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Results

An Extended Pilot for the Human Cell Atlas: Adult tissues, human development and inflammation-mediated pathologies 30 Sep 2018

The Human Cell Atlas (HCA) is an international, collaborative effort that "...aims to define all human cell types in terms of their distinctive patterns of gene expression, physiological states, developmental trajectories, and location". Here, we will contribute directly to the first phase of the HCA by forming an ‘extended pilot’ to implement UK infrastructure for large-scale, high quality human cell atlas experiments. We will generate a high-level atlas, with spatial resolution, for multiple adult human tissues along with matched data from human fetal material. We will then illustrate the power of a deep and focused investigation of a single tissue (skin) to produce highly-detailed data describing its cellular composition and spatial organisation. Finally, for selected tissues that have been profiled in adults and fetal material, we will analyse samples from immune-mediated disorders as a comparison with our reference data to gain deeper understanding of the pathological mechanisms. This will demonstrate the utility of the HCA as a ‘healthy reference’ for comparison with disease. Throughout, we will generate profound biological insight from primary human cells and lay a foundation of technology development and optimisation with a set of hardened and scalable methods for single-cell RNA-sequencing, spatially-resolved gene expression, and tissue imaging.

Amount: £3,878,823
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

The host response to Staphylococcus aureus infection. 01 Apr 2015

How is the host response to Staphylococcus aureus orchestrated? How does S. aureus trigger release of nerve growth factor (NGF) from host cells? How does NGF trigger host effector immunity to S. aureus?

Amount: £121,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Identifying new intervention and diagnostic targets through characterisation and functional analysis of the P. falciparum extracellular secretome. SANGER COSTS for Dr Abdi's fellowship. 18 Jun 2014

I plan to describe the extracellular secretome of P. falciparum clinical isolates; the causative agent of the most severe form of malaria. The secretome is essential for interactions within the pathogen population and with the host. Analysing the secretome of pathogens may provide new targets for vaccines, drugs, diagnostics and biomarkers for understanding mechanisms of virulence of pathogens. The secretome of P. falciparum has not been comprehensively described. Only one study has attempted t o characterise it proteomically using a single laboratory isolate. Furthermore, the secretome of clinical isolates may well be significantly different from laboratory isolates, just as the secretome of primary hepatocytes was shown to be different in quantity and composition from that of hepatocytes derived cell lines. Analysis of the P. falciparum secretome based on a single laboratory line is therefore unlikely to capture the full spectrum of the composition. I therefore, propose to comprehen sively describe the proteomic and genetic composition of both the vesicular-packaged and soluble forms of P. falciparum secretome using short-term cultured clinical isolates with available full genome sequences. I will also investigate whether P. falciparum secreted proteins play a role in immunity taking advantage of the unique resources available at KWTRP, Kilifi.

Amount: £9,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

The relative importance of human and animal sources of vancomycin-resistant Enterococcus faecium in immunocompromised patients in hospital. 18 Feb 2014

Enterococcus faecium (Efm), a human and animal gut commensal, has emerged as a leading nosocomial infection in immunocompromised patients. The rise of Efm has been driven by the global spread of a hospital-adapted lineage, characterised by mobile genetic elements coding for antimicrobial resistance and virulence determinants. Two further lineages are recognised, one associated with community carriage and the other livestock-associated. Vancomycin-resistant Efm (VREfm) has spread across all three lineages, and represents a significant healthcare problem responsible for outbreaks and infections in vulnerable hospitalised patients. Whole-genome sequencing (WGS) promises to close the gaps in our understanding of Efm epidemiology. I will conduct a study to investigate the hypothesis that WGS will determine the origin of VREfm in a cohort of hospitalised patients at Addenbrooke's Hospital, a centre which ranks top in VREfm bacteraemia numbers nationally. The project will consist of: i) a lo ngitudinal survey of Efm gut carriage in patients with haematological malignancy and first hospital admission and their ward contacts; ii) cross-sectional surveys of Efm in farm slurry and wastewater in the East of England; iii) WGS and bioinformatic analysis of recovered isolates to determine the origin, within-host evolution, transmission of VREfm between patients, and a possible zoonotic source.

