Bioinformatics

Lead Research Organisation: Medical Research Council

Abstract

We are building computer models of how cells produce energy from food. We are using these models to understand what happens when these processes go wrong in diseases where energy production is affected, such as obesity, diabetes, cancer and heart disease. We are working with experimental researchers and clinicians to improve our models, test predictions from the model and experimental data, and suggest therapies and drug targets for these diseases. We are also using our computational techniques to identify disease genes from the DNA sequencing of patients with mitochondrial disorders.

Technical Summary

The overall aim of our research is to use computer-based techniques to understand the metabolism and energy-production of the mitochondrion, and identity the genetic causes of genetic disease.
Our first objective has been the development of MitoMiner, a public resource database that describes the proteins of the mitochondrion from many different species, including human. We gather and integrate results from experimental studies that identify mitochondrial proteins, and link them with data about diseases, metabolism and evolution. Using this database, researchers can find evidence about whether a protein is mitochondrial, which tissues it is expressed in, which species it is found in, and if it is associated with disease.
Next, we are using MitoMiner with its catalogue of mitochondrial proteins to build computer models of mitochondrial metabolism and energy production. We are building tissue-specific models, as mitochondrial metabolism varies amongst different organs and in different diseases, such as cancer. We use “flux balance analysis” to simulate the flow of metabolites in these models, and predict what happens to energy production and metabolism when mitochondrial proteins are affected by genetic mutations as in mitochondrial diseases, or the supply of metabolites is increased or decreased, as in heart disease or cancer. In collaboration with experimental researchers and clinicians, we are investigating how modelling can lead to a greater understanding of mitochondrial function in health and disease, leading to possible new therapies and drug targets.
Taken together, mitochondrial genetic diseases affect about 1 in 8,000 live births, and may be the cause of many pregnancy losses. For affected families, genetic diagnosis is essential for counselling, can enable appropriate clinical management, and eventually drive suitable treatment of patients. A new and important diagnostic strategy for identifying disease genes is the exome sequencing of patients with mitochondrial disease. Furthermore, the identified variants in novel mitochondrial genes provide valuable insight into mitochondrial function and disease, can be transferred to diagnostic tests, including high-throughput targeted sequencing, and potentially suggest therapies to alleviate symptoms. The MRC MBU carries out whole exome sequencing of patient samples in-house. But exome sequencing produces huge amounts of data and identifies candidate variants in 1000’s of genes, meaning computational analyses are essential to manage and mine these data. Thus we have built an analysis pipeline and are developing and applying computational tools to analyse these data and identify and prioritise variants in mitochondrial genes that can be pathogenic.

Publications

10 25 50

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Duncan AL (2018) Cardiolipin dynamics and binding to conserved residues in the mitochondrial ADP/ATP carrier. in Biochimica et biophysica acta. Biomembranes

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Duncan AL (2016) Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases. in Proceedings of the National Academy of Sciences of the United States of America

 
Title Game to explain use of fruit flies in genetic research 
Description I conceived and designed a game to explain why fruit flies are used in genetic research. The game is based on "Guess Who?" where the players try to guess the mutant fly of their competitor by asking a series of questions about what it looks like (its phenotype). 
Type Of Art Artefact (including digital) 
Year Produced 2016 
Impact Will be used at Cambrige Science Festival 2017 
URL http://www.mrc-mbu.cam.ac.uk/event/2770/cambridge-science-festival-2017
 
Title Puzzle games to explain "NextGen" DNA sequencing 
Description I conceived and developed a series of puzzle games for use in schools that helped explain how we sequence the DNA of patients and find variants in their DNA. The game has also been used at science festivals, including 
Type Of Art Artefact (including digital) 
Year Produced 2015 
Impact The game was used during the Cambridge Science Festival 2016. 
URL http://www.mrc-mbu.cam.ac.uk/news/2561/cambridge-science-festival-2016
 
Description MRCT DGF Gap funding
Amount £33,000 (GBP)
Organisation MRC-Technology 
Sector Academic/University
Country United Kingdom
Start 07/2012 
End 06/2015
 
Title BioPerl toolkit 
Description Contributions to the BioPerl software library (www.bioperl.org) for the comparative analysis of genomes. 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact Contributions to the latest developments of the OpenSource BioPerl libraries for genome, phylogenetic and transcriptome analysis. 
URL http://www.bioperl.org
 
Title IMPI 
Description Many diseases are caused by malfunction of proteins that are in the mitochondrion. IMPI is a comprehensive list of mitochondrial proteins for human, mouse and rat. IMPI was developed to objectively appraise the evidence for mitochondrial localisation of a protein by evaluating many different data types including experimental proteomics data in MitoMiner, mitochondrial targeting sequence predictions and antibody localization staining from the Human Protein Atlas. We use machine learning algorithms to select those proteins that have similar properties and evidence to already characterised mitochondrial proteins. This approach solves the problem of deciding an arbitrary threshold for what level of evidence can be considered "mitochondrial". 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact The collection is being used to prioritise genes identified in next generation sequencing of patients with mitochondrial disease. It is being used to identify novel mitochondrial proteins. 
URL http://impi.mrc-mbu.cam.ac.uk/
 
Title MitoCore computer model of central metabolism 
Description We are building models of the central metabolism of cell types, including cardiomyocytes, hepatocytes, and cancerous glioma cells. We have used these models to simulate normal and disease metabolism. The cardiomyocyte model is published in the BIOMODELS database: MODEL1106160000 
Type Of Material Computer model/algorithm 
Year Produced 2011 
Provided To Others? Yes  
Impact Publications: 21714867; 22405071; 25383517 This model has been used to interpret biomedical and clinical data on cardiomyocyte function and dysfunction, including ischaemia, leading to publications. 
URL http://www.mrc-mbu.cam.ac.uk/projects/61/modelling-mitochondrial-metabolism
 
Title MitoMiner 
Description MitoMiner: A data warehouse of the mitochondrial proteome and related information. Resourse is publicly available. Reource was developed using the Open Source InterMine infrastructure, which reduced development time to less than a year. 
Type Of Material Database/Collection of data 
Year Produced 2008 
Provided To Others? Yes  
Impact Publications about resource: 19208617; 22121219; 26432830. Resource being used by other groups within Unit to analyse mitochondrial proteome and has led to a publications. Resource has been used by external groups and cited in publications. 
URL http://mitominer.mrc-mbu.cam.ac.uk/
 
Title SHAARE 
Description We have produced a new database designed for a clinical research audience that integrates gene annotation, expression by developmental stage and tissue, phenotypic data, human disease info, and data on protein and genetic interactions, across a series of model organisms (human, mouse, rat, fly, zebrafish, worm and monkey). The hope is that by bringing all this data together it will facilitate the cross-analysis of new candidates in regenerative medicine, particularly mitochondrial proteins, which would otherwise be very difficult and time consuming if the underlying datasources were consulted directly. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Used in collaboration with researchers from the Sanger Institute studying regeneration of heart tissue. Manuscript about resource submitted. 
URL http://www.shaare.org.uk
 
Description Analysis of DNA of patients with neurological disease 
Organisation Newcastle University
Department Wellcome Trust Centre for Mitochondrial Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Bioinformatics analysis of DNA sequence data from patients with neurological disease that has a mitochondrial dysfunction.
Collaborator Contribution Provided anonymised DNA sequences of patients.
Impact Enabled us to QC our in-house bioinformatics pipeline for analysis of patient DNA for mutations. Provided data sets to test and validate bioinformatics tools that we have developed to highlight genes that may cause mitochondrial or neurological disease. Multidisciplinary: bioinformatics, genetics, disease
Start Year 2015
 
Description Bioinformatics analysis of mitochondrial carriers 
Organisation University of Bari
Country Italy 
Sector Academic/University 
PI Contribution Bioinformatics analysis of mitochondrial carriers to predict function.
Collaborator Contribution Characterisation of mitochondrial carriers Mutation of mitochondrial carrier proteins to assess affects on function and substrate specificity
Impact Multidisciplinary: Biochemistry, molecular biology, bioinforamtics Several publications on the mitochondrial carrier transport proteins integrating bioinformatics and biochemical and genetic studies. Latest publication in 2012: PMID 22262851
 
Description Computer model of cardiomyocyte central metabolism 
Organisation University of Bordeaux
Department Institute of Biochemistry and Cell Genetics
Country France 
Sector Academic/University 
PI Contribution Collaborating to produce a high quality model of central metabolism in human cardiomyocytes. They will be converting this human model to a yeast model for comparison to their experimental studies.
Collaborator Contribution Are contributing their expertise in mitochondrial and central metabolism to assess the model. Will be validating the results of the model simulations.
Impact First draft of model has been completed, and sent to our partners for evaluation. Manuscript describing the work is under review at PLOS Computational Biology
Start Year 2015
 
Description Function and evolution of the mitochondrial carrier homolog 2 (MTCH2) in apoptosis 
Organisation Weizmann Institute of Science
Department Department of Biological Regulation
Country Israel 
Sector Academic/University 
PI Contribution Computational analyses of protein sequences to evaluate function, structure and evolution
Collaborator Contribution Isolation and biochemical characterisation of the protein from mice
Impact Multidisciplinary: Genetics, biochemistry, molecular biology and bioinformatics Publication in 2012: PMID: 22326460
Start Year 2011
 
Description Metabolism of cancer cells 
Organisation University of Birmingham
Department School of Cancer Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have built computer models of metabolism in cancer cells, and simulated these under the hypoxic conditions. These simulations have predicted features of cancer metabolism that are aberrant.
Collaborator Contribution Our collaborators are running metabolomics studies on cancer cells and cell lines to test the predictions of metabolite consumption and efflux. The results will be used to refine and extend the computer model, and suggest therapeutic strategies.
Impact Multi-disciplinary: Computational biology and Biochemistry/metabolomics.
Start Year 2013
 
Description Next generation sequencing (NGS) of the DNA of patients with mitochondrial disease 
Organisation Carlo Besta Neurological Institute
Country Italy 
Sector Public 
PI Contribution Bioinformatics analysis of DNA sequence data from patients with mitochondria disease to identify pathogenic gene mutations
Collaborator Contribution Provided tissue samples that were sequenced
Impact Papers published: - Martinez Lyons A, Ardissone A, Reyes A, Robinson AJ, Moroni I, Ghezzi D, Fernandez-Vizarra E.. Zeviani M. (2016). COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency. Journal of Medical Genetics, 53 (12), pp. 846-849 - Legati A, Reyes A, Nasca A, Invernizzi F, Lamantea E, Tiranti V, Garavaglia B.. Zeviani M. (2016). New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochimica et biophysica acta, 1857 (8), pp. 1326-35 Multidisciplinary: bioinformatics, genetics, mitochondrial disease
Start Year 2013
 
Description Regenerative medicine and mitochondrial physiology 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are producing a new database designed for a clinical research audience that integrates gene annotation, expression by developmental stage and tissue, phenotypic data, human disease info, and data on protein and genetic interactions, across a series of model organisms (human, mouse, rat, fly, zebrafish, worm and monkey). The hope is that by bringing all this data together it will facilitate the cross-analysis of new candidates in regenerative medicine, particularly mitochondrial proteins, which would otherwise be very difficult and time consuming if the underlying datasources were consulted directly.
Collaborator Contribution Dr. Rameen Shakur has brought his expertise on cardiology and regenerative medicine. He has provided data from his zebrafish mutation programme and working on human ipsc modelling for cardiovascular diseases, namely the cardiomyoapthies. The goal being to simulate and better understand the role of mitochondria in generation of different lineages as we attempt to sub-classify differing functional myocytes, such as ventricular and atrial.
Impact Multi-disciplinary project: bioinformatics, IT, cardiology, regenerative medicine Production of a public resource to share data: http://www.shaare.org.uk/ Manuscript submitted for publication on the web resource
Start Year 2014
 
Description Simulating mitochondrial function in human cardiomyocytes derived from iPS cells 
Organisation The Wellcome Trust Sanger Institute
Department Zebrafish Mutation Programme
Country United Kingdom 
Sector Academic/University 
PI Contribution We have identified proteins likely to be present in the mitochondria during stages of cardiomyocyte differentiation.
Collaborator Contribution Developing human ipsc modelling for cardiovascular diseases, namely the cardiomyoapthies. Using zebrafish as a model in simulating and better understanding the role of the mitochondria in the generation of different lineages and attempt to subclassify the differing functional myocytes such as ventricular and atrial.
Impact Multidisciplinary: Computational biology, genetics, proteomics, cardiology, and development.
Start Year 2013
 
Description Simulation of fuel-switching and progression of diabetes 
Organisation Yeshiva University
Department Stable Isotope & Metabolomics Core
Country United States 
Sector Academic/University 
PI Contribution We have analysed data from proteomics studies on the fasted-to-fed transition and mouse models of diabetes. This has identified possible control points and mechanisms for fuel switching between glycolysis, amino acid breakdown and fatty acid oxidation.
Collaborator Contribution Collaborator has provided proteomics data from wild-type and insulin-resistant mice. These data are measures of post-translational modifications of proteins under different feeding regimes.
Impact Multidisciplinary collaboration involving computational biology, proteomics and metabolomics, physiology and genetic studies in model organisms. Manuscript published in Journal of Proteomics Research in 2011. Two further manuscripts are in preparation on mouse models of insulin resistance and how post-translational modifications of mitochondrial proteins may be affected and lead to the symptoms of diabetes.
Start Year 2010
 
Description Simulation of mitochondrial cardiovascular metabolism 
Organisation John Radcliffe Hospital
Department Department of Cardiology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have simulated mitochondrial metabolism in cardiomyocytes to study the mechanisms of cardioprotection after ischaemia.
Collaborator Contribution Have provided data on cardioprotection from their mouse models that we use in our simulations and to improve our computer models.
Impact Research is multidisciplinary including computational biology, physiology, biochemistry and genetics. Our collaborators are now testing the effect of compounds in heart patients. Publication in 2012: PMID 22405071
Start Year 2010
 
Description Big Biology Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Showcase of MBU's work. Visitors grew crystals of protein and looked at and analysed their structures using the latest computer programs.

Feedback: "MBU's activity is the best I have seen today"
Year(s) Of Engagement Activity 2015
URL http://www.hillsroad.ac.uk/college-life/news/2015/10/15/big-biology-day-at-hills-road-sixth-form-col...
 
Description Cambourne Village College 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Careers Carousel for 13-14 year olds (year 9)

The aims of the event were a) to give Year 9 students a greater insight into some of the career options available to them so that they are better informed to make career choices and motivated to succeed in the coming months and b) to assist students with CV writing and interviewing skills.

Impact: increased awareness
Year(s) Of Engagement Activity 2015
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Attendees asked lots of questions and there was much discussion during the event.

Interest in attending the Unit's open day in June.
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Careers Carousel, CAMAST 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Event aimed at providing inside information about the different Science and IT career opportunities available for year 11 students. Representatives from different STEM industries and with different job types explain what different subjects the students have to study and skills they need to acquire if they want to be part of that industry, but obviously this gives an opportunity to explain why their jobs make them happy and show them a bit of it if it's possible.
Year(s) Of Engagement Activity 2017
 
Description Comberton Village College 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Careers Carousel for Year 9 Students (ages 13-14)
The aims of the event were a) to give Year 9 students a greater insight into some of the career options available to them so that they are better informed to make career choices and motivated to succeed in the coming months and b) to assist students with CV writing and interviewing skills.

During the morning, students experienced over a dozen interactive workshops, and had an opportunity to ask questions about career choices, career pathways, working conditions, job roles and responsibilities. The MRC Mitochondrial Biology Unit gave an overview on careers in biomedical research. At the beginning of the MBU's workshop, student teams were given a word puzzle to solve. They then learnt their puzzle-solving used the same techniques as we use to assemble millions of DNA sequences in the genetic diagnosis of patients with mitochondrial disease. The event was organised by "Form the Future CIC", a social enterprise with a mission to prepare students for future careers by connecting schools with businesses. It is hoped that students appreciate the key employability skills they need to continue to develop in readiness for their future careers.

Impact: increased awareness
Year(s) Of Engagement Activity 2015
 
Description Dispelling myths 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Sharing of ideas and explanations

Collaboration: Made contact with MRC LMB person also writing web content to explain animal research
Year(s) Of Engagement Activity 2015
 
Description Dissemination of scientific achievements via the internet 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Dissemination of scientific achievements and publications to the general public, scientists and others via the Unit's website, Twitter and Facebook.

https://www.facebook.com
Twitter - @MRC_MBU
http://www.mrc-mbu.cam.ac.uk
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.mrc-mbu.cam.ac.uk/people/alan-robinson
 
Description Mentoring program for local sixth form colleges (2016) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Mentoring scheme organised by "Form the Future" and "South Cambridge Police Force" to partner mentors with mentees at local sixth form colleges.
Year(s) Of Engagement Activity 2016
URL http://www.formthefuture.org.uk/index.php/activities/mentoring/
 
Description Mentoring program for local sixth form colleges (2017) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Mentoring scheme partnering metors awith mentees from local sixth form colleges.
Year(s) Of Engagement Activity 2017
URL http://www.formthefuture.org.uk/index.php/activities/mentoring/
 
Description Murray Edwards College 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Year 9 Careers Day at Murray Edwards College for students from the Parkside Federation, Stephen Perse and Chesterton Community College. Speed dating type workshop talking about careers in science or STEM and aiming to show the Year 9s all the exciting options available to them. During the session, volunteers talk to students for 2-3 minutes about what they do.
Year(s) Of Engagement Activity 2016
 
Description Opportunites Ahead 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The event is aimed at school students in years 5 & 6 in the morning followed by students from secondary schools, sixth-forms, recent school and college leavers and parents in the afternoon. The idea is to showcase the wide variety of companies in the Cambridge area and get young people excited about their future.

Signpost 2 Skills is a new service designed to guide students from education and into working life by bringing employers into schools and students into businesses. It is funded by the Greater Cambridge Greater Peterborough LEP and the Greater Cambridge City Deal, and delivered by social enterprise, Form the Future.
Year(s) Of Engagement Activity 2016,2017
URL http://www.mrc-mbu.cam.ac.uk/news/2768/opportunities-ahead-careers-fair-cambridge
 
Description Queen Edith's Primary School, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Members of the MBU visited Queen Edith's Primary School, Cambridge to participate in their Science Day. This was a carousel-type event, with students in years 1-4 rotating around the room. The demonstrations included Lego models, computer games, pipetting and DNA sequencing puzzles. Feedback: Thank you so much for coming here today. The children have not stopped talking about it since leaving the room.
Year(s) Of Engagement Activity 2017
 
Description Sawston Village College 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Mentoring activities - secondary school students
Year(s) Of Engagement Activity 2016,2017
 
Description St Faith's Careers Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Interaction with prep school students, talking about science careers.
Year(s) Of Engagement Activity 2016
 
Description St Mary's School, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The aims of the event was to give Year 5 and 6 students (ages 9 and 10) a greater insight into some of the career options available to them so that they are better informed in advance of making career choices.

Impact: increased awareness.
Year(s) Of Engagement Activity 2016
 
Description Summer school (Cambridge 2012) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact FEBS workshop / MiP Summerschool on Mitochondria (7-12th July, 2012), Cambridge UK. (http://www.mitophysiology.org/index.php?id=mipschool-2012) "Modelling the metabolism of the mitochondrion"

Dissemination of knowledge
Year(s) Of Engagement Activity 2012
URL http://www.mitophysiology.org/index.php?id=mipschool-2012
 
Description UTC Cambridge (on two occasions) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Short talk at careers day re IT and Computer Science

The students involved really liked Alan's workshop and Alan has been invited to return to future events. He is already committed to participating in the College's science event in November and, possibly, a maths event in December.
Year(s) Of Engagement Activity 2015
 
Description Work Experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Visit by three Year 10 students (age 15) to the Unit for a week each - work experience/shadowing in various research groups/environments, chaperoned throughout by individual members of the Unit. Presentation by the visitors at the end of their week.
Year(s) Of Engagement Activity 2016,2017