Newsletter July 2015
A few of our team were lucky enough to adventure off to other parts of the world in the name of science! Please find their stories below!
Doug Speed’s trip to Australia
One of the perks of the MRC Career Fellowship is that the award insists fellows spend time in an overseas research organisation. Therefore, with the world-leaders of my field based in Brisbane, and my sponsor David Balding now in Melbourne, the obvious country to choose was Australia. I spent the first two weeks in Peter Visscher's Group in the Queensland Brain Institute (QBI). Peter, along with his postdoc Jian Yang, effectively invented the area of SNP-based mixed model analysis, the focus of my research efforts. Their key insight was that you could apply methods developed for animal and plant breeding --- e.g. to predict which cows would produce most milk, or strains of wheat highest yield --- to human data to reveal insights into the genetic architecture of complex traits. Their breakthrough paper demonstrated that common genetic mutations explain the majority of variation in human height, and effectively ended the "missing heritability" debate, and follow-up papers demonstrated that most common human diseases are highly polygenic, such that many hundreds of variants impact susceptibility, but most have only a minute effect individually. The visit was both exciting and daunting; exciting to work with people who know my area of research inside-out, but daunting because the competition between them and I is intense. Although the two weeks flew by, hopefully some useful collaborations will result. I spent the next five weeks in David's new department in the University of Melbourne. Again, the atmosphere was highly stimulating, as I was able to discuss ideas with members of the Population Genetics, Systems Biology, Biostatistics and Animal Genetics Groups, as well as researchers in the Walter and Eliza Hall Institute, Biosciences 21 and the Murdoch Children's Research Centre. But perhaps the most useful time was my trip to the Epilepsy Group at the Melbourne Brain Centre. There I had the chance to speak to clinicians who deal with epilepsy patients and their families on a daily basis, who understand the nuances of the condition in very fine detail and many of whom have spent thirty years or more at the forefront of epilepsy research. As a mathematician at heart, most of my work is phenotype-agnostic, meaning the methods can be used by human, plant and animal geneticists alike; however, the time spent with these epilepsy experts makes me realise that specialisation is also important, and so one of the next challenges will be integrating the knowledge of clinicians into these cutting-edge methods.
Doug leaves his mark on the QBI
Chris Steel’