ORCID Profile
0000-0002-5023-0176
Current Organisations
Hannover Medical School
,
Wellcome Sanger Institute
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Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2020
Publisher: Public Library of Science (PLoS)
Date: 31-12-2008
Publisher: Springer Science and Business Media LLC
Date: 25-11-2013
DOI: 10.1038/SREP03318
Publisher: Public Library of Science (PLoS)
Date: 18-07-2011
Publisher: Oxford University Press (OUP)
Date: 03-1993
Publisher: Springer Science and Business Media LLC
Date: 05-06-2008
DOI: 10.1038/GENE.2008.38
Publisher: Wiley
Date: 07-2004
DOI: 10.1002/ART.20358
Abstract: We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin alpha (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401. Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes. Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097). The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequilibrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2019
Abstract: The FPN Q248H mutation protects children from anemia, hemolysis, and iron deficiency, but not malaria or bacterial infection.
Publisher: Proceedings of the National Academy of Sciences
Date: 26-04-1994
Abstract: Heterogeneity in parasite virulence is one of several factors that have been proposed to contribute to the wide spectrum of disease severity in Plasmodium falciparum malaria. We used observed age-structured patterns of disease to define a population structure of P. falciparum, where the latter contains several independently transmitted antigenic types or "strains" that each induce some degree of strain-specific antidisease immunity upon infection. Patterns of incidence of severe and mild disease may be explained by assuming that a majority of these strains are associated with mild disease and that although severe malarial anemia is a complication occurring in a certain proportion of early infections with "mild" parasites, cerebral malaria is caused by a few distinct highly virulent strains. Considerable variation in parasite virulence, as a major factor of disease severity in malaria, is made possible by the absence of competition between the various parasite strains, arising from weak shared immune responses. The theoretical framework presented in this paper can explain other epidemiological observations, such as the results of interventions with insecticide-impregnated bednets.
Publisher: Public Library of Science (PLoS)
Date: 29-02-2012
Publisher: Oxford University Press (OUP)
Date: 21-11-2014
Publisher: Oxford University Press (OUP)
Date: 29-04-2009
DOI: 10.1093/HMG/DDP192
Publisher: Springer Science and Business Media LLC
Date: 07-06-2012
DOI: 10.1038/GENE.2012.25
Publisher: Springer Science and Business Media LLC
Date: 11-12-1994
DOI: 10.1038/NATURE15393
Publisher: Springer Science and Business Media LLC
Date: 30-09-2015
DOI: 10.1038/NATURE15390
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2019
DOI: 10.1101/824730
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2008
Publisher: American Society for Microbiology
Date: 08-2018
DOI: 10.1128/IAI.00485-17
Abstract: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3 PF11_0521 , in comparison to four control antigens, including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant.
Publisher: Elsevier BV
Date: 08-2018
Publisher: Public Library of Science (PLoS)
Date: 02-02-2022
DOI: 10.1371/JOURNAL.PCBI.1009801
Abstract: Investigation of the ersity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum , have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global ersity and population structure of leading vaccine candidate antigens of P . falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene ‘haplotypes’ from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp , trap , eba175 , ama1 , rh5 , and CelTOS . Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of ersity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the ersity of P . falciparum antigens to be considered in the design of the next generation of malaria vaccines.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2022
DOI: 10.1038/S42003-022-04352-2
Abstract: Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection’s country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-02-1998
DOI: 10.1126/SCIENCE.279.5354.1173
Abstract: Host-parasite coevolution has been likened to a molecular arms race, with particular parasite genes evolving to evade specific host defenses. Study of the variants of an antigenic epitope of Plasmodium falciparum that induces a cytotoxic T cell response supports this view. In African children with malaria, the variants present are influenced by the presence of a human leukocyte antigen (HLA) type that restricts the immune response to this epitope. The distribution of parasite variants may be further influenced by the ability of cohabiting parasite strains to facilitate each other's survival by down-regulating cellular immune responses, using altered peptide ligand antagonism.
Publisher: Oxford University Press (OUP)
Date: 24-07-2016
Publisher: Public Library of Science (PLoS)
Date: 16-12-2020
DOI: 10.1371/JOURNAL.PNTD.0008945
Abstract: Plasmodium vivax has been recently discovered as a significant cause of malaria in Mauritania, although very rare elsewhere in West Africa. It has not been known if this is a recently introduced or locally remnant parasite population, nor whether the genetic structure reflects epidemic or endemic transmission. To investigate the P . vivax population genetic structure in Mauritania and compare with populations previously analysed elsewhere, multi-locus genotyping was undertaken on 100 clinical isolates, using a genome-wide panel of 38 single nucleotide polymorphisms (SNPs), plus seven SNPs in drug resistance genes. The Mauritanian P . vivax population is shown to be genetically erse and ergent from populations elsewhere, indicated consistently by genetic distance matrix analysis, principal components analyses, and fixation indices. Only one isolate had a genotype clearly indicating recent importation, from a southeast Asian source. There was no linkage disequilibrium in the local parasite population, and only a small number of infections appeared to be closely genetically related, indicating that there is ongoing genetic recombination consistent with endemic transmission. The P . vivax ersity in a remote mining town was similar to that in the capital Nouakchott, with no indication of local substructure or of epidemic population structure. Drug resistance alleles were virtually absent in Mauritania, in contrast with P . vivax in other areas of the world. The molecular epidemiology indicates that there is long-standing endemic transmission that will be very challenging to eliminate. The virtual absence of drug resistance alleles suggests that most infections have been untreated, and that this endemic infection has been more neglected in comparison to P . vivax elsewhere.
Publisher: Public Library of Science (PLoS)
Date: 04-01-2013
Publisher: Oxford University Press (OUP)
Date: 19-06-2014
Publisher: Springer Science and Business Media LLC
Date: 10-02-2012
Abstract: Genome and transcriptome studies of Plasmodium nucleic acids obtained from parasitized whole blood are greatly improved by depletion of human DNA or enrichment of parasite DNA prior to next-generation sequencing and microarray hybridization. The most effective method currently used is a two-step procedure to deplete leukocytes: centrifugation using density gradient media followed by filtration through expensive, commercially available columns. This method is not easily implemented in field studies that collect hundreds of s les and simultaneously process s les for multiple laboratory analyses. Inexpensive syringes, hand-packed with CF11 cellulose powder, were recently shown to improve ex vivo cultivation of Plasmodium vivax obtained from parasitized whole blood. This study was undertaken to determine whether CF11 columns could be adapted to isolate Plasmodium falciparum DNA from parasitized whole blood and achieve current quantity and purity requirements for Illumina sequencing. The CF11 procedure was compared with the current two-step standard of leukocyte depletion using parasitized red blood cells cultured in vitro and parasitized blood obtained ex vivo from Cambodian patients with malaria. Procedural variations in centrifugation and column size were tested, along with a range of blood volumes and parasite densities. CF11 filtration reliably produces 500 nanograms of DNA with less than 50% human DNA contamination, which is comparable to that obtained by the two-step method and falls within the current quality control requirements for Illumina sequencing. In addition, a centrifuge-free version of the CF11 filtration method to isolate P. falciparum DNA at remote and minimally equipped field sites in malaria-endemic areas was validated. CF11 filtration is a cost-effective, scalable, one-step approach to remove human DNA from P. falciparum -infected whole blood s les.
Publisher: Wiley
Date: 2003
DOI: 10.1002/ART.10719
Abstract: HLA-DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA-DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes. We identified 274 HLA-DRB1*04-positive cases of RA and 271 HLA-DRB1*04-positive population controls. Each subject was typed for 6 single-nucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin alpha (LTA). LTA-TNF haplotypes in these unrelated in iduals were determined using a combination of family data and the PHASE software program. Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04. The LTA-TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among in iduals carrying DRB1*0401, the LTA-TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3-0.8], P = 0.007), while in those with DRB1*0404, the opposite effect was observed (P = 0.007). These findings suggest that the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to RA.
