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Search Results: 1 - 10 of 167728 matches for " Stylianos E Antonarakis "
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From sequence to functional understanding: the difficult road ahead
Periklis Makrythanasis, Stylianos E Antonarakis
Genome Medicine , 2011, DOI: 10.1186/gm235
Abstract: The recent development of high-throughput sequencing (HTS) and its application for sequencing the exomes or genomes of thousands of people (including participants of the 1000 Genomes Project) has provided experimental evidence of the extensive variability of the human genome (both in single nucleotide polymorphisms (SNPs) and copy number variations (CNVs)). Within the coding fraction of the genome (the exome), each individual is estimated to have approximately 8,500 to 10,500 non-synonymous variants, 350 to 400 of which are predicted to cause loss-of-function alleles affecting 250 to 300 genes [1]. HTS data have also provided experimental evidence that the mutation rate of the human genome is 10-8 per nucleotide per generation, resulting in two to seven new variants in each individual exome [2].The most difficult challenge for HTS projects aiming to discover pathogenic variants is the correct identification of the disease-causing mutations among thousands of additional variants that could be either contributing to unrecognized phenotypes or neutral [3]. At present, most HTS projects focus on the known functional elements of the genome. Protein-coding genes are at the heart of this analysis, along with non-coding transcripts and highly conserved non-coding sequences. The rules of heredity, gene expression data, evolutionary principles and protein structure-function relationships provide the current set of criteria for deciding between potential contributing and non-contributing variants relative to the phenotype in question. The phenotype is also an important consideration because identified variants may contribute to other phenotypes but not the one in question. Furthermore, the correlation between genome variation and phenotypic variation is relatively simple for monogenic/oligogenic phenotypes and highly penetrant variants, but is complicated for polygenic phenotypes and for medium or low-penetrance variants.More precise examples of these criteria are: the presenc
Identifying protein-coding genes in genomic sequences
Jennifer Harrow, Alinda Nagy, Alexandre Reymond, Tyler Alioto, Laszlo Patthy, Stylianos E Antonarakis, Roderic Guigó
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-1-201
Abstract: The genome sequence is an organism's blueprint: the set of instructions dictating its biological traits. The unfolding of these instructions is initiated by the transcription of the DNA into RNA sequences. According to the standard model, the majority of RNA sequences originate from protein-coding genes; that is, they are processed into messenger RNAs (mRNAs) which, after their export to the cytosol, are translated into proteins. While the importance of noncoding RNAs has come to the fore over the past ten years [1-5], proteins are still assumed to be the main functional and structural players in the cell. The delineation of the complete set of protein-coding genes and their alternative splice forms is, therefore, essential to the task of translating the information in the sequence of the genome into biologically relevant knowledge. This is not a trivial task, as illustrated by the fact that many years after the first drafts of the human genome sequence became available [6-8], uncertainty remains regarding the exact number of protein-coding genes [9], a number that might actually vary between individuals - and even between cells within the same individual - as extensive structural variation has been reported in the human genome [10-12].Even the concept of a 'gene' is under revision. Genes have long been regarded as discrete entities located linearly along chromosomes, but recent investigations have demonstrated extensive transcriptional overlap between different genes. Specifically, genomic regions from otherwise distinct and apparently well characterized protein-coding loci (which may be very far apart in linear genomic space) often appear to combine to produce transcripts with the potential for encoding novel protein species [13,14].Despite all these caveats, delineating the set of protein-coding genes is invariably the first step taken after completing the DNA sequencing of a genome. Indeed, the vast majority of the biology of a genome is initially inferred from
Detection of Genomic Variation by Selection of a 9 Mb DNA Region and High Throughput Sequencing
Sergey I. Nikolaev, Christian Iseli, Andrew J. Sharp, Daniel Robyr, Jacques Rougemont, Corinne Gehrig, Laurent Farinelli, Stylianos E. Antonarakis
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006659
Abstract: Detection of the rare polymorphisms and causative mutations of genetic diseases in a targeted genomic area has become a major goal in order to understand genomic and phenotypic variability. We have interrogated repeat-masked regions of 8.9 Mb on human chromosomes 21 (7.8 Mb) and 7 (1.1 Mb) from an individual from the International HapMap Project (NA12872). We have optimized a method of genomic selection for high throughput sequencing. Microarray-based selection and sequencing resulted in 260-fold enrichment, with 41% of reads mapping to the target region. 83% of SNPs in the targeted region had at least 4-fold sequence coverage and 54% at least 15-fold. When assaying HapMap SNPs in NA12872, our sequence genotypes are 91.3% concordant in regions with coverage≥4-fold, and 97.9% concordant in regions with coverage≥15-fold. About 81% of the SNPs recovered with both thresholds are listed in dbSNP. We observed that regions with low sequence coverage occur in close proximity to low-complexity DNA. Validation experiments using Sanger sequencing were performed for 46 SNPs with 15-20 fold coverage, with a confirmation rate of 96%, suggesting that DNA selection provides an accurate and cost-effective method for identifying rare genomic variants.
