MRC Human Genetics Unit
MRC Human Genetics Unit
News Article | April 24, 2017
The incidence of bile duct cancer (cholangiocarcinoma) is increasing year on year throughout the world. More than 2,500 people will be diagnosed with this cancer in the UK in the next year and for most this will be a lethal diagnosis. Fewer than 5% will survive for 12 months – an appalling statistic which hasn’t changed in decades. In light of this, UK’s leading charity dedicated to bile duct cancer, AMMF, will bring together scientists, researchers, medics and patients from across the globe at its third Conference and Information Day dedicated exclusively to bile duct cancer, on 11 May, 2017 at the Radisson Blu Hotel, Stansted Airport, Essex. Amongst AMMF-funded researchers who will be presenting updates on their work at this year’s AMMF Conference, will be Professor Stuart Forbes from the MRC Centre for Regenerative Medicine, explaining his research into the signals Wnt and Notch which are thought to drive the growth of cholangiocarcinoma. In addition, Dr Luke Boulter from Edinburgh’s Institute of Genetics & Molecular Medicine will be discussing his very promising work, “Discovering driver mutations in cholangiocarcinoma using forward genetics”. The work of both these teams, if successful, could bring closer some ‘game changing’ treatment targets for cholangiocarcinoma. This year’s Conference also sees Professor Narong Khuntikeo from Khon Kaen University, Thailand presenting the work of the CASCAP (Cholangiocarcinoma Screening and Care Program) team in north east Thailand, which has the world’s highest incidence of cholangiocarcinoma. Professor Khuntikeo is vice-president of the Cholangiocarcinoma Foundation of Thailand and recipient of The Royal College of Surgeons of Thailand Outstanding Surgeon Honours Award 2016. Conference to highlight latest surgical treatments and targeted therapies for bile duct cancer Other topics to be addressed at this year’s Conference will include the latest surgical developments in the treatment of bile duct cancer, updates on clinical trials, and the status of targeted therapies for cholangiocarcinoma. Helen Morement, founder and CEO of the AMMF explains, “Although bile duct cancer is the second most common primary liver cancer in the world, with an increasing incidence globally, and despite its appalling survival rates due to late diagnosis and few treatment options, it remains poorly understood and under researched. The Conference is a key platform for an international panel of experts to share news and information about clinical studies and latest research. The findings bring the prospect of early diagnosis and more effective treatments one step closer.” Helen continues, “We are especially delighted that Professor Richard Syms from Imperial College London, who is also working collaboratively with the team at Khon Kaen University on an AMMF-funded internal imaging project, will be presenting the positive early results of this work at the Conference.” Bile duct cancer is a rare cancer that occurs in the bile duct in or outside the liver. With few noticeable and often misunderstood symptoms, this disease is frequently diagnosed too late for surgery, the only potentially curative treatment. Without treatment fewer than 5% of patients will survive beyond 12 months. Cases of bile duct cancer have risen steeply and steadily across the world over the past decades. According to the recent NCIN/Cancer52 report, 2,161 people died in 2013 from this disease in England alone. About AMMF AMMF (The Alan Morement Memorial Fund) was founded and registered as a charity with the Charity Commission in 2002 (registered charity no 1091915). AMMF is the UK’s only cholangiocarcinoma charity, dedicated to tackling this devastating cancer on all fronts: providing information and support, campaigning to raise awareness, and encouraging and supporting research. In recent years an enormous and extremely worrying worldwide increase in cholangiocarcinoma’s incidence has been noted. Latest figures show there were 2,161 deaths caused by cholangiocarcinoma in 2013 in England alone (NCIN/Cancer52 report). The incidence appears to be increasing across all age groups, including younger people, and the cause of this ongoing increase is unknown. Much more research is desperately needed. AMMF is dedicated to bringing about improvement for the cholangiocarcinoma patient, working closely throughout the UK with patients, families, carers, clinicians, healthcare professionals, researchers, politicians and policy makers. For more information visit: www.ammf.org.uk (registered charity no.1091915). About the Conference & Information Day AMMF is not