Institution
Wellcome Trust Sanger Institute
Nonprofit•Cambridge, United Kingdom•
About: Wellcome Trust Sanger Institute is a nonprofit organization based out in Cambridge, United Kingdom. It is known for research contribution in the topics: Population & Genome. The organization has 4009 authors who have published 9671 publications receiving 1224479 citations.
Topics: Population, Genome, Gene, Genome-wide association study, Genomics
Papers published on a yearly basis
Papers
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TL;DR: A remarkable picture of tumor type specificity for histone H 3.3.3 driver alterations emerges, indicating that hist one H3.
Abstract: It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.
624 citations
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Medical Research Council1, National Institute for Health Research2, King's College London3, University of Cambridge4, Trinity College, Dublin5, University of Nottingham6, Queen's University Belfast7, University of Southampton8, University of Manchester9, John Radcliffe Hospital10, University of Bristol11, UCL Institute of Neurology12, University of Bonn13, University of Hamburg14, University of Erlangen-Nuremberg15, University of Duisburg-Essen16, Ludwig Maximilian University of Munich17, Heidelberg University18, University College Dublin19, University of Freiburg20, Washington University in St. Louis21, Brigham Young University22, Wellcome Trust Sanger Institute23, National Institutes of Health24, University of Göttingen25, Mayo Clinic26
TL;DR: Independent evidence from two large studies demonstrates that these processes related to cholesterol metabolism and the innate immune response are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Abstract: Background
1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.
Methodology
We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.
Principal Findings
We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.
Significance
Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
624 citations
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TL;DR: Saturation-scale mutagenesis allows prioritization of intervention targets in the genome of the most important cause of malaria, and confirms the proteasome-degradation pathway is a high-value druggable target.
Abstract: INTRODUCTION Malaria remains a devastating global parasitic disease, with the majority of malaria deaths caused by the highly virulent Plasmodium falciparum . The extreme AT-bias of the P. falciparum genome has hampered genetic studies through targeted approaches such as homologous recombination or CRISPR-Cas9, and only a few hundred P. falciparum mutants have been experimentally generated in the past decades. In this study, we have used high-throughput piggyBac transposon insertional mutagenesis and quantitative insertion site sequencing (QIseq) to reach saturation-level mutagenesis of this parasite. RATIONALE Our study exploits the AT-richness of the P. falciparum genome, which provides numerous piggyBac transposon insertion targets within both gene coding and noncoding flanking sequences, to generate more than 38,000 P. falciparum mutants. At this level of mutagenesis, we could distinguish essential genes as nonmutable and dispensable genes as mutable. Subsequently, we identified 2680 genes essential for in vitro asexual blood-stage growth. RESULTS We calculated mutagenesis index scores (MISs) and mutagenesis fitness scores (MFSs) in order to functionally define the relative fitness cost of disruption for 5399 genes. A competitive growth phenotype screen confirmed that MIS and MFS were predictive of the fitness cost for in vitro asexual growth. Genes predicted to be essential included genes implicated in drug resistance—such as the “ K13 ” Kelch propeller, mdr , and dhfr-ts —as well as targets considered to be high value for drugs development, such as pkg and cdpk5 . The screen revealed essential genes that are specific to human Plasmodium parasites but absent from rodent-infective species, such as lipid metabolic genes that may be crucial to transmission commitment in human infections. MIS and MFS profiling provides a clear ranking of the relative essentiality of gene ontology (GO) functions in P. falciparum . GO pathways associated with translation, RNA metabolism, and cell cycle control are more essential, whereas genes associated with protein phosphorylation, virulence factors, and transcription are more likely to be dispensable. Last, we confirm that the proteasome-degradation pathway is a high-value druggable target on the basis of its high ratio of essential to dispensable genes, and by functionally confirming its link to the mode of action of artemisinin, the current front-line antimalarial. CONCLUSION Saturation-scale mutagenesis allows prioritization of intervention targets in the genome of the most important cause of malaria. The identification of more than 2680 essential genes, including ~1000 Plasmodium -conserved essential genes, will be valuable for antimalarial therapeutic research.
622 citations
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TL;DR: It is shown here that the seventh pandemic has spread from the Bay of Bengal in at least three independent but overlapping waves with a common ancestor in the 1950s, and several transcontinental transmission events are identified.
Abstract: Vibrio cholerae is a globally important pathogen that is endemic in many areas of the world and causes 3–5 million reported cases of cholera every year. Historically, there have been seven acknowledged cholera pandemics; recent outbreaks in Zimbabwe and Haiti are included in the seventh and ongoing pandemic1. Only isolates in serogroup O1 (consisting of two biotypes known as ‘classical’ and ‘El Tor’) and the derivative O139 (refs 2, 3) can cause epidemic cholera2. It is believed that the first six cholera pandemics were caused by the classical biotype, but El Tor has subsequently spread globally and replaced the classical biotype in the current pandemic1. Detailed molecular epidemiological mapping of cholera has been compromised by a reliance on sub-genomic regions such as mobile elements to infer relationships, making El Tor isolates associated with the seventh pandemic seem superficially diverse. To understand the underlying phylogeny of the lineage responsible for the current pandemic, we identified high-resolution markers (single nucleotide polymorphisms; SNPs) in 154 whole-genome sequences of globally and temporally representative V. cholerae isolates. Using this phylogeny, we show here that the seventh pandemic has spread from the Bay of Bengal in at least three independent but overlapping waves with a common ancestor in the 1950s, and identify several transcontinental transmission events. Additionally, we show how the acquisition of the SXT family of antibiotic resistance elements has shaped pandemic spread, and show that this family was first acquired at least ten years before its discovery in V. cholerae.
621 citations
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University of Queensland1, Nuffield Orthopaedic Centre2, Hanyang University3, Cedars-Sinai Medical Center4, National Institutes of Health5, University of Paris6, University of Oslo7, King Abdulaziz University8, National Institute for Health and Welfare9, Danube University Krems10, Second Military Medical University11, Ghent University12, National Autonomous University of Mexico13, University of Otago14, University of Toronto15, Royal Brisbane and Women's Hospital16, Autonomous University of Madrid17, Central University, India18, Wellcome Trust Sanger Institute19, University of Oxford20, Norfolk and Norwich University Hospital21, University of Cambridge22, University Health Network23, Memorial University of Newfoundland24, University of Alberta25, Nova Southeastern University26, Norwegian University of Science and Technology27, Universidad de La Sabana28, Spanish National Research Council29, Université Paris-Saclay30, Medical Research Council31
TL;DR: In this paper, the authors used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls.
Abstract: Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.
620 citations
Authors
Showing all 4058 results
Name | H-index | Papers | Citations |
---|---|---|---|
Nicholas J. Wareham | 212 | 1657 | 204896 |
Gonçalo R. Abecasis | 179 | 595 | 230323 |
Panos Deloukas | 162 | 410 | 154018 |
Michael R. Stratton | 161 | 443 | 142586 |
David W. Johnson | 160 | 2714 | 140778 |
Michael John Owen | 160 | 1110 | 135795 |
Naveed Sattar | 155 | 1326 | 116368 |
Robert E. W. Hancock | 152 | 775 | 88481 |
Julian Parkhill | 149 | 759 | 104736 |
Nilesh J. Samani | 149 | 779 | 113545 |
Michael Conlon O'Donovan | 142 | 736 | 118857 |
Jian Yang | 142 | 1818 | 111166 |
Christof Koch | 141 | 712 | 105221 |
Andrew G. Clark | 140 | 823 | 123333 |
Stylianos E. Antonarakis | 138 | 746 | 93605 |