Early History of Mammals Is Elucidated with the ENCODE Multiple Species Sequencing Data
Sergey Nikolaev ,Juan I Montoya-Burgos,Elliott H Margulies,NISC Comparative Sequencing Program,Jacques Rougemont,Bruno Nyffeler,Stylianos E Antonarakis
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030002
Abstract: Understanding the early evolution of placental mammals is one of the most challenging issues in mammalian phylogeny. Here, we addressed this question by using the sequence data of the ENCODE consortium, which include 1% of mammalian genomes in 18 species belonging to all main mammalian lineages. Phylogenetic reconstructions based on an unprecedented amount of coding sequences taken from 218 genes resulted in a highly supported tree placing the root of Placentalia between Afrotheria and Exafroplacentalia (Afrotheria hypothesis). This topology was validated by the phylogenetic analysis of a new class of genomic phylogenetic markers, the conserved noncoding sequences. Applying the tests of alternative topologies on the coding sequence dataset resulted in the rejection of the Atlantogenata hypothesis (Xenarthra grouping with Afrotheria), while this test rejected the second alternative scenario, the Epitheria hypothesis (Xenarthra at the base), when using the noncoding sequence dataset. Thus, the two datasets support the Afrotheria hypothesis; however, none can reject both of the remaining topological alternatives.
Evolutionary Comparison Provides Evidence for Pathogenicity of RMRP Mutations
Luisa Bonafé ,Emmanouil T Dermitzakis,Sheila Unger,Cheryl R Greenberg,Belinda A Campos-Xavier,Andreas Zankl,Catherine Ucla,Stylianos E Antonarakis,Andrea Superti-Furga,Alexandre Reymond
PLOS Genetics , 2005, DOI: 10.1371/journal.pgen.0010047
Abstract: Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.
In Vitro Whole-Genome Analysis Identifies a Susceptibility Locus for HIV-1
Corinne Loeuillet,Samuel Deutsch,Angela Ciuffi,Daniel Robyr,Patrick Taffé,Miguel Mu?oz,Jacques S. Beckmann,Stylianos E. Antonarakis,Amalio Telenti
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060032
Abstract: Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to infectious agents. We report here the use of an in vitro system for the identification of a locus on HSA8q24.3 associated with cellular susceptibility to HIV-1. This locus was mapped through quantitative linkage analysis using cell lines from multigeneration families, validated in vitro, and followed up by two independent association studies in HIV-positive individuals. Single nucleotide polymorphism rs2572886, which is associated with cellular susceptibility to HIV-1 in lymphoblastoid B cells and in primary T cells, was also associated with accelerated disease progression in one of two cohorts of HIV-1–infected patients. Biological analysis suggests a role of the rs2572886 region in the regulation of the LY6 family of glycosyl-phosphatidyl-inositol (GPI)–anchored proteins. Genetic analysis of in vitro cellular phenotypes provides an attractive approach for the discovery of susceptibility loci to infectious agents.
Chromosome Conformation Capture Uncovers Potential Genome-Wide Interactions between Human Conserved Non-Coding Sequences
Daniel Robyr,Marc Friedli,Corinne Gehrig,Mélanie Arcangeli,Marilyn Marin,Michel Guipponi,Laurent Farinelli,Isabelle Barde,Sonia Verp,Didier Trono,Stylianos E. Antonarakis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017634
Abstract: Comparative analyses of various mammalian genomes have identified numerous conserved non-coding (CNC) DNA elements that display striking conservation among species, suggesting that they have maintained specific functions throughout evolution. CNC function remains poorly understood, although recent studies have identified a role in gene regulation. We hypothesized that the identification of genomic loci that interact physically with CNCs would provide information on their functions. We have used circular chromosome conformation capture (4C) to characterize interactions of 10 CNCs from human chromosome 21 in K562 cells. The data provide evidence that CNCs are capable of interacting with loci that are enriched for CNCs. The number of trans interactions varies among CNCs; some show interactions with many loci, while others interact with few. Some of the tested CNCs are capable of driving the expression of a reporter gene in the mouse embryo, and associate with the oligodendrocyte genes OLIG1 and OLIG2. Our results underscore the power of chromosome conformation capture for the identification of targets of functional DNA elements and raise the possibility that CNCs exert their functions by physical association with defined genomic regions enriched in CNCs. These CNC-CNC interactions may in part explain their stringent conservation as a group of regulatory sequences.