making a charge for attendance at the conference; it is open to all who have an interest in cholangiocarcinoma. However, if delegates would like to help to offset costs, a suggested donation of £25 per head can be made to the AMMF 2017 Conference Justgiving Page by clicking here: https://www.justgiving.com/fundraising/AMMF-Charity2 About the MRC Centre for Regenerative Medicine at the University of Edinburgh The MRC Centre for Regenerative Medicine (CRM) is a research institute based at the University of Edinburgh. Scientists and clinicians study stem cells, disease and tissue repair to advance human health. For more information please visit: http://www.crm.ed.ac.uk/ About the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh (IGMM). The MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh (IGMM), formed in 2007, is a strategic partnership of the: • MRC Human Genetics Unit (MRC HGU) • Cancer Research UK Edinburgh Centre (CRUK EC) • Centre for Genomic and Experimental Medicine (CGEM). The IGMM constitutes one of the largest aggregates of human molecular genetics and biology research capacity in the UK with over 70 Principal Investigators and 500 staff and PhD students. By pooling the resources and complementary skills of the constituent centres, IGMM brings together the scientific expertise, technology and support services needed to maximise scientific discovery. The Institute enables rapid translation of basic scientific discoveries into new treatments, clinical guidelines and innovative products that have significant impact on the society in the UK and Worldwide. For more information please visit: http://www.ed.ac.uk/igmm/about About CASCAP (Cholangiocarcinoma Screening and Care Program), Thailand CASCAP stands for the Cholangiocarcinoma Screening and Care Program. The aim of CASCAP is to accelerate the transition of CCA from being a neglected disease to being on the public health national agenda. Its specific focus is to develop and make available a high quality database of compiled information about CCA in the region, to determine the optimal screening program for early diagnosis to maximize the success of surgical treatment, and to increasing both the quality of life and long-term survival of patients. For more information please visit http://www.cascap.info/main/index.php/about-us/about-cascap.html National Cancer Intelligence Network (NCIN) and Cancer52 For more information please visit: http://www.ncin.org.uk/publications/rare_and_less_common_cancers For media inquiries and interviews, please contact: ESTHER PORTA, 3CommPR LONDON, United Kingdom 07870439158 email@example.com The post Why latest work from top UK cancer researchers could hold potential for future ‘game-changing’ treatments for rare bile duct cancer, cholangiocarcinoma appeared first on PR Fire.
Lian G.,Beth Israel Deaconess Medical Center |
Lu J.,Beth Israel Deaconess Medical Center |
Hu J.,Beth Israel Deaconess Medical Center |
Zhang J.,Beth Israel Deaconess Medical Center |
And 3 more authors.
Journal of Neuroscience | Year: 2012
Cytoskeleton-associated proteins play key roles not only in regulating cell morphology and migration but also in proliferation. Mutations in the cytoskeleton-associated gene filamin A (FlnA) cause the human disorder periventricular heterotopia (PH). PH is a disorder of neural stem cell development that ischaracterized by disruption of progenitors along the ventricular epithelium and subsequent formation of ectopic neuronal nodules. FlnA-dependent regulation of cytoskeletal dynamics is thought to direct neural progenitor migration and proliferation. Here we show that embryonic FlnA-null mice exhibited a reduction in brain size and decline in neural progenitor numbers over time. The dropinthe progenitor population was not attributable to cell death or changes in premature differentiation, but to prolonged cell cycle duration. Suppression of FlnA led to prolongation of the entire cell cycle length, principally in M phase. FlnA loss impaired degradation of cyclin B1-related proteins, thereby delaying the onset and progression through mitosis. We found that the cdk1 kinase Wee1 bound FlnA, demonstrated increased expression levels after loss of FlnA function, and was associated with increased phosphorylation of cdk1. Phosphorylation of cdk1 inhibited activation of the anaphase promoting complex degradation system, which wasresponsibleforcyclinB1degradationandprogressionthrough mitosis. Collectively, our results demonstrate a molecular mechanism whereby FlnA loss impaired G2 to M phase entry, leading to cell cycle prolongation, compromised neural progenitor proliferation, and reduced brain size. © 2012 the authors.