Publisher: Massachusetts Medical Society
Date: 03-06-2010
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1038/NATURE21038
Publisher: Public Library of Science (PLoS)
Date: 11-2012
Publisher: Oxford University Press (OUP)
Date: 06-01-2016
Publisher: eLife Sciences Publications, Ltd
Date: 09-01-2017
DOI: 10.7554/ELIFE.15085
Abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each in idual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2012
DOI: 10.1038/NG.2435
Publisher: Springer Science and Business Media LLC
Date: 18-02-2009
DOI: 10.1038/EJHG.2009.8
Publisher: Public Library of Science (PLoS)
Date: 15-01-2009
Publisher: Springer Science and Business Media LLC
Date: 12-2008
DOI: 10.1038/NATURE07632
Publisher: Public Library of Science (PLoS)
Date: 06-06-2011
Publisher: Springer Science and Business Media LLC
Date: 03-12-2014
DOI: 10.1038/NATURE13997
Publisher: Springer Science and Business Media LLC
Date: 13-03-2009
Publisher: Oxford University Press (OUP)
Date: 13-11-2007
DOI: 10.1093/HMG/DDM331
Publisher: Public Library of Science (PLoS)
Date: 11-08-2011
Publisher: Springer Science and Business Media LLC
Date: 25-03-2021
DOI: 10.1038/S41586-021-03470-X
Abstract: The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2019
DOI: 10.1101/776781
Abstract: Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax . Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from −1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2021
Publisher: Elsevier BV
Date: 10-2015
Publisher: Public Library of Science (PLoS)
Date: 08-11-2012
Publisher: Public Library of Science (PLoS)
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 27-06-2016
DOI: 10.1038/NG.3599
Publisher: Springer Science and Business Media LLC
Date: 28-04-2013
DOI: 10.1038/NG.2624
Publisher: Oxford University Press (OUP)
Date: 16-08-2009
DOI: 10.1093/BIOINFORMATICS/BTP488
Abstract: Summary: Array-based comparative genomic hybridization (CGH) technology is used to discover and validate genomic structural variation, including copy number variants, insertions, deletions and other structural variants (SVs). The visualization and summarization of the array CGH data outputs, potentially across many s les, is an important process in the identification and analysis of SVs. We have developed a software tool for SV analysis using data from array CGH technologies, which is also amenable to short-read sequence data. Availability and implementation: SnoopCGH is written in java and is available from snoopcgh.sourceforge.net/ Contact: jg10@sanger.ac.uk tc5@sanger.ac.uk
Publisher: IOP Publishing
Date: 10-2020
DOI: 10.1088/1755-1315/578/1/012044
Abstract: The paper presents the analysis’ results of the generation and economic efficiency of a solar power station functioning in the private sector in conjunction with a centralized power grid. Based on data analysis of the generation of a test solar power plant with a capacity of 1.86 kW, a comparative analysis of the calculated and actual characteristics in real functioning conditions is carried out. The estimated power generation capacity of the station during 5 months (December 2019 - April 2020) was 680.1 kWh, and the actual generation for the same period was 525.86 kWh. Using data on the solar radiation’s level on the Chechen Republic territory, as well as data on electricity tariffs in the region, the economic effect of using a grid solar power plant is predicted. Taking into account the electricity tariff for private consumers, the estimated payback period of the system was 25 years. At a rate for commercial consumers - 12 years. Based on the analysis, it was concluded that the use of grid solar power plants is economically feasible only for electricity consumers in the Chechen Republic who purchase electricity at a commercial rate.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2008
Publisher: Proceedings of the National Academy of Sciences
Date: 17-12-2012
Abstract: The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum -specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.
Publisher: Public Library of Science (PLoS)
Date: 15-12-2020
DOI: 10.1371/JOURNAL.PPAT.1009133
Abstract: The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical s les. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical s les from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1 , ferredoxin , atg18 and pnp . These findings suggest that a P . falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Publisher: Cold Spring Harbor Laboratory
Date: 04-01-2021
DOI: 10.1101/2020.12.30.20249034
Abstract: The SARS-CoV-2 lineage B.1.1.7, now designated Variant of Concern 202012/01 (VOC) by Public Health England, originated in the UK in late Summer to early Autumn 2020. We examine epidemiological evidence for this VOC having a transmission advantage from several perspectives. First, whole genome sequence data collected from community-based diagnostic testing provides an indication of changing prevalence of different genetic variants through time. Phylodynamic modelling additionally indicates that genetic ersity of this lineage has changed in a manner consistent with exponential growth. Second, we find that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S-gene target failures (SGTF) in community-based diagnostic PCR testing. Third, we examine growth trends in SGTF and non-SGTF case numbers at local area level across England, and show that the VOC has higher transmissibility than non-VOC lineages, even if the VOC has a different latent period or generation time. Available SGTF data indicate a shift in the age composition of reported cases, with a larger share of under 20 year olds among reported VOC than non-VOC cases. Fourth, we assess the association of VOC frequency with independent estimates of the overall SARS-CoV-2 reproduction number through time. Finally, we fit a semi-mechanistic model directly to local VOC and non-VOC case incidence to estimate the reproduction numbers over time for each. There is a consensus among all analyses that the VOC has a substantial transmission advantage, with the estimated difference in reproduction numbers between VOC and non-VOC ranging between 0.4 and 0.7, and the ratio of reproduction numbers varying between 1.4 and 1.8. We note that these estimates of transmission advantage apply to a period where high levels of social distancing were in place in England extrapolation to other transmission contexts therefore requires caution.