Amount: £34,560
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Combinatorial therapeutics to target the cancer genome 10 Oct 2013

Alterations in cancer genomes strongly influence clinical responses to anti-cancer therapies and can provide potent biomarkers to identify patients most likely to benefit from treatment. Despite some notable successes, such asBRAF mutations in melanoma, and EGFR and EML4-ALK mutations in lung cancer, the majority of cancers have not been linked to a genetically matched therapeutic strategy and most drugs do not currently have associated biomarkers to direct their clinical use. New genetic targe ts and novel drug classes hold great promise, but emerging data indicate that combinations of drugs will be necessary to obtain better and durable responses. The high ordercomplexity of drug combinations, many of which are unpredictable and tissue- and genotype-specific, necessitates methodical and high throughput preclinicaltesting as all potential combinations cannot be explored in clinical trials. Our proposed research aims at providing a framework for the discovery of novelcancer thera peutics and their clinical application. Our key goals are: 1. To discover therapeutic strategies combining targeted agents so as to circumvent native or acquired drug resistance. 2. To identify and validate clinical biomarkers of drug susceptibility across a spectrum of novel compounds. 3. Useclinically-derived cells to accelerate translation of our findings into early phase clinical trials.

Amount: £2,999,973
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Exploring the biological processes underlying mutational signatures identified in cancers. 20 Nov 2012

Somatic mutations in cancer genomes have been generated by multiple DNA damage processes, the effects of which may have been mitigated by the cellular repertoire of DNA repair mechanisms. Each process will leave a characteristic imprint, or mutational signature, on the cancer genome. Our understanding of these signatures and their underlying mutational processes is remarkably limited. The overarching theme of this proposal is to explore the biological basis of mutational signatures that emerge f rom sequencing whole cancer genomes. The first aim is to systematically manipulate components of the DNA repair/replicative machinery in model systems, by targeted disruption or over-expression, followed by re-sequencing of clones to define genome-wide mutational signatures generated by these engineered abnormalities. The second main aim is to establish a resource of induced pluripotent stem cells (iPSCs) and/or lymphoblastoid cell lines (LCLs) from patients with naturally occurring germline defects in genes involved in DNA repair/replication to study mutational patterns in these patients. Thirdly, the large projected datasets generated from these experiments will require computationally demanding exploration and downstream analyses. Ultimately, experimentally generated datasets will be compared to mutational signatures extracted from large-scale sequencing of cancer genomes, giving us insight into the perturbations that happen during cancer development.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Role of early life gut microbiota in colonisation resistance development 08 Apr 2013

We are born completely sterile, but soon become colonised by complex microbial communities that shapes our immune defense for life. Disturbances in early colonisation events, such as antibiotic exposure, can lead to increased susceptibility to enteric pathogens in later life. Knowledge on the composition and diversity of a healthy gastrointestinal tract microbiota, and on how changes in the microbiota increase susceptibility to enteric infection, is incomplete. These gaps in our knowledge are du e, in large part, to a lack of mechanistic data on initial development of the microbiota during the critical early life window. Hypothesis: Early life exposure to intestinal Bifidobacteria species protects from enteric infections later in life. This timely New Investigator proposal seeks to uncover how the dominant early life microbiota genus, Bifidobacterium, colonise the host gastrointestinal tract and subsequently modulate critical resistance to enteric infection, through microbial colo nisation (termed colonisation resistance). I aim to understand how antibiotic-induced early life perturbations may alter this microbial community, ultimately leading to a breakdown in pathogen protection. Finally, I will seek to identify bifidobacterial strains and communities that can restore an early life microbiota ecosystem able to control enteric pathogen infection. We will exploit state-of-the-art genomic and culturing technologies, in combination with unique in vitro and in vivo murine mo dels, to study these early life microbiota-host interactions. Gaining further knowledge about the colonisation of pioneer bacteria, and their associated products, may provide a powerful opportunity for manipulating community restructuring after perturbations in the microbiota, which is crucial in infectious disease settings.

