National Institute for Bioinformatics INB

Barcelona, Spain

National Institute for Bioinformatics INB

Barcelona, Spain
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Spataro N.,University Pompeu Fabra | Rodriguez J.A.,University Pompeu Fabra | Navarro A.,University Pompeu Fabra | Navarro A.,National Institute for Bioinformatics INB | And 3 more authors.
Human Molecular Genetics | Year: 2017

Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to nondisease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease. © The Author 2016.

Navarro A.,University Pompeu Fabra | Navarro A.,National Institute for Bioinformatics INB | Navarro A.,Catalan Institution for Research and Advanced Studies | Faria R.,University Pompeu Fabra | Faria R.,University of Porto
Molecular Ecology | Year: 2014

The early period of genetics is closely associated with the study of chromosomal inversions. For almost a century, evolutionary biologists found evidence for the role of inversions in central processes such as adaptation and speciation. In spite of huge efforts, many questions remain about the evolutionary forces underlying the distribution and dynamics of inversions in natural populations. Fortunately, old problems can be solved with new tools. In this issue, Kapun et al. (2014) present a remarkable combination of resources and techniques, including publicly available data, karyotyping, statistical estimation of haplotypes, Pool-Seq data and experimental evolution, setting the ground for exciting developments in the field. © 2014 John Wiley & Sons Ltd.

Marigorta U.M.,University Pompeu Fabra | Navarro A.,University Pompeu Fabra | Navarro A.,National Institute for Bioinformatics INB | Navarro A.,Catalan Institution for Research and Advanced Studies
PLoS Genetics | Year: 2013

Genome-wide association studies (GWAS) have detected many disease associations. However, the reported variants tend to explain small fractions of risk, and there are doubts about issues such as the portability of findings over different ethnic groups or the relative roles of rare versus common variants in the genetic architecture of complex disease. Studying the degree of sharing of disease-associated variants across populations can help in solving these issues. We present a comprehensive survey of GWAS replicability across 28 diseases. Most loci and SNPs discovered in Europeans for these conditions have been extensively replicated using peoples of European and East Asian ancestry, while the replication with individuals of African ancestry is much less common. We found a strong and significant correlation of Odds Ratios across Europeans and East Asians, indicating that underlying causal variants are common and shared between the two ancestries. Moreover, SNPs that failed to replicate in East Asians map into genomic regions where Linkage Disequilibrium patterns differ significantly between populations. Finally, we observed that GWAS with larger sample sizes have detected variants with weaker effects rather than with lower frequencies. Our results indicate that most GWAS results are due to common variants. In addition, the sharing of disease alleles and the high correlation in their effect sizes suggest that most of the underlying causal variants are shared between Europeans and East Asians and that they tend to map close to the associated marker SNPs. © 2013 Marigorta, Navarro.

Laayouni H.,Institute of Evolutionary Biology UPF CSIC | Montanucci L.,Institute of Evolutionary Biology UPF CSIC | Sikora M.,Institute of Evolutionary Biology UPF CSIC | Mele M.,Institute of Evolutionary Biology UPF CSIC | And 14 more authors.
PLoS ONE | Year: 2011

Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humans. © 2011 Laayouni et al.

Santpere G.,University Pompeu Fabra | Santpere G.,Yale University | Lopez-Valenzuela M.,University Pompeu Fabra | Petit-Marty N.,University Pompeu Fabra | And 6 more authors.
BMC Genomics | Year: 2016

Background: The rise of the primate lineage is accompanied by an outstanding emergence of microRNAs, small non-coding RNAs with a prominent role in gene regulation. In spite of their biological importance little is known about the way in which natural selection has influenced microRNAs in the human lineage. To study the recent evolutionary history of human microRNAs and to analyze the signatures of natural selection in genomic regions harbouring microRNAs we have investigated the nucleotide substitution rates of 1,872 human microRNAs in the human and chimpanzee lineages. Results: We produced a depurated set of microRNA alignments of human, chimpanzee and orang-utan orthologs combining BLAT and liftOver and selected 1,214 microRNA precursors presenting optimal secondary structures. We classified microRNAs in categories depending on their genomic organization, duplication status and conservation along evolution. We compared substitution rates of the aligned microRNAs between human and chimpanzee using Tajima's Relative Rate Test taking orang-utan as out-group and found several microRNAs with particularly high substitution rates in either the human or chimpanzee branches. We fitted different models of natural selection on these orthologous microRNA alignments and compared them using a likelihood ratio test that uses ancestral repeats and microRNA flanking regions as neutral sequences. We found that although a large fraction of human microRNAs is highly conserved among the three species studied, significant differences in rates of molecular evolution exist among microRNA categories. Particularly, primate-specific microRNAs, which are enriched in isolated and single copy microRNAs, more than doubled substitution rates of those belonging to older, non primate-specific microRNA families. Conclusions: Our results corroborate the remarkable conservation of microRNAs, a proxy of their functional relevance, and indicate that a subset of human microRNAs undergo nucleotide substitutions at higher rates, which may be suggestive of the action of positive selection. © 2016 The Author(s).

