NIHRDataInsights/HRCSData huggingface dataset:
Title: Bioinformatics and Regulatory Genomics
Funder: Medical Research Council

Abstract: Recent advances in high throughput sequencing efficiency have begun to revolutionize our view of vertebrate genome structure. It is now possible to probe the intricacies of chromatin structure and function across the genome at high resolution, and study their dynamics across development, disease and evolutionary time. We intend to strengthen our position at the intersections between comparative genomics, transcriptomics and epigenomics, exploiting the flood of new sequence data from human and model organism genomes to investigate vertebrate evolution, development and human disease. We want to understand the impact of chromatin structure on the functional repertoire and evolution of the vertebrate genome. We aim to develop novel computational approaches to high throughput data analysis, and to provide new insights into transcriptional regulation. We will continue our established studies of promoter activities and evolution, and of chromatin structure and mutation rate. We have extended our work into novel areas such as divergence in higher order chromatin structure and the relationships between chromatin structure and complex trait loci. We are well placed to test hypotheses generated by our investigations, through established and new collaborations with experimental scientists, both within and outside the HGU and IGMM. We have three specific research objectives. (1) We will extend our studies of promoter function and evolution, to novel analyses of promoter activity dynamics between cell types and species. We hope to discover new constellations of loci under common regulatory influences, and to define regulatory landscapes playing important roles during evolution or disease. (2) We will explore the divergence of chromatin structure across cell types and over mammalian evolution. We will continue our work examining the interplay between structural and underlying sequence level divergence, to shed light on the variability in mutation rates found across the vertebrate genome. In parallel we will investigate the relationships between the panoply of lower level chromatin variants (histone modifications and variants, DNA methylation etc) and higher levels of structural organization (chromatin domains, replication timing and nuclear lamina association). (3) We will probe the relationships between chromatin structure and the genetic architecture of complex traits. We will conduct searches for heritable human sequence variants associated with allele-specific chromatin structure and seek to validate their effects on function. We will also interrogate the results of GWAS to identify examples of disease risk mediated by chromatin structure.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Nutrition, Development and Lifelong Health: Studies in European Populations
Funder: Medical Research Council

Abstract: Objective: To (a) define the early environmental determinants of later chronic disease and their mechanistic basis, and (b) translate this work into policy measures and interventions to improve public health. We aim to: (1) maximise the potential of the ERC cohorts to enable the definition of developmental influences on major childhood and adult disorders, and examine hypotheses relating to prenatal/postnatal mismatch, epigenetic processes and economic consequences; and (2) conduct intervention studies in young women to improve their health and that of their children. Research proposals: Within the SWS and our other mother-offspring cohorts we shall examine the hypothesis that maternal and lifestyle influences from before conception, and mismatches between the fetal/infant and later childhood environment, have detrimental effects on body composition, cardiovascular structure and function, respiratory disease and atopy, and cognition. Data from Helsinki and from other European cohorts will be used to increase our understanding of influences on major adult disorders, notably cardiovascular disease and cancer. Within our EpiGen consortium we aim to define epigenetic biomarkers of later disease risk that will inform intervention studies. Our data resources spanning the lifecourse provide opportunities for comprehensive mechanistic and behavioural insights into chronic diseases and markers at different stages of life. Moreover, in an international collaboration we are defining the economic consequences of a poor start to life, which will inform public health policy and assess the potential impact of focused interventions. Finally, our work has led to four interventions to improve the diets and health behaviours of young women. Three of these target women in pregnancy. The fourth focuses on women of child-bearing age who already have young children. The aim is to improve the health of the women prior to any subsequent pregnancy and that of their children. Impact: Our work contributes to three current MRC research priorities: clinical and public health research, ageing-related research, and biomarkers. The work has a strong clinical and public health focus, our lifecourse approach increases understanding of ageing, and our work on epigenetic processes aims to identify biomarkers that assist in the characterisation of new interventions to improve public health. Our cohort studies will provide evidence as to whether mismatches between the maternal, infant and childhood environments are associated with cardiovascular risk, impaired respiratory health, cognitive development, and obesity. Our intervention studies will provide translational data on the benefits of better nutrition of young women, and have the potential to improve the health of women and children now, and that of future generations.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Causal analyses, statistical efficiency and phenotypic precision through study design: Genotype based sampling
Funder: Medical Research Council