Amount: £73,909
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses 08 Apr 2013

The aryl hydrocarbon receptor (AhR), a ligand dependent transcription factor best known for mediating the toxic effects of xenobiotics, has recently been shown to play important roles in the immune system, although mechanistic insight is lacking. AhR is expressed in a wide range of haematopoietic cells, but also on epithelial cells interfacing with the environment, eg skin, lung, intestine. We plan to investigate the physiological functions of AhR in the immune system by generating AhR-FTAP mice to identify protein interactions with AhR in different cells types and immunological conditions to gain mechanistic insight into how AhR works. Furthermore, we will focus on the physiological regulation of AhR signaling via metabolic enzymes such as CYP1A1 that are induced by AhR activation and subsequently metabolise the agonist in a negative feedback loop. Mice with targeted deletion of the three CYP enzymes under control of AhR show increased AhR stimulation and have a range of immunological phenotypes, which we plan to explore, using infection/inflammation models targeting skin, lung or intestine. AhR deficient mice on the other hand show hyperinflammatory reactions, suggesting that interference with the regulation of AhR activation adversely affect homeostasis at these barrier sites. Analysis of mice with cell type specific AhR deletion will identify cell intrinsic consequences of defective AhR signalling. We furthermore plan to generate mice overexpressing CYP1A1 to test the hyp othesis that rapid degradation of physiological AhR ligands may result in dysregulation of immune responses at mucosal barriers sites.

Amount: £60,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Karonga Prevention Study (KPS) : whole genome sequencing in a whole population: supplementary proposal for tuberculosis whole genome sequencing 30 Nov 2011

HIV, tuberculosis and pneumococcal disease are leading causes of mortality and morbidity in Africa. They interact, and undermine development. Control measures exist but are inadequate (HIV, tuberculosis) or unproven (pneumococcus). By combining the established large-scale Karonga epidemiological studies and knowledge of long-term disease trends with detailed laboratory and genomic analysis we will: 1. measure pneumococcal carriage, transmission and serotype change at a household level fo llowing pneumococcal conjugate vaccine (PCV) introduction into the EPI schedule, trial alternate PCV schedules, and determine options to maximise vaccine benefits using modelling methods. 2. identify where M.tuberculosis is being transmitted by screening patients at antiretroviral clinics, by tuberculin testing and by defining transmission chains using whole genome sequencing, to target control efforts. 3. establish genomic determinants of virulence in M.tuberculosis by comparing s trains that have transmitted and caused disease with those that have not, and investigate long term non-progression of latent infection to better understand the host and pathogen determinants of M.tuberculosis natural history 4. assess the long-term direct and indirect benefits and limitations of antiretroviral therapy on adults and children. We will continue to develop the capacity of the site as a centre of excellence for research and training, relevant to Malawi.

Amount: £21,091
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Mechanistic role of CUX1 in haematopoiesis and leukaemogenesis and identification of therapeutic vulnerabilities in CUX1-deficient malignancies. 13 Nov 2014

Complete or partial monoallelic losses of chromosome 7 [-7/del(7q)] are recurrent lesions observed in myelodysplasia (MDS) and acute myeloid leukaemia (AML), suggesting that chromosome 7q harbours tumour suppressors that promote disease development. Although these gene targets have been elusive, we recently identified inactivating mutations in the chromosome 7q transcription factor gene, CUX1, in MDS and AML cases, thereby implicating CUX1 as a key target gene lost in -7/del(7q) MDS and AML. In support, CUX1 mutations were found to confer adverse survival similar to the poor prognosis of -7/del(7q) MDS and AML cases. This proposal firstly aims to elucidate the function of CUX1 in haematopoiesis and leukaemogenesis in vivo by using a novel conditional Cux1 knockout mouse model we have generated. Secondly, by using genome-editing and transposon-mediated expression systems to generate epitope-tagged cell lines, this proposal aims to identify CUX1 target genes and interacting proteins that are critical mediators of CUX1 function. Finally, CUX1-deficient cells will be subjected to large-scale drug-sensitivity and genome-wide genetic synthetic lethality screens to identify drugs and genetic pathways that specifically target CUX1-deficient tumours. These complementary approaches will enhance our understanding of the role of CUX1 in cancer and identify potential new treatments for these poor-prognosis disorders.

