol 2007 ;8(6):R109

Bioinformatics Department, Centro de Investigación Príncipe Felipe, Autopista del Saler, 46013 Valencia, Spain.

Background: Phylogenomics analyses serve to establish evolutionary relationships among organisms and their genes. A phylome, the complete collection of all gene phylogenies in a genome, constitutes a valuable source of information, but its use in large genomes still constitutes a technical challenge. The use of phylomes also requires the development of new methods that help us to interpret them.

Results: We reconstruct here the human phylome, which includes the evolutionary relationships of all human proteins and their homologs among 39 fully sequenced eukaryotes. Phylogenetic techniques used include alignment trimming, branch length optimization, evolutionary model testing and maximum likelihood and Bayesian methods. Although differences with alternative topologies are minor, most of the trees support the Coelomata and Unikont hypotheses as well as the grouping of primates with laurasatheria to the exclusion of rodents. We assess the extent of gene duplication events and their relationship with the functional roles of the protein families involved. We find support for at least one, and probably two, rounds of whole genome duplications before vertebrate radiation. Using a novel algorithm that is independent from a species phylogeny, we derive orthology and paralogy relationships of human proteins among eukaryotic genomes.

Conclusion: Topological variations among phylogenies for different genes are to be expected, highlighting the danger of gene-sampling effects in phylogenomic analyses. Several links can be established between the functions of gene families duplicated at certain phylogenetic splits and major evolutionary transitions in those lineages. The pipeline implemented here can be easily adapted for use in other organisms.
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http://dx.doi.org/10.1186/gb-2007-8-6-r109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394744PMC
February 2008

Phylemon: a suite of web tools for molecular evolution, phylogenetics and phylogenomics.

Nucleic Acids Res 2007 Jul 22;35(Web Server issue):W38-42. Epub 2007 Apr 22.

Bioinformatics Department, Centro de Investigación Príncipe Felipe, INB, CIPF, Valencia 46013, Spain.

Phylemon is an online platform for phylogenetic and evolutionary analyses of molecular sequence data. It has been developed as a web server that integrates a suite of different tools selected among the most popular stand-alone programs in phylogenetic and evolutionary analysis. It has been conceived as a natural response to the increasing demand of data analysis of many experimental scientists wishing to add a molecular evolution and phylogenetics insight into their research. Tools included in Phylemon cover a wide yet selected range of programs: from the most basic for multiple sequence alignment to elaborate statistical methods of phylogenetic reconstruction including methods for evolutionary rates analyses and molecular adaptation. Phylemon has several features that differentiates it from other resources: (i) It offers an integrated environment that enables the direct concatenation of evolutionary analyses, the storage of results and handles required data format conversions, (ii) Once an outfile is produced, Phylemon suggests the next possible analyses, thus guiding the user and facilitating the integration of multi-step analyses, and (iii) users can define and save complete pipelines for specific phylogenetic analysis to be automatically used on many genes in subsequent sessions or multiple genes in a single session (phylogenomics). The Phylemon web server is available at http://phylemon.bioinfo.cipf.es.
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http://dx.doi.org/10.1093/nar/gkm224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933211PMC
July 2007

From genes to functional classes in the study of biological systems.

BMC Bioinformatics 2007 Apr 3;8:114. Epub 2007 Apr 3.

Bioinformatics Department, Valencia, Spain.

Background: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed.

Results: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics.

Conclusion: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.
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http://dx.doi.org/10.1186/1471-2105-8-114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853114PMC
April 2007

PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes.

Nucleic Acids Res 2006 Jul;34(Web Server issue):W621-5

Department of Bioinformatics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, 46013, Spain.

We have developed a web tool, PupaSuite, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect, specifically oriented to help in the design of large-scale genotyping projects. PupaSuite uses a collection of data on SNPs from heterogeneous sources and a large number of pre-calculated predictions to offer a flexible and intuitive interface for selecting an optimal set of SNPs. It improves the functionality of PupaSNP and PupasView programs and implements new facilities such as the analysis of user's data to derive haplotypes with functional information. A new estimator of putative effect of polymorphisms has been included that uses evolutionary information. Also SNPeffect database predictions have been included. The PupaSuite web interface is accessible through http://pupasuite.bioinfo.cipf.es and through http://www.pupasnp.org.
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http://dx.doi.org/10.1093/nar/gkl071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1538854PMC
July 2006