Abstract: A full understanding of the biological underpinnings of health and disease requires appropriate use of genomic data with high quality phenotypic measures. However the exhaustive collection of phenotypic measurements in large studies is impractical and not the most efficient approach to the allocation of finite resources. Therefore the targeted measurement of dense or precise phenotypic characteristics within selected groups is appealing. This programme will comprehensively assess and test the use of genotypes known to be correlated with features of interest, or which require further examination given unexplained correlations with disease, to define strata or subsamples for intense or directed phenotypic data collection. This will allow examination of detailed phenotypic information in financially and pragmatically feasible sample sizes, with analytical power optimized for measurement depth and precision. The motivation for employing genotypic data in this way is the pursuit of causal relationships based on the Mendelian randomization paradigm. This programme will develop and apply Recall By Genotype (RBG): a study design where the recruitment of a sub-set of participants from an existing study, analysis of their biosamples or collection of new data is undertaken on the basis of measured genotypic variation. This work falls naturally into the MRC University of Bristol Integrated Epidemiology Unit (IEU) midway between methodological development and application and intervention, since it aims to (i) develop methods for incorporating prior knowledge of genotype into study design; and (ii) to apply this approach to specific clinical examples. The development of RBG is boundary-pushing as it directly addresses the integration of genetic data into study design, harnesses the theoretical developments around causal inference derived from Mendelian randomization and combines these within study frameworks suitable for the collection of ground-breaking phenotypic data. There are numerous benefits to this approach, however central to this programme is causal inference and the ability of RBG to capture this in relationships observed across strata assigned solely on the basis of genetic variation. This programme will produce an operational toolkit for the application of RBG within MRC/UoB IEU and elsewhere, and will initiate a series of novel studies which will progress into an established programme of genotype-driven study designs.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Determinants, Consequences and Modification of Health Behaviours
Funder: Medical Research Council

Abstract: Modifiable lifestyle health behaviours, such as tobacco use, alcohol consumption, exercise and dietary behaviour reflect the primary modifiable causes of morbidity and mortality in developed countries such as the United Kingdom. Despite concerted public health campaigns, in some cases over several decades, the prevalence of unhealthy lifestyle behaviours remains high, and in many cases is strongly socially patterned, contributing substantially to health inequalities. Understanding the developmental trajectories of, and pathways into, these behaviours is therefore necessary if we are to develop new interventions, in order to improve individual and public health, and reduce associated personal and societal harms. In addition, although some of the negative health and mental health consequences of these behaviours are known, many are not, or remain controversial. A more complete understanding of the consequences of these behaviours will also inform public health campaigns and other interventions. This programme will focus initially on tobacco and alcohol use, as two of the largest contributors to morbidity and premature mortality in developed countries, and extend this work into other health behaviours (e.g., caffeine use, overeating and obesity, exercise). The work will proceed along three parallel workstreams, to address three primary aims: 1) to understand the developmental trajectories and determinants of health behaviours; 2) to conduct causal analyses of the causes and consequences of health behaviours; and 3) to develop interventions to modify health behaviours in adolescence and adulthood. This work will be integrated across the other programmes within the MRC University of Bristol Integrative Epidemiology (IEU) Unit, making use of methodological developments in Mendelian randomization (including the use of allelic risk scores), epigenetics, and recall-by-genotype methods, as well as conventional epidemiological and experimental methods. Ultimately, we aim to provide a much more detailed understanding of the factors that lead to unhealthy lifestyle behaviours, and clarify the impact of these behavioural on physical and mental health where this remains uncertain. This, in turn, will enable us to develop interventions to modify health behaviours at an individual and population level.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing Novel Methods of Data Capture in Epidemiological Studies
Funder: Medical Research Council