Amount: £704,856
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Deep evolutionary history of bacterial pathogens 05 Jul 2016

How old are bacterial pathogens, and what evolutionary steps have they undergone? Comparative genomics can accurately resolve recent demography and genealogy of bacterial pathogens. Some historical pathogenic lineages have also been reconstructed by taking advantage of ancient genomes (aDNA), including the causes of plague, cholera, tuberculosis and leprosy. Although ground-breaking, these lineages were relatively easy to analyse using conventional tools due to limited genetic diversity and little recombination, and prior studies on existing genomic diversity. Generating a historical framework for most bacterial pathogens that currently threaten human health, and our food supply, is much more challenging because historical records do not provide unambiguous bacterial identification. Furthermore, the long-term population structure and genealogies of most bacteria are not well defined due to high levels of genetic diversity and frequent recombination, including Salmonella enterica. We will reconstruct the long-term evolutionary history of bacterial pathogens using both metagenomic data from ancient samples and population genetic data from present-day bacteria. We will use the latest developments in aDNA sequencing, develop new bioinformatic approaches for metagenomic analyses, and create a big-data overview of modern genetic diversity. This strategy will be implemented for S. enterica, and then applied to other pathogens.

Amount: £255,764
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Generation and validation of isogenic TP53 knock-out AML cell lines for use in genome-wide drop-out screens 01 Apr 2016

Acute myeloid leukaemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed significantly for decades. To identify new therapeutic targets in AML, Dr Vassiliou's group recently performed CRISPR-Cas9 dropout screens and identified 492 AML-specific cell-essential genes, including several established anti-leukaemic drug targets and many novel therapeutic candidates. Going forward they will apply this technology to AML subtypes defined by particular somatic mutations. One subtype of AML is defined by TP53 gene mutations and is associated with an abysmal prognosis, with For this, I will design and test different gRNAs for their effectiveness in knocking-out TP53. Cas9-expressing MOLM13 and MV4-11 cell lines will be transfected (separately) with lentiviruses carrying TP53-targeting or control gRNAs. Pooled cells will then be single-cell-sorted and clones assessed for TP53 knock-out efficiency using qRT-qPCR and western blotting. The best clones will then be used for downstream genome-wide screens.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Exploring the genomes of rare childhood tumours: genetic and epigenetic driver mechanisms. 19 Nov 2015

As the first wave of cancer genome sequencing efforts conclude, studying rare tumours has emerged as a fruitful endeavour. Rare cancers have provided remarkable insights into tumour biology, with potential to be translated into patient care. Scarcity of fresh frozen tumour material, however, has precluded the study of many types of rare tumours. As massively parallel sequencing of fixed formalin paraffin embedded (FFPE) tissue is now technically feasible, sequencing rare tumours stored in p athology archives has become a tractable endeavour. I therefore propose to study rare solid childhood tumours. I intend to describe the landscape of cancer genes in 20 different tumour types (n = 200 tumours). In addition, I will define the methylome of each tumour to study whether it is a clinically useful diagnostic adjunct. A further question I propose will investigate the role of epigenetic mechanism to tumour development. In many cancers, including the bone sarcomas I studied previously, a cancer-causing (driver) variant remained elusive in some patients. A pertinent question is whether epigenetic mechanisms explain these tumours, which I will address in 25 tumours through integrative analyses of DNA, RNA, and DNA methylation sequences.

Amount: £1,227,018
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

10,000 UK genome sequences: accessing the role of rare genetic variants in health and disease. 14 Dec 2009

We propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related m etabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. We will make the sequence data we obtain available for further research purposes, empowering many additional research directions both on these samples and by imputation on further samples from the UK and beyond.

Amount: £2,932,535
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Resource centre for genomic epidemiology of malaria. 14 Dec 2009

Our goal is to understand how natural genome variation in human, Plasmodium and Anopheles populations affects the epidemiology and biology of malaria, and to use this knowledge to develop more effective ways of controlling the disease. This requires a concerted effort by many research groups around the world. We propose to establish a resource centre that will support this community effort by: - developing genome technologies and statistical methodologies to underpin global efforts to inv estigate genome variation in human, Plasmodium and Anopheles populations - building informatics systems and open-source web software for integrating and sharing large genetic and epidemiological datasets, to enable malaria researchers around the world to collaborate effectively to investigate how genome variation affects patterns of disease and biological phenotypes - providing scientific leadership in trans-ethnic genome-wide association studies of human resistance to malaria, and in de veloping a global system for monitoring Plasmodium populations by next-generation sequencing.