Rodriguez J.A.,Institute of Evolutionary Biology UPF CSIC PRBB | Marigorta U.M.,Georgia Institute of Technology | Navarro A.,Institute of Evolutionary Biology UPF CSIC PRBB | Navarro A.,Center for Genomic Regulation | And 2 more authors.
Current Opinion in Genetics and Development | Year: 2014

The application of the principles of evolutionary biology into medicine was suggested long ago and is already providing insight into the ultimate causes of disease. However, a full systematic integration of medical genomics and evolutionary medicine is still missing. Here, we briefly review some cases where the combination of the two fields has proven profitable and highlight two of the main issues hindering the development of evolutionary genomic medicine as a mature field, namely the dissociation between fitness and health and the still considerable difficulties in predicting phenotypes from genotypes. We use publicly available data to illustrate both problems and conclude that new approaches are needed for evolutionary genomic medicine to overcome these obstacles. © 2014.

Hartasanchez D.A.,University Pompeu Fabra | Valles-Codina O.,University Pompeu Fabra | Braso-Vives M.,University Pompeu Fabra | Navarro A.,University Pompeu Fabra | And 3 more authors.
G3: Genes, Genomes, Genetics | Year: 2014

Interlocus gene conversion is a major evolutionary force that drives the concerted evolution of duplicated genomic regions. Theoretical models successfully have addressed the effects of interlocus gene conversion and the importance of crossover in the evolutionary fate of gene families and duplications but have not considered complex recombination scenarios, such as the presence of hotspots. To study the interplay between interlocus gene conversion and crossover, we have developed a forward-time simulator that allows the exploration of a wide range of interlocus gene conversion rates under different crossover models. Using it, we have analyzed patterns of nucleotide variation and linkage disequilibrium within and between duplicate regions, focusing on a neutral scenario with constant population size and validating our results with the existing theoretical models. We show that the interaction of gene conversion and crossover is nontrivial and that the location of crossover junctions is a fundamental determinant of levels of variation and linkage disequilibrium in duplicated regions. We also show that if crossover activity between duplications is strong enough, recurrent interlocus gene conversion events can break linkage disequilibrium within duplicates. Given the complex nature of interlocus gene conversion and crossover, we provide a framework to explore their interplay to help increase knowledge on molecular evolution within segmental duplications under more complex scenarios, such as demographic changes or natural selection. © 2014 Hartasánchez et al.

Ventura M.,University of Washington | Ventura M.,University of Bari | Catacchio C.R.,University of Washington | Catacchio C.R.,University of Bari | And 21 more authors.
Genome Research | Year: 2011

Structural variation has played an important role in the evolutionary restructuring of human and great ape genomes. Recent analyses have suggested that the genomes of chimpanzee and human have been particularly enriched for this form of genetic variation. Here, we set out to assess the extent of structural variation in the gorilla lineage by generating 10-fold genomic sequence coverage from a western lowland gorilla and integrating these data into a physical and cytogenetic framework of structural variation. We discovered and validated over 7665 structural changes within the gorilla lineage, including sequence resolution of inversions, deletions, duplications, and mobile element insertions. A comparison with human and other ape genomes shows that the gorilla genome has been subjected to the highest rate of segmental duplication. We show that both the gorilla and chimpanzee genomes have experienced independent yet convergent patterns of structural mutation that have not occurred in humans, including the formation of subtelomeric heterochromatic caps, the hyperexpansion of segmental duplications, and bursts of retroviral integrations. Our analysis suggests that the chimpanzee and gorilla genomes are structurally more derived than either orangutan or human genomes. © 2011 by Cold Spring Harbor Laboratory Press.

Muniz-Fernandez F.,University Pompeu Fabra | Muniz-Fernandez F.,National Institute for Bioinformatics INB | Carreno-Torres A.,University Pompeu Fabra | Carreno-Torres A.,National Institute for Bioinformatics INB | And 7 more authors.
Bioinformatics | Year: 2011

Motivation: Genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays are the most widely used approach to detect loci associated to human traits. Due to the complexity of the methods and software packages available, each with its particular format requiring intricate management workflows, the analysis of GWAS usually confronts scientists with steep learning curves. Indeed, the wide variety of tools makes the parsing and manipulation of data the most time consuming and error prone part of a study. To help resolve these issues, we present GWASpi, a user-friendly, multiplatform, desktop-able application for the management and analysis of GWAS data, with a novel approach on database technologies to leverage the most out of commonly available desktop hardware. GWASpi aims to be a start-to-finish GWAS management application, from raw data to results, containing the most common analysis tools. As a result, GWASpi is easy to use and reduces in up to two orders of magnitude the time needed to perform the fundamental steps of a GWAS. © The Author 2011. Published by Oxford University Press. All rights reserved.

Camina-Tato M.,Autonomous University of Barcelona | Fernandez M.,Autonomous University of Barcelona | Morcillo-Suarez C.,University Pompeu Fabra | Morcillo-Suarez C.,National Institute for Bioinformatics INB | And 6 more authors.
Journal of Neuroimmunology | Year: 2010

We investigated caspase 8 (CASP8) as a candidate gene for multiple sclerosis (MS) susceptibility. Three SNPs (rs2037815, rs12990906 and rs1035140) were genotyped in 546 MS patients and 547 controls. For SNP rs2037815, GG homozygosity was associated with primary progressive multiple sclerosis (PPMS) when compared with relapse-onset MS and controls. We identified risk (GCA) and protective (ACT) haplotypes associated with PPMS when compared with relapse-onset MS and controls. GG homozygosity for SNP rs2037815 in PPMS patients was associated with a trend towards faster disease progression. These findings point to a role of CASP8 polymorphisms in the MS genetic risk in PPMS patients. © 2010 Elsevier B.V.

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