Publisher: Oxford University Press (OUP)
Date: 15-02-2009
DOI: 10.1086/596320
Publisher: F1000 Research Ltd
Date: 14-04-2022
DOI: 10.12688/WELLCOMEOPENRES.17795.1
Abstract: This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 s les of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new s les contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published s les from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each s le has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr , dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.
Publisher: Cold Spring Harbor Laboratory
Date: 25-12-2020
DOI: 10.1101/2020.12.23.424229
Abstract: Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around the world. The modest mutation rate and rapid transmission of SARS-CoV-2 prevents the reconstruction of transmission chains from consensus genome sequences, but within-host genetic ersity could theoretically help identify close contacts. Here we describe the patterns of within-host ersity in 1,181 SARS-CoV-2 s les sequenced to high depth in duplicate. 95% of s les show within-host mutations at detectable allele frequencies. Analyses of the mutational spectra revealed strong strand asymmetries suggestive of damage or RNA editing of the plus strand, rather than replication errors, dominating the accumulation of mutations during the SARS-CoV-2 pandemic. Within and between host ersity show strong purifying selection, particularly against nonsense mutations. Recurrent within-host mutations, many of which coincide with known phylogenetic homoplasies, display a spectrum and patterns of purifying selection more suggestive of mutational hotspots than recombination or convergent evolution. While allele frequencies suggest that most s les result from infection by a single lineage, we identify multiple putative ex les of co-infection. Integrating these results into an epidemiological inference framework, we find that while sharing of within-host variants between s les could help the reconstruction of transmission chains, mutational hotspots and rare cases of superinfection can confound these analyses.
Publisher: Canadian Science Publishing
Date: 02-1990
DOI: 10.1139/O90-077
Abstract: The hepatic glycine cleavage system (GCS) is the principal route for the metabolism of glycine in mammals. Flux through the GCS in isolated rat hepatocytes was stimulated by about 100% by glucagon (10 −7 M), forskolin (10 −4 M), and dibutyryl cAMP (10 −4 M). The stimulation of flux through the GCS by these agents was accompanied by marked elevation of cellular cAMP levels. A significant correlation was observed between increased cellular cAMP levels induced by glucagon and stimulation of flux through the GCS by glucagon. Exclusion of calcium from the incubation medium reduced the basal flux by 38%, but did not affect the degree of stimulation of flux through the GCS by glucagon. A single intraperitoneal injection of glucagon to rats prior to isolation of hepatocytes resulted in a 76% stimulation of flux through the GCS. These hepatocytes with stimulated flux through the GCS showed reduced sensitivity for further stimulation by glucagon. Half-maximal stimulation of flux through the GCS occurred at 3.8 ± 1.1 and 8.5 ± 1.4 nM glucagon in hepatocytes isolated from control and glucagon-injected rats, respectively. We conclude that cAMP is involved in the regulation of flux through the GCS by gluagon.Key words: amino acid, metabolism, liver, mitochondria, hormones.
Publisher: F1000 Research Ltd
Date: 24-02-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.1
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: F1000 Research Ltd
Date: 13-07-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.2
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2015
Publisher: Oxford University Press (OUP)
Date: 16-06-2010
DOI: 10.1093/BIOINFORMATICS/BTQ327
Abstract: Motivation: Quantifying differences in linkage disequilibrium (LD) between sub-groups can highlight genetic regions or sites under selection and/or associated with disease, and may have utility in trans-ethnic mapping studies. Results: We present a novel pseudo Bayes factor (PBF) approach that assess differences in covariance of genotype frequencies from single nucleotide polymorphism (SNP) data from a genome-wide study. The magnitude of the PBF reflects the strength of evidence for a difference, while accounting for the s le size and number of SNPs, without the requirement for permutation testing to establish statistical significance. Application of the PBF to HapMap and Gambian malaria SNP data reveals regional LD differences, some known to be under selection. Availability and implementation: The PBF approach has been implemented in the BALD (Bayesian analysis of LD differences) C++ software, and is available from homepages.lshtm.ac.uk/tgclark/downloads Contact: taane.clark@lshtm.ac.uk
Publisher: Springer Science and Business Media LLC
Date: 04-12-2018
DOI: 10.1038/S41467-018-07588-X
Abstract: The predisposition of parasites acquiring artemisinin resistance still remains unclear beyond the mutations in Pfk13 gene and modulation of the unfolded protein response pathway. To explore the chain of casualty underlying artemisinin resistance, we reanalyze 773 P. falciparum isolates from TRACI-study integrating TWAS, GWAS, and eQTL analyses. We find the majority of P. falciparum parasites are transcriptomically converged within each geographic site with two broader physiological profiles across the Greater Mekong Subregion (GMS). We report 8720 SNP-expression linkages in the eastern GMS parasites and 4537 in the western. The minimal overlap between them suggests differential gene regulatory networks facilitating parasite adaptations to their unique host environments. Finally, we identify two genetic and physiological backgrounds associating with artemisinin resistance in the GMS, together with a farnesyltransferase protein and a thioredoxin-like protein which may act as vital intermediators linking the Pfk13 C580Y mutation to the prolonged parasite clearance time.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2010
Abstract: Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue. Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331 . None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2 , a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more in iduals in 39 candidate genes (18%). Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term placenta. ZNF331 is imprinted in human term placenta and might be a new ubiquitously imprinted gene, part of a primate-specific locus. Demonstration of partial imprinting of PHACTR2 calls for re-evaluation of the allelic pattern of expression for the PHACTR2-PLAGL1 locus. ASE was common in human term placenta.
