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, Gene, Locus (genetics)
Papers published on a yearly basis
Papers
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TL;DR: APC genotypes in sporadic CRCs demonstrate ‘fine-tuned’ interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different ‘optimal’ thresholds for proximal and distal cancers.
Abstract: Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/β-catenin signalling levels ‘just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282–1581) leaving 1–3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5′ to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2–3 intact 20AARs were associated with 5′ mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3′ to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2–3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate ‘fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different ‘optimal' thresholds for proximal and distal cancers.
124 citations
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TL;DR: Surface plasmon resonance is used to study the binding of soluble forms of KIR2DL1 and Kir2DL3 to several peptide-HLA-Cw7 complexes and indicates that KIR/peptide-MHC class I interactions have properties typical of other cell-cell recognition molecules, and they highlight the unusual nature of TCR/peptic-M HC recognition.
123 citations
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TL;DR: The results suggest that centered site-mediated interactions are much more frequent than previously thought, and may explain the evolutionary conservation of the central region of miRNAs, and has significant implications for decoding miRNA-regulated genetic networks, and for predicting the functional effect of variants that do not alter protein sequence.
Abstract: Background
MicroRNAs (miRNAs) bind to mRNAs and target them for translational inhibition or transcriptional degradation. It is thought that most miRNA-mRNA interactions involve the seed region at the 5′ end of the miRNA. The importance of seed sites is supported by experimental evidence, although there is growing interest in interactions mediated by the central region of the miRNA, termed centered sites. To investigate the prevalence of these interactions, we apply a biotin pull-down method to determine the direct targets of ten human miRNAs, including four isomiRs that share centered sites, but not seeds, with their canonical partner miRNAs.
123 citations
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TL;DR: The results suggest that G6PD-deficient male hemizygotes and female heterozygotes are protected from severe malaria.
Abstract: Several lines of evidence link glucose-6-phosphate dehydrogenase (G6PD) deficiency to protection from severe malaria Early reports suggested most G6PD deficiency in sub-Saharan Africa was because of the 202A/376G G6PD A− allele, and recent association studies of G6PD deficiency have employed genotyping as a convenient way to determine enzyme status However, further work has suggested that other G6PD deficiency alleles are relatively common in some regions of West Africa To investigate the consequences of unrecognized allelic heterogeneity on association studies, in particular studies of G6PD deficiency and malaria, we carried out a case–control analysis of 2488 Gambian children with severe malaria and 3875 controls No significant association was found between severe malaria and the 202A/376G G6PD A− allele when analyzed alone, but pooling 202A/376G with other deficiency alleles revealed the signal of protection (male odds ratio (OR) 077, 95% CI 062–095, P=0016; female OR 071, 95% CI 056–089, P=0004) We have identified the 968C mutation as the most common G6PD A− allele in The Gambia Our results highlight some of the consequences of allelic heterogeneity, particularly the increased type I error They also suggest that G6PD-deficient male hemizygotes and female heterozygotes are protected from severe malaria
123 citations
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TL;DR: In medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia, the bias in male incidence is largely restricted to the DR3/X category of patients with a M:F ratio of 1.7, evidence for aetiological heterogeneity at the IDDM1/MHC locus and, therefore, in the search for non-M HC loci in type 1 diabetes, conditioning of linkage data by HLA type is advised.
Abstract: It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio1. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases2,3,4. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X ≠ DR4) with a M:F ratio of 1.7 (P = 9.3 × 10–7), compared with a ratio of 1.0 in the DR4/Y category (Y ≠ DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes5,6,7,8,9,10,11,12,13. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13–p11 was in the DR3/X affected sibpair families (n = 97; peak multipoint MLS at DXS1068 = 3.5, P = 2.7 × 10–4; single point MLS = 4.5, P = 2.7 × 10–5). This is evidence for aetiological heterogeneity at the IDDM1/MHC locus and, therefore, in the search for non-MHC loci in type 1 diabetes, conditioning of linkage data by HLA type is advised.
123 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 |