In Vitro Whole-Genome Analysis Identifies a Susceptibility Locus for HIV-1
Corinne Loeuillet equal contributor,Samuel Deutsch equal contributor,Angela Ciuffi,Daniel Robyr,Patrick Taffé,Miguel Mu?oz,Jacques S Beckmann ,Stylianos E Antonarakis ,Amalio Telenti
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060032
Abstract: Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to infectious agents. We report here the use of an in vitro system for the identification of a locus on HSA8q24.3 associated with cellular susceptibility to HIV-1. This locus was mapped through quantitative linkage analysis using cell lines from multigeneration families, validated in vitro, and followed up by two independent association studies in HIV-positive individuals. Single nucleotide polymorphism rs2572886, which is associated with cellular susceptibility to HIV-1 in lymphoblastoid B cells and in primary T cells, was also associated with accelerated disease progression in one of two cohorts of HIV-1–infected patients. Biological analysis suggests a role of the rs2572886 region in the regulation of the LY6 family of glycosyl-phosphatidyl-inositol (GPI)–anchored proteins. Genetic analysis of in vitro cellular phenotypes provides an attractive approach for the discovery of susceptibility loci to infectious agents.
Genome-Wide Associations of Gene Expression Variation in Humans
Barbara E Stranger equal contributor,Matthew S Forrest equal contributor,Andrew G Clark,Mark J Minichiello,Samuel Deutsch,Robert Lyle,Sarah Hunt,Brenda Kahl,Stylianos E Antonarakis,Simon Tavaré,Panagiotis Deloukas ,Emmanouil T Dermitzakis
PLOS Genetics , 2005, DOI: 10.1371/journal.pgen.0010078
Abstract: The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12–13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs) with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis-) to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I) HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.
A Teratocarcinoma-Like Human Embryonic Stem Cell (hESC) Line and Four hESC Lines Reveal Potentially Oncogenic Genomic Changes
Outi Hovatta,Marisa Jaconi,Virpi T?h?nen,Frédérique Béna,Stefania Gimelli,Alexis Bosman,Frida Holm,Stefan Wyder,Evgeny M. Zdobnov,Olivier Irion,Peter W. Andrews,Stylianos E. Antonarakis,Marco Zucchelli,Juha Kere,Anis Feki
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010263
Abstract: The first Swiss human embryonic stem cell (hESC) line, CH-ES1, has shown features of a malignant cell line. It originated from the only single blastomere that survived cryopreservation of an embryo, and it more closely resembles teratocarcinoma lines than other hESC lines with respect to its abnormal karyotype and its formation of invasive tumors when injected into SCID mice. The aim of this study was to characterize the molecular basis of the oncogenicity of CH-ES1 cells, we looked for abnormal chromosomal copy number (by array Comparative Genomic Hybridization, aCGH) and single nucleotide polymorphisms (SNPs). To see how unique these changes were, we compared these results to data collected from the 2102Ep teratocarcinoma line and four hESC lines (H1, HS293, HS401 and SIVF-02) which displayed normal G-banding result. We identified genomic gains and losses in CH-ES1, including gains in areas containing several oncogenes. These features are similar to those observed in teratocarcinomas, and this explains the high malignancy. The CH-ES1 line was trisomic for chromosomes 1, 9, 12, 17, 19, 20 and X. Also the karyotypically (based on G-banding) normal hESC lines were also found to have several genomic changes that involved genes with known roles in cancer. The largest changes were found in the H1 line at passage number 56, when large 5 Mb duplications in chromosomes 1q32.2 and 22q12.2 were detected, but the losses and gains were seen already at passage 22. These changes found in the other lines highlight the importance of assessing the acquisition of genetic changes by hESCs before their use in regenerative medicine applications. They also point to the possibility that the acquisition of genetic changes by ESCs in culture may be used to explore certain aspects of the mechanisms regulating oncogenesis.
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