Abstract: As internet, smartphone, tablet computer and sensor technologies develop, it is becoming increasingly possible to collect detailed behavioural data through active and passive means using these technologies. This has the potential to dramatically increase the quality and reach of data collected in epidemiological studies and clinical trials. In particular, it enables the collection of data in naturalistic settings, including the home environment, which should in principle increase the validity of the data collected compared with clinic assessments. We aim to develop accurate and efficient tools for measurement of variables from molecules to lifestyles. A key component of this work will be the advancement of novel methods, such as remote sensing, digital data harvesting, biosensing and biomarkers of behaviours. We will work in areas that reflect expertise across the University of Bristol, such as diet and nutrition, smoking and cardiometabolic biomarkers and will also collaborate closely with other MRC units/centres and international groups as relevant, and to avoid inefficiency and duplication. Such data collection will be linked to the extensive series of ongoing national and international cohort studies and randomised controlled trials with which we have existing links. The primary aim of this work is to deliver research capability which can be piloted and implemented across the research programmes within the Unit, and then used in future data collection sweeps in ongoing cohort studies and associated sub-studies. The platforms we develop for data capture will also be tested for the potential value in delivering interventions (e.g., behaviour change).


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Data mining and bioinformatics cross-cutting theme
Funder: Medical Research Council

Abstract: A core feature of the Unit will be the generation, storage and analysis of large volumes of epidemiological and “omics” (genomic, epigenomic, metabolomic and metagenomic) data from a range of cohort studies. The Data Mining and Bioinformatics theme will be responsible for the development of novel tools and strategies to access, integrate, merge, visualise and analyse the multi-dimensional datasets within and across the various studies involved in the Unit Programmes. In particular the application of data mining and machine learning algorithms will allow hypothesis-free approaches to data interrogation (Programme 1), which can be followed by hypothesis testing in the other Programmes. Bioinformatics will also underpin the genetic, epigenetic and omics association studies that will be undertaken in all of the Programmes. Objectives and plans: Integration of diverse data types, including large-scale “omics” datasets: integration of very high-dimensional omics data to facilitate data mining and specific hypothesis-based analyses. Filtering and annotation of omics association results: integration of internally generated data with public data from projects such as ENCODE, the NIH roadmap epigenomics project and others to prioritise and filter results. Developing approaches for combining variables in omics data: collapsing and dimensionality-reduction approaches will be developed and applied to reduce the computational burden of association analysis between high-dimensional omics datasets. Development of methods for hypothesis-free mining of complex data: using allele-score based approaches to de novo identification of potential causal relationships across a wide range of phenotypes/outcomes. Training in bioinformatics and data-mining: specific training will be developed to build in-house skills in bioinformatics and data mining methodology in the context of high-dimensional data. This theme will further develop the existing core expertise in bioinformatics and data mining to enable Unit researchers to work effectively with the data generated by the Unit and collaborators. The new methods developed will be of broad applicability in the field of molecular epidemiology, and the Unit will train a new cadre of researchers with essential skills in medical bioinformatics.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Statistics and Econometrics Methodology
Funder: Medical Research Council

Abstract: (around 400 words – max. 3,500 characters including spaces) Aim: The aim of this programme is to develop methods for causal inference that are robust to missing data and can investigate change over time, in order to draw unbiased conclusions about realistic problems, using complex observational data. Importance: Causal inference methods - in particular instrumental variable (IV) and Mendelian randomization (MR) methods - are now straightforward to implement, can be used with summary data, and are widely used by epidemiologists and medical researchers. However, the majority of real-world clinical research settings are more complex than the standard methods allow: data are missing; samples are selected; exposures and outcomes evolve jointly over time; and data from a wide variety of sources need to be integrated. Methods for causal inference, including IV, may be biased by missing data, including individuals missing due to sample selection. Standard IV methods are not able to address complex (and possibly time-varying) relationships between exposure, covariates and outcome. Multiple studies may provide information about the same causal effect, or about different paths in a network of causal effects, and we need to develop better methods to integrate evidence from different study types in order to draw causal inferences. Objectives: 1. Develop methods to minimise bias due to missing data 2. Develop methods to model complex exposures and outcomes 3. Develop IV methods to examine causal influences of multiple exposures 4. Integrate evidence to improve causal models Research plans: Part 1 of this programme will develop methods to use study information, and information external to the study, to infer the missing data structure, to inform all types of causal analyses. We will then focus on methods to maximise the robustness of IV methods to different types of missing data. We will pay particular attention to two cases: two-sample IV (using individual or summary data), and the investigation of disease prognosis. Part 2 will extend current methods for modelling trajectories and variability of exposures and outcomes. We will then focus on overcoming some of the current limitations of IV methods, by using structural equation modelling (SEM) and multivariable IV to examine impacts of time-varying exposures. Finally, we will maximise the use of all research data by extending methods to combine and use external information to inform causal models and sensitivity analyses.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of genome stability by FAN1 and SLX4
Funder: Medical Research Council

Abstract: Defects in DNA repair or in the ability of cells to slow cell cycle progression after DNA damage can increase cellular mutation rates and cause genome instability leading to variety of debilitating diseases that are accompanied by heightened predispostion to cancer. DNA lesions trigger a highly conserved signal transduction pathway that regulates many aspects of the cellular response to DNA damage and the principal regulators of this pathway are the ATM and ATR protein kinases, critical regulators of genome stability. These kinases rapidly translocate to sites of DNA damage or to stalled DNA replisomes where they are activated by mechanisms that are not yet clear. This causes phosphorylation of a range of proteins including the BRCA1 and p53 tumour suppressors, and the conserved Chk1 and Chk2 protein kinases that when activated by ATM/ATR in turn phosphorylate effectors of cell cycle progression. It is still not known how they carry out many of their cellular functions at the molecular level. For example, it is not clear how ATM and ATR increase cellular DNA repair capacity, how ATR prevents firing of origins of replication when the DNA replication machinery stalls, how these kinases restore chromatin configuration after DNA damage or how they promote recovery from DNA damage. The main goal of my laboratory is to understand how ATM/ATR regulate these processes. We are using several approaches biochemical, genetic and structural - to investigate how ATM/ATR recognise their substrates, what these substrates are, and how these targets contribute to the maintenance of genome stability. We are also using yeast to investigate how, at the molecular level, stalled replisomes bypass replication fork-blocking lesions.We identified several new targets of ATM and ATR and have investigated their cellular functions using budding yeast as a model organism. Phosphorylation of Esc4 by ATR, for example, is essential for the resumption of DNA replication when the DNA replication apparatus stalls at sites of DNA damage. Another new target of ATM and ATR, Slx4, prevents abnormal DNA structures from arising in the vicinity of stalled replication forks. Recently we found that Slx4 is an important regulator of the ability of stalled replisomes to bypass replisome-blocking lesions and we are currently investigating the molecular mechanisms involved. We are currently studying human Slx4-containing complexes and their role(s) in maintenance of genome stability. In mammalian cells we have shown that phosphorylation of the 53BP1 tumour suppressor at Ser25 by ATM caused 53BP1 to physically associate with the hPTIP mediator protein that we identified previously. Interaction of these two proteins is essential for intact responses to DNA damage and we are currently investigating this at the molecular level.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Chromosome Replication and the Regulation of Genome Integrity
Funder: Medical Research Council

Abstract: My group aims to understand how the molecular machinery at DNA replication forks allows eukaryotic cells to preserve their highly complex chromosomes from one generation to the next. One of the most important challenges for proliferating cells is to make a single and precise copy of each chromosome before cell division. In eukaryotes this is a particularly complex task, involving the duplication of vast amounts of DNA, the reproduction of epigenetic chromatin modifications along each chromosome, and other tasks such as the establishment of cohesion between the two sister chromatids that are the products of replication. For these reasons, chromosome replication is one of the most complex and fascinating of all cellular processes in eukaryotes, with mechanisms and regulation that are still understood poorly in all species. A better understanding of chromosome replication is particularly important from the viewpoint of human cancer, since defects in chromosome replication are a very early feature in cancer development, providing a target for the future development of new therapies that might selectively kill cancer cells. Many of the proteins involved in chromosome replication associate with each other to form a multi-protein assembly known as the replisome, which physically connects the essential DNA helicase that unwinds the parental duplex, to the DNA polymerases and other factors. My group is focussed on defining the nature of eukaryotic replisome, understanding its mechanisms of action, and studying its regulation by post-translational modifications. Most of the proteins that we study have a single orthologue from humans to yeast, reflecting the very high degree of conservation of the eukaryotic replisome, and indicating the value of using simple experimental systems. Our work exploits the unique advantages of budding yeast for studies of chromosome replication, combining state of the art biochemical and genetic techniques, but we are also extending our work into other species where appropriate, including mammalian cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE