Publications by authors named "Francois Serra"

22 Publications

  • Page 1 of 1

Analysis, Modeling, and Visualization of Chromosome Conformation Capture Experiments.

Methods Mol Biol 2021 ;2157:35-63

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Chromatin Conformation Capture techniques have unveiled several layers of chromosome organization such as the segregation in compartments, the folding in topologically associating domains (TADs), and site-specific looping interactions. The discovery of this genome hierarchical organization emerged from the computational analysis of chromatin capture data. With the increasing availability of such data, automatic pipelines for the robust comparison, grouping, and classification of multiple experiments are needed. Here we present a pipeline based on the TADbit framework that emphasizes reproducibility, automation, quality check, and statistical robustness. This comprehensive modular pipeline covers all the steps from the sequencing products to the visualization of reconstructed 3D models of the chromatin.
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http://dx.doi.org/10.1007/978-1-0716-0664-3_4DOI Listing
January 2021

Transcriptional activation during cell reprogramming correlates with the formation of 3D open chromatin hubs.

Nat Commun 2020 05 22;11(1):2564. Epub 2020 May 22.

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain.

Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Chromosome conformation capture (3C)-based experiments combined with computational modelling are pivotal for unveiling 3D chromosome structure. Here, we introduce TADdyn, a tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci in a completely data-driven way. We apply TADdyn on in situ Hi-C time-course experiments studying the reprogramming of murine B cells to pluripotent cells, and characterize the structural rearrangements that take place upon changes in the transcriptional state of 21 genomic loci of diverse expression dynamics. By measuring various structural and dynamical properties, we find that during gene activation, the transcription starting site contacts with open and active regions in 3D chromatin domains. We propose that these 3D hubs of open and active chromatin may constitute a general feature to trigger and maintain gene transcription.
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http://dx.doi.org/10.1038/s41467-020-16396-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244774PMC
May 2020

4D Genome Rewiring during Oncogene-Induced and Replicative Senescence.

Mol Cell 2020 05 26;78(3):522-538.e9. Epub 2020 Mar 26.

Institute of Human Genetics, UMR 9002, CNRS and University of Montpellier, Montpellier, France. Electronic address:

To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.
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http://dx.doi.org/10.1016/j.molcel.2020.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208559PMC
May 2020

The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.

Nat Med 2018 06 21;24(6):868-880. Epub 2018 May 21.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.
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http://dx.doi.org/10.1038/s41591-018-0028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363101PMC
June 2018

Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming.

Nat Genet 2018 02 15;50(2):238-249. Epub 2018 Jan 15.

Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.
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http://dx.doi.org/10.1038/s41588-017-0030-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810905PMC
February 2018

Parallel sequencing lives, or what makes large sequencing projects successful.

Gigascience 2017 11;6(11):1-6

Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain.

T47D_rep2 and b1913e6c1_51720e9cf were 2 Hi-C samples. They were born and processed at the same time, yet their fates were very different. The life of b1913e6c1_51720e9cf was simple and fruitful, while that of T47D_rep2 was full of accidents and sorrow. At the heart of these differences lies the fact that b1913e6c1_51720e9cf was born under a lab culture of Documentation, Automation, Traceability, and Autonomy and compliance with the FAIR Principles. Their lives are a lesson for those who wish to embark on the journey of managing high-throughput sequencing data.
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http://dx.doi.org/10.1093/gigascience/gix100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714127PMC
November 2017

Automatic analysis and 3D-modelling of Hi-C data using TADbit reveals structural features of the fly chromatin colors.

PLoS Comput Biol 2017 Jul 19;13(7):e1005665. Epub 2017 Jul 19.

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

The sequence of a genome is insufficient to understand all genomic processes carried out in the cell nucleus. To achieve this, the knowledge of its three-dimensional architecture is necessary. Advances in genomic technologies and the development of new analytical methods, such as Chromosome Conformation Capture (3C) and its derivatives, provide unprecedented insights in the spatial organization of genomes. Here we present TADbit, a computational framework to analyze and model the chromatin fiber in three dimensions. Our package takes as input the sequencing reads of 3C-based experiments and performs the following main tasks: (i) pre-process the reads, (ii) map the reads to a reference genome, (iii) filter and normalize the interaction data, (iv) analyze the resulting interaction matrices, (v) build 3D models of selected genomic domains, and (vi) analyze the resulting models to characterize their structural properties. To illustrate the use of TADbit, we automatically modeled 50 genomic domains from the fly genome revealing differential structural features of the previously defined chromatin colors, establishing a link between the conformation of the genome and the local chromatin composition. TADbit provides three-dimensional models built from 3C-based experiments, which are ready for visualization and for characterizing their relation to gene expression and epigenetic states. TADbit is an open-source Python library available for download from https://github.com/3DGenomes/tadbit.
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http://dx.doi.org/10.1371/journal.pcbi.1005665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540598PMC
July 2017

ETE 3: Reconstruction, Analysis, and Visualization of Phylogenomic Data.

Mol Biol Evol 2016 06 26;33(6):1635-8. Epub 2016 Feb 26.

Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany Germany Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg and European Molecular Biology Laboratory, 69117 Heidelberg, Germany Max Delbrück Centre for Molecular Medicine, 13125 Berlin, Germany.

The Environment for Tree Exploration (ETE) is a computational framework that simplifies the reconstruction, analysis, and visualization of phylogenetic trees and multiple sequence alignments. Here, we present ETE v3, featuring numerous improvements in the underlying library of methods, and providing a novel set of standalone tools to perform common tasks in comparative genomics and phylogenetics. The new features include (i) building gene-based and supermatrix-based phylogenies using a single command, (ii) testing and visualizing evolutionary models, (iii) calculating distances between trees of different size or including duplications, and (iv) providing seamless integration with the NCBI taxonomy database. ETE is freely available at http://etetoolkit.org.
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http://dx.doi.org/10.1093/molbev/msw046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868116PMC
June 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

Restraint-based three-dimensional modeling of genomes and genomic domains.

FEBS Lett 2015 Oct 14;589(20 Pt A):2987-95. Epub 2015 May 14.

Genome Biology Group, Centre Nacional d'Anàlisi Genòmica (CNAG), Barcelona, Spain; Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address:

Chromosomes are large polymer molecules composed of nucleotides. In some species, such as humans, this polymer can sum up to meters long and still be properly folded within the nuclear space of few microns in size. The exact mechanisms of how the meters long DNA is folded into the nucleus, as well as how the regulatory machinery can access it, is to a large extend still a mystery. However, and thanks to newly developed molecular, genomic and computational approaches based on the Chromosome Conformation Capture (3C) technology, we are now obtaining insight on how genomes are spatially organized. Here we review a new family of computational approaches that aim at using 3C-based data to obtain spatial restraints for modeling genomes and genomic domains.
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http://dx.doi.org/10.1016/j.febslet.2015.05.012DOI Listing
October 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

Assessing the limits of restraint-based 3D modeling of genomes and genomic domains.

Nucleic Acids Res 2015 Apr 23;43(7):3465-77. Epub 2015 Mar 23.

Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona, Spain Genome Biology Group, Centre Nacional d'Anàlisi Genòmica (CNAG), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean-field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications.
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http://dx.doi.org/10.1093/nar/gkv221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402535PMC
April 2015

Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation.

Genes Dev 2014 Oct;28(19):2151-62

Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;

The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ∼ 2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as "regulons" to enable spatially proximal genes to be coordinately transcribed in response to hormones.
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http://dx.doi.org/10.1101/gad.241422.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180976PMC
October 2014

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

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

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

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