Institution
Wellcome Trust Centre for Human Genetics
Facility•Oxford, 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.
Topics: Population, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Linkage disequilibrium
Papers published on a yearly basis
Papers
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TL;DR: How observations on this model system generate important hypotheses for the understanding of malaria biology are discussed, and how these might guide the rational analysis of interventions against the transmission of the malaria parasites of humans by their diverse vector species.
Abstract: It is well documented that the density of Plasmodium in its vertebrate host modulates the physiological response induced; this in turn regulates parasite survival and transmission. It is less clear that parasite density in the mosquito regulates survival and transmission of this important pathogen. Numerous studies have described conversion rates of Plasmodium from one life stage to the next within the mosquito, yet few have considered that these rates might vary with parasite density. Here we establish infections with defined numbers of the rodent malaria parasite Plasmodium berghei to examine how parasite density at each stage of development (gametocytes; ookinetes; oocysts and sporozoites) influences development to the ensuing stage in Anopheles stephensi, and thus the delivery of infectious sporozoites to the vertebrate host. We show that every developmental transition exhibits strong density dependence, with numbers of the ensuing stages saturating at high density. We further show that when fed ookinetes at very low densities, oocyst development is facilitated by increasing ookinete number (i.e., the efficiency of ookinete-oocyst transformation follows a sigmoid relationship). We discuss how observations on this model system generate important hypotheses for the understanding of malaria biology, and how these might guide the rational analysis of interventions against the transmission of the malaria parasites of humans by their diverse vector species.
122 citations
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TL;DR: It is established that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but goes on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.
122 citations
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TL;DR: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore the data support the implementation of universal EC screening for LS.
122 citations
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TL;DR: Four individuals with ataxic cerebral palsy likely due to de novo dominant mutations associated with increased paternal age are described and investigated for genetic causes before the disorder is ascribed to asphyxia.
Abstract: Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.
122 citations
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TL;DR: The interaction determinants reveal previously uncharacterized and distinct functions for the Hh Zn2+ and Ca2+ binding sites—functions that may be common to all vertebrate Hh proteins.
Abstract: Hedgehog (Hh) morphogens play fundamental roles in development whilst dysregulation of Hh signaling leads to disease. Multiple cell surface receptors are responsible for transducing and/or regulating Hh signals. Among these, the hedgehog-interacting protein (HIP) is a highly conserved, vertebrate-specific, inhibitor of Hh signaling. We have solved a series of crystal structures for the human HIP ectodomain and Desert Hh in isolation, as well as Sonic and Desert Hh-HIP complexes, with and without calcium. The interaction determinants, confirmed by biophysical studies and mutagenesis, reveal novel and distinct functions for Hh zinc- and calcium-binding sites; functions which appear common to all vertebrate Hhs. Zinc makes a key contribution to the Hh-HIP interface while calcium prevents electrostatic repulsion between the two proteins, thus playing a major modulatory role. This interplay of several metal-binding sites suggests a tuneable mechanism for regulation of Hh signaling.
122 citations
Authors
Showing all 2127 results
Name | H-index | Papers | Citations |
---|---|---|---|
Mark I. McCarthy | 200 | 1028 | 187898 |
John P. A. Ioannidis | 185 | 1311 | 193612 |
Gonçalo R. Abecasis | 179 | 595 | 230323 |
Simon I. Hay | 165 | 557 | 153307 |
Robert Plomin | 151 | 1104 | 88588 |
Ashok Kumar | 151 | 5654 | 164086 |
Julian Parkhill | 149 | 759 | 104736 |
James F. Wilson | 146 | 677 | 101883 |
Jeremy K. Nicholson | 141 | 773 | 80275 |
Hugh Watkins | 128 | 524 | 91317 |
Erik Ingelsson | 124 | 538 | 85407 |
Claudia Langenberg | 124 | 452 | 67326 |
Adrian V. S. Hill | 122 | 589 | 64613 |
John A. Todd | 121 | 515 | 67413 |
Elaine Holmes | 119 | 560 | 58975 |