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Institution

Wellcome Trust Centre for Human Genetics

FacilityOxford, United Kingdom
About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.


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Journal ArticleDOI
TL;DR: A commercially available strain of outbred mice, MF1, can be treated as an ultrafine mosaic of standard inbred strains and accordingly used to dissect a known quantitative trait locus influencing anxiety, which contains Rgs2, which encodes a regulator of G protein signaling.
Abstract: Here we present a strategy to determine the genetic basis of variance in complex phenotypes that arise from natural, as opposed to induced, genetic variation in mice. We show that a commercially available strain of outbred mice, MF1, can be treated as an ultrafine mosaic of standard inbred strains and accordingly used to dissect a known quantitative trait locus influencing anxiety. We also show that this locus can be subdivided into three regions, one of which contains Rgs2, which encodes a regulator of G protein signaling. We then use quantitative complementation to show that Rgs2 is a quantitative trait gene. This combined genetic and functional approach should be applicable to the analysis of any quantitative trait.

288 citations

Journal ArticleDOI
20 Aug 2015-Oncogene
TL;DR: It is shown that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.
Abstract: Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.

287 citations

Journal ArticleDOI
TL;DR: This work reports the highest density genetic map yet created for any organism, except humans, using more than 10,000 single nucleotide polymorphisms evenly spaced across the mouse genome, and separately for males and females.
Abstract: High-resolution genetic maps are required for mapping complex traits and for the study of recombination. We report the highest density genetic map yet created for any organism, except humans. Using more than 10,000 single nucleotide polymorphisms evenly spaced across the mouse genome, we have constructed genetic maps for both outbred and inbred mice, and separately for males and females. Recombination rates are highly correlated in outbred and inbred mice, but show relatively low correlation between males and females. Differences between male and female recombination maps and the sequence features associated with recombination are strikingly similar to those observed in humans. Genetic maps are available from http://gscan.well.ox.ac.uk/#genetic_map and as supporting information to this publication.

286 citations

Journal ArticleDOI
TL;DR: The findings indicate that the QTL affects both phonological and orthographic skills and is not specific to phoneme awareness, as has been previously suggested.
Abstract: Summary Recent application of nonparametric-linkage analysis to reading disability has implicated a putative quantitative-trait locus (QTL) on the short arm of chromosome 6. In the present study, we use QTL methods to evaluate linkage to the 6p25-21.3 region in a sample of 181 sib pairs from 82 nuclear families that were selected on the basis of a dyslexic proband. We have assessed linkage directly for several quantitative measures that should correlate with different components of the phenotype, rather than using a single composite measure or employing categorical definitions of subtypes. Our measures include the traditional IQ/reading discrepancy score, as well as tests of word recognition, irregular-word reading, and nonword reading. Pointwise analysis by means of sib-pair trait differences suggests the presence, in 6p21.3, of a QTL influencing multiple components of dyslexia, in particular the reading of irregular words ( P =.0016) and nonwords ( P =.0024). A complementary statistical approach involving estimation of variance components supports these findings (irregular words, P =.007; nonwords, P =.0004). Multipoint analyses place the QTL within the D6S422-D6S291 interval, with a peak around markers D6S276 and D6S105 consistently identified by approaches based on trait differences (irregular words, P =.00035; nonwords, P =.0035) and variance components (irregular words, P =.007; nonwords, P =.0038). Our findings indicate that the QTL affects both phonological and orthographic skills and is not specific to phoneme awareness, as has been previously suggested. Further studies will be necessary to obtain a more precise localization of this QTL, which may lead to the isolation of one of the genes involved in developmental dyslexia.

286 citations

Journal ArticleDOI
TL;DR: This study provides the global community with the Phase 1 data from MARC, where the reproducibility of the performance of the MinION was evaluated at multiple sites, and a preliminary analysis of the characteristics of typical runs including the consistency, rate, volume and quality of data produced.
Abstract: The advent of a miniaturized DNA sequencing device with a high-throughput contextual sequencing capability embodies the next generation of large scale sequencing tools. The MinION™ Access Programme (MAP) was initiated by Oxford Nanopore Technologies™ in April 2014, giving public access to their USB-attached miniature sequencing device. The MinION Analysis and Reference Consortium (MARC) was formed by a subset of MAP participants, with the aim of evaluating and providing standard protocols and reference data to the community. Envisaged as a multi-phased project, this study provides the global community with the Phase 1 data from MARC, where the reproducibility of the performance of the MinION was evaluated at multiple sites. Five laboratories on two continents generated data using a control strain of Escherichia coli K-12, preparing and sequencing samples according to a revised ONT protocol. Here, we provide the details of the protocol used, along with a preliminary analysis of the characteristics of typical runs including the consistency, rate, volume and quality of data produced. Further analysis of the Phase 1 data presented here, and additional experiments in Phase 2 of E. coli from MARC are already underway to identify ways to improve and enhance MinION performance.

286 citations


Authors

Showing all 2127 results

NameH-indexPapersCitations
Mark I. McCarthy2001028187898
John P. A. Ioannidis1851311193612
Gonçalo R. Abecasis179595230323
Simon I. Hay165557153307
Robert Plomin151110488588
Ashok Kumar1515654164086
Julian Parkhill149759104736
James F. Wilson146677101883
Jeremy K. Nicholson14177380275
Hugh Watkins12852491317
Erik Ingelsson12453885407
Claudia Langenberg12445267326
Adrian V. S. Hill12258964613
John A. Todd12151567413
Elaine Holmes11956058975
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202221
202183
202074
2019134
2018182
2017323