News Article | December 10, 2015
An interactive Periodic Table of Protein Complexes is available at http://sea31.user.srcf.net/periodictable/. Credit: EMBL-EBI / Spencer Phillips The Periodic Table of Protein Complexes, published today in Science, offers a new way of looking at the enormous variety of structures that proteins can build in nature, which ones might be discovered next, and predicting how entirely novel structures could be engineered. Created by an interdisciplinary team led by researchers at the Wellcome Genome Campus and the University of Cambridge, the Table provides a valuable tool for research into evolution and protein engineering. Almost every biological process depends on proteins interacting and assembling into complexes in a specific way, and many diseases are associated with problems in complex assembly. The principles underpinning this organisation are not yet fully understood, but by defining the fundamental steps in the evolution of protein complexes, the new 'periodic table' presents a systematic, ordered view on protein assembly, providing a visual tool for understanding biological function. "Evolution has given rise to a huge variety of protein complexes, and it can seem a bit chaotic," explains Joe Marsh, formerly of the Wellcome Genome Campus and now of the MRC Human Genetics Unit at the University of Edinburgh. "But if you break down the steps proteins take to become complexes, there are some basic rules that can explain almost all of the assemblies people have observed so far." Different ballroom dances can be seen as an endless combination of a small number of basic steps. Similarly, the 'dance' of protein complex assembly can be seen as endless variations on dimerization (one doubles, and becomes two), cyclisation (one forms a ring of three or more) and subunit addition (two different proteins bind to each other). Because these happen in a fairly predictable way, it's not as hard as you might think to predict how a novel protein would form. "We're bringing a lot of order into the messy world of protein complexes," explains Sebastian Ahnert of the Cavendish Laboratory at the University of Cambridge, a physicist who regularly tangles with biological problems. "Proteins can keep go through several iterations of these simple steps, , adding more and more levels of complexity and resulting in a huge variety of structures. What we've made is a classification based on these underlying principles that helps people get a handle on the complexity." The exceptions to the rule are interesting in their own right, adds Sebastian, as are the subject of on-going studies. "By analysing the tens of thousands of protein complexes for which three-dimensional structures have already been experimentally determined, we could see repeating patterns in the assembly transitions that occur - and with new data from mass spectrometry we could start to see the bigger picture," says Joe. "The core work for this study is in theoretical physics and computational biology, but it couldn't have been done without the mass spectrometry work by our colleagues at Oxford University," adds Sarah Teichmann, Research Group Leader at the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust Sanger Institute. "This is yet another excellent example of how extremely valuable interdisciplinary research can be." More information: "Principles of assembly reveal a periodic table of protein complexes" www.sciencemag.org/lookup/doi/10.1126/science.aaa2245
News Article | December 11, 2015
Researchers have devised a periodic table of protein complexes, making it easier to visualize, understand and predict how proteins combine to drive biological processes. A new ‘periodic table’ of protein complexes, devised by an interdisciplinary team of researchers, provides a unified way to classify and visualize protein complexes, which drive a huge range of biological processes, from DNA replication to catalyzing metabolic reactions. The table, published in the journal Science, offers a new way of looking at almost all known molecular structures and predicting how new ones could be made, providing a valuable tool for research into evolution and protein engineering. By using the table, researchers are able predict the likely forms of protein complexes with unknown structure, estimate the feasibility of entirely new structures, and identify possible errors in existing structural databases. It was created by an interdisciplinary team led by researchers at the University of Cambridge and the Wellcome Genome Campus. Almost every biological process depends on proteins interacting and assembling into complexes in a specific way, and many diseases, such as Alzheimer’s and Parkinson’s, are associated with problems in complex assembly. The principles underpinning this organization are not yet fully understood, but the new periodic table presents a systematic, ordered view on protein assembly, providing a visual tool for understanding biological function. “We’re bringing a lot of order into the messy world of protein complexes,” said the paper’s lead author Sebastian Ahnert of Cambridge’s Cavendish Laboratory, a physicist who regularly tangles with biological problems. “Proteins can keep combining in these simple ways, adding more and more levels of complexity and resulting in a huge variety of structures. What we’ve made is a classification based on underlying principles that helps people get a handle on the complexity.” The exceptions to the rule are interesting in their own right, added Ahnert, and are the subject of continuing studies. “Evolution has given rise to a huge variety of protein complexes, and it can seem a bit chaotic,” said study co-author Joe Marsh, formerly of the Wellcome Genome Campus and now of the MRC Human Genetics Unit at the University of Edinburgh. “But if you break down the steps proteins take to become complexes, there are some basic rules that can explain almost all of the assemblies people have observed so far.” Ballroom dancing can be seen as an endless combination of riffs on the waltz, fox trot and cha-cha. Similarly, the ‘dance’ of protein complex assembly can be seen as endless variations on dimerization (one doubles, and becomes two), cyclisation (one forms a ring of three or more) and subunit addition (two different proteins bind to each other). Because these happen in a fairly predictable way, it’s not as hard as you might think to predict how a novel protein would form. Some protein complexes, called homomers, feature multiple copies of a single protein, while others, called heteromers, are made from several different types of proteins. The table shows that there is a very close relationship between the possible structures of heteromers and homomers. In fact, the vast majority of heteromers can be thought of as homomers in which the single protein is replaced by a repeated unit of several proteins. The table was constructed using computational analysis of a large database of protein-protein interfaces. “By analyzing the tens of thousands of protein complexes for which three-dimensional structures have already been experimentally determined, we could see repeating patterns in the assembly transitions that occur – and with new data from mass spectrometry we could start to see the bigger picture,” said Walsh. “The core work for this study is in theoretical physics and computational biology, but it couldn’t have been done without the mass spectrometry work by our colleagues at Oxford University,” said Sarah Teichmann, Research Group Leader at the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust Sanger Institute. “This is yet another excellent example of how extremely valuable interdisciplinary research can be.”
Cotterell J.,EMBL CRG Systems Biology Research Unit |
Cotterell J.,MRC Human Genetics Unit |
Sharpe J.,EMBL CRG Systems Biology Research Unit |
Sharpe J.,Catalan Institution for Research and Advanced Studies
Molecular Systems Biology | Year: 2010
The interpretation of morphogen gradients is a pivotal concept in developmental biology, and several mechanisms have been proposed to explain how gene regulatory networks (GRNs) achieve concentration-dependent responses. However, the number of different mechanisms that may exist for cells to interpret morphogens, and the importance of design features such as feedback or local cell-cell communication, is unclear. A complete understanding of such systems will require going beyond a case-by-case analysis of real morphogen interpretation mechanisms and mapping out a complete GRN 'design space.' Here, we generate a first atlas of design space for GRNs capable of patterning a homogeneous field of cells into discrete gene expression domains by interpreting a fixed morphogen gradient. We uncover multiple very distinct mechanisms distributed discretely across the atlas, thereby expanding the repertoire of morphogen interpretation network motifs. Analyzing this diverse collection of mechanisms also allows us to predict that local cell-cell communication will rarely be responsible for the basic dose-dependent response of morphogen interpretation networks. © 2010 EMBO and Macmillan Publishers Limited. All rights reserved.
Vandiedonck C.,University of Oxford |
Vandiedonck C.,French Institute of Health and Medical Research |
Vandiedonck C.,University Paris Diderot |
Taylor M.S.,University of Oxford |
And 8 more authors.
Genome Research | Year: 2011
The human major histocompatibility complex (MHC) on chromosome 6p21 is a paradigm for genomics, showing remarkable polymorphism and striking association with immune and non-immune diseases. The complex genomic landscape of the MHC, notably strong linkage disequilibrium, has made resolving causal variants very challenging. A promising approach is to investigate gene expression levels considered as tractable intermediate phenotypes in mapping complex diseases. However, how transcription varies across the MHC, notably relative to specific haplotypes, remains unknown. Here, using an original hybrid tiling and splice junction microarray that includes alternate allele probes, we draw the first high-resolution strand-specific transcription map for three common MHC haplotypes (HLA-A1-B8-Cw7-DR3, HLA-A3-B7-Cw7-DR15, and HLA-A26-B18-Cw5-DR3-DQ2) strongly associated with autoimmune diseases including type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. We find that haplotype-specific differences in gene expression are common across the MHC, affecting 96 genes (46.4%), most significantly the zing finger protein gene ZFP57. Differentially expressed probes are correlated with polymorphisms between haplotypes, consistent with cis effects that we directly demonstrate for ZFP57 in a cohort of healthy volunteers (P = 1.2 × 10-14). We establish that alternative splicing is significantly more frequent in the MHC than genome-wide (72.5% vs. 62.1% of genes, P ≤ 1 × 10-4) and shows marked haplotypic differences. We also unmask novel and abundant intergenic transcription involving 31% of transcribed blocks identified. Our study reveals that the renowned MHC polymorphism also manifests as transcript diversity, and our novel haplotype-based approach marks a new step toward identification of regulatory variants involved in the control of MHCassociated phenotypes and diseases. © 2011 by Cold Spring Harbor Laboratory Press.
Cotterell J.,EMBL CRG Systems Biology Research Unit |
Cotterell J.,MRC Human Genetics Unit |
Sharpe J.,EMBL CRG Systems Biology Research Unit |
Sharpe J.,Catalan Institution for Research and Advanced Studies
PLoS ONE | Year: 2013
The extent and the nature of the constraints to evolutionary trajectories are central issues in biology. Constraints can be the result of systems dynamics causing a non-linear mapping between genotype and phenotype. How prevalent are these developmental constraints and what is their mechanistic basis? Although this has been extensively explored at the level of epistatic interactions between nucleotides within a gene, or amino acids within a protein, selection acts at the level of the whole organism, and therefore epistasis between disparate genes in the genome is expected due to their functional interactions within gene regulatory networks (GRNs) which are responsible for many aspects of organismal phenotype. Here we explore epistasis within GRNs capable of performing a common developmental function - converting a continuous morphogen input into discrete spatial domains. By exploring the full complement of GRN wiring designs that are able to perform this function, we analyzed all possible mutational routes between functional GRNs. Through this study we demonstrate that mechanistic constraints are common for GRNs that perform even a simple function. We demonstrate a common mechanistic cause for such a constraint involving complementation between counter-balanced gene-gene interactions. Furthermore we show how such constraints can be bypassed by means of "permissive" mutations that buffer changes in a direct route between two GRN topologies that would normally be unviable. We show that such bypasses are common and thus we suggest that unlike what was observed in protein sequence-function relationships, the "tape of life" is less reproducible when one considers higher levels of biological organization. © 2013 Cotterell, Sharpe.
Wong T.H.,University of Edinburgh |
Jackson I.J.,MRC Human Genetics Unit |
Rees J.L.,University of Edinburgh
Experimental Dermatology | Year: 2010
Experimental study of the in vivo kinetics of tanning in human skin has been limited by the difficulties in measuring changes in melanin pigmentation independent of the ultraviolet-induced changes in erythema. The present study attempted to experimentally circumvent this issue. We have studied erythemal and tanning responses following a single exposure to a range of doses of ultraviolet B irradiation on the buttock and the lower back in 98 subjects. Erythema was assessed using reflectance techniques at 24 h and tanning measured as the L* spectrophotometric score at 7 days following noradrenaline iontophoresis. We show that dose (. P < 0.0001), body site (. P < 0.0001), skin colour (. P < 0.0001), ancestry (. P = 0.0074), phototype (. P = 0.0019) and sex (. P = 0.04) are all independent predictors of erythema. Quantitative estimates of the effects of these variables are reported, but the effects of ancestry and phototype do not appear solely explainable in terms of L* score. Dose (. P < 0.0001), body site (. P < 0.0001) and skin colour (. P = 0.0365) or, as an alternative to skin colour, skin type (. P = 0.0193) predict tanning, with those with lighter skin tanning slightly more to a defined UVB dose. If erythema is factored into the regression, then only dose and body site remain significant predictors of tanning: therefore neither phototype nor pigmentary factors, such as baseline skin colour, or eye or hair colour, predict change in skin colour to a unit erythemal response. © 2010 John Wiley & Sons A/S.
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 77.00 | Year: 2015
Each one of us carries mutations (genetic “blemishes”) which make us susceptible to diseases, such as infections or cancer. Finding these harmful mutations is difficult because they exist in a sea of more numerous, inconsequential DNA changes. We use the latest cutting-edge technologies and computational analyses to find the consequential mutations and to work out what changes they incur for molecules, cells, organs and individuals. Our studies not just consider proteins – the “work-horses of the cell” – but also RNAs which also help to orchestrate the cell’s function. We also try to understand how single cells change when their DNA is altered, or over time, or when their environments alter. In this way we are seeking to bridge between DNA mutations and disease, whilst understanding in which type of cell the disease is first manifested.
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 508.27K | Year: 2012
Many different factors influence the health of individuals, be they domestic animals or humans. These factors can broadly be categorised as either genetic or environmental. Thus the genes inherited from parents and the environments encountered during life are paramount in determining health status as one ages. These factors may also interact, such that individuals with one genetic make-up may react well to a particular environment, whereas a different genetic make-up may react badly. Where a substantial proportion of the genetic and environmental factors can be identified it is possible to provide accurate predictions of individuals health as they age. Using such genetic information in prediction has great potential as it can be measured early in life and is unchanging throughout life. So there is the potential to be aware in advance of the environmental conditions that will optimise the future health of individuals. Such prediction is potentially a powerful tool to promote healthy ageing and wellbeing in both humans and companion animals, as it allows increasing efficiency of interventions, such as recommended diets or even drug treatments, and the targeting interventions towards those individuals who will most benefit. Combining genetic and environmental information is therefore the natural way to proceed when predicting how animals or humans will age and this project is concerned with developing accurate mathematical and statistical models to do this. Research in animals and humans has started the process of identifying genes affecting the traits associated with healthy ageing such as obesity or bone strength. However it has become clear that traits associated with healthy ageing are generally controlled by large numbers of genes with small effects. To unequivocally find such genes and accurately estimate their effects requires very large studies and relatively few genes have as yet been identified. Thus the amount of variation explained jointly by all the genes found in studies so far is usually much less than 10%, even though genetic variation in total may explain as much as 80% of the overall variation. Alongside genetic information, factors such as age, gender, diet and other lifestyle characteristics are often major contributors to how individuals develop. In addition, it is often known that metabolic or predisposing traits like glucose or lipid concentration in blood may correlate with health. Such traits may be more amenable to measurement or may be measured earlier than overall health status and may be used as indicators or predictors of future health. Thus information can also be combined across traits to improve the accuracy of prediction, and to allow prediction of (unmeasured) correlated traits. With this background we propose to develop mathematical methods which make best use of available genomic information and to combine this information with environmental data and across multiple traits. We will use several different approaches and compare them in their ability to accurately predict performance and how they may be extended to account for data from many traits and environments. We plan to apply and extend methods currently used in animal breeding for the related task of identifying genetically superior animals for breeding. These will be compared with machine learning methods from computer science. We plan to demonstrate the effectiveness of these methods applied to the analysis of data from human populations on body mass index - a proxy for obesity - and blood glucose levels, and will also include in the analyses environmental variables like smoking, diet and exercise. The data are currently available from human studies and methods and results will be relevant to this species. In due course, the methods developed will be directly applicable to companion animals as data become available.