Publisher: Cold Spring Harbor Laboratory
Date: 16-03-2023
DOI: 10.1101/2023.03.13.23287179
Abstract: Challenges in understanding the origin of recurrent Plasmodium vivax infections constrains the surveillance of antimalarial efficacy and transmission of this neglected parasite. Recurrent infections within an in idual may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or new inoculations (reinfection). Molecular inference of familial relatedness (identity-by-descent or IBD) based on whole genome sequence data, together with analysis of the intervals between parasitaemic episodes (“time-to-event” analysis), can help resolve the probable origin of recurrences. Whole genome sequencing of predominantly low-density P. vivax infections is challenging, so an accurate and scalable genotyping method to determine the origins of recurrent parasitaemia would be of significant benefit. We have developed a P. vivax genome-wide informatics pipeline to select specific microhaplotype panels that can capture IBD within small, lifiable segments of the genome. Using a global set of 615 P. vivax genomes, we derived a panel of 100 microhaplotypes, each comprising 3-10 high frequency SNPs within bp sequence windows. This panel exhibits high ersity in regions of the Asia-Pacific, Latin America and the horn of Africa (median H E = 0.70-0.81) and it captured 89% (273/307) of the polyclonal infections detected with genome-wide datasets. Using data simulations, we demonstrate lower error in estimating pairwise IBD using microhaplotypes, relative to traditional biallelic SNP barcodes. Our panel exhibited high accuracy in predicting the country of origin (median Matthew’s correlation coefficient .9 in 90% countries tested) and it also captured local infection outbreak and bottlenecking events. The informatics pipeline is available open-source and yields microhaplotypes that can be readily transferred to high-throughput licon sequencing assays for surveillance in malaria-endemic regions.
Publisher: Elsevier BV
Date: 07-2016
Publisher: F1000 Research Ltd
Date: 16-01-2023
DOI: 10.12688/WELLCOMEOPENRES.18681.1
Abstract: We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 s les from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot s les that were sequenced after selective whole genome lification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show ex les of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 16-12-2019
DOI: 10.1038/S41467-019-13480-Z
Abstract: The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 s les. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4 , but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these s les. This large dataset will provide a foundation for further research on the genetic determinants of malaria resistance in erse populations.
Publisher: Oxford University Press (OUP)
Date: 10-09-2007
DOI: 10.1093/BIOINFORMATICS/BTM443
Abstract: Motivation: Large-scale genotyping relies on the use of unsupervised automated calling algorithms to assign genotypes to hybridization data. A number of such calling algorithms have been recently established for the Affymetrix GeneChip genotyping technology. Here, we present a fast and accurate genotype calling algorithm for the Illumina BeadArray genotyping platforms. As the technology moves towards assaying millions of genetic polymorphisms simultaneously, there is a need for an integrated and easy-to-use software for calling genotypes. Results: We have introduced a model-based genotype calling algorithm which does not rely on having prior training data or require computationally intensive procedures. The algorithm can assign genotypes to hybridization data from thousands of in iduals simultaneously and pools information across multiple in iduals to improve the calling. The method can accommodate variations in hybridization intensities which result in dramatic shifts of the position of the genotype clouds by identifying the optimal coordinates to initialize the algorithm. By incorporating the process of perturbation analysis, we can obtain a quality metric measuring the stability of the assigned genotype calls. We show that this quality metric can be used to identify SNPs with low call rates and accuracy. Availability: The C++ executable for the algorithm described here is available by request from the authors. Contact: teo@well.ox.ac.uk or tgc@well.ox.ac.uk
Publisher: Springer Science and Business Media LLC
Date: 04-2008
Publisher: Springer Science and Business Media LLC
Date: 15-05-2007
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Dominic Kwiatkowski.