Amount: £485,306
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

WTCCC3 core activities. 01 Apr 2009

Not available

Amount: £1,059,350
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

The Genomics of host adaptation in campylobacter 23 Jun 2009

A comparative functional genomics approach will describe the genetic basis and ecology of host specificity and niche adaptation in Campylobacter and how this relates to the emergence of virulence. Recent advances in Illumina GA resequencing technologies, specifically isolate multiplexing, enable high-throughput sequencing of multiple genomes and open the new field of population genomics . Large in-house isolate collections, genotyped at 7 loci, are the starting point for this multidisciplin ary fellowship studying the evolution and ecology of pathogens, in three major types of experiment: (i) Genome-wide association mapping in natural populations; (ii) Quantifying adaptability and generalism in in vitro experimental evolution systems; (iii) in vivo competition experiments in specific-pathogen free chickens. Genomic experiments will describe the mechanisms and nature of adaptations to host. The competition experiments will assay the absolute fitness differences of strains with diffe rent degrees of host-adaptation and allow rigorous tests of specific adaptive hypotheses. The laboratory experiments will help to elucidate variation in genome plasticity and its relationship to host adaptation. Experimental results will feed into the Genome Evolution by Recombination and Mutation (GERM) program, designed for this project to provide a systems approach to the investigation of niche adaptation and population structuring in bacteria.

Amount: £28,335
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Sanger Costs for Annette MacLeod's SBBF (095201/Z/10/Z) - Genetic determinants of host/parasite interactions in African trypanosomiasis. 13 Apr 2011

The aim of this project is to examine the role of natural genetic variation in both the human host and parasite in determining the outcome of infection with either T.b. gambiense or T.b. rhodesiense. There is now a body of data, which shows there is variation in the factors that: (a) prevent initial host infection; and (b) determine disease severity. However, we have a relatively limited knowledge of the mechanisms involved and how genetic variation affects disease outcome. This proposal will ex ploit natural genetic variation to identify the key features and molecules involved using a combination of host association of candidate genes, parasite population genomics and molecular analysis of trypanolytic complexes present in serum. In addition, the proposal will create a large genomic sequence resource of >140 parasite strains together with a biobank of the parasites strains for those working in other areas. Thus, by dissecting some of the key components of both host and parasite which are determinants of infection and disease outcome, a series of pathways and molecules will be identified which could be the targets of novel interventions aimed at preventing or controlling the disease.

Amount: £118,679
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Does treatment of invasive and persistent non-typhoid Salmonella in HIV-infected African adults cause evolution of antibiotic resistance? 16 Jun 2010

Multi-drug-resistant non-Typhoid-Salmonella (NTS) are a serious, emerging infection in HIV-infected African adults. In Blantyre, Malawi, NTS are a common cause of bacteraemia with a 25% case-fatality. Survivors are at high risk of recrudescence of invasive NTS (iNTS), necessitating multiple courses of ciprofloxacin, yet the sanctuary site of persistence remains unknown. Resistance (MIC) to ciprofloxacin has risen gradually since it was introduced in 2002, and threatens to spread among NTS and ot her major pathogens. Recent high-throughput whole-genome sequencing has shown that novel epidemic iNTS strains in Sub-Saharan Africa have become more human-adapted, with genetic similarities to S.Typhi. A cohort of HIV-infected adults with iNTS and their spouses will therefore be recruited to: 1) Evaluate mechanisms of persistence and clinical outcomes of iNTS, in the era of rapid anti-retroviral(ARV) roll-out 2) Investigate how iNTS persistence influences the emergence of fluoroquinolon e resistance following repeated ciprofloxacin treatment 3) Determine how iNTS persistence influences further NTS human-adaptation and microevolution. These data, including high-throughput sequencing and SNP-typing of isolates, will inform the design of alternative interventions that prevent episodes of iNTS without promoting antibiotic resistance; and generate locally-implementable molecular tools to further understand the dynamics of molecular evolution of epidemic MDR-NTS in individuals an d populations.

Amount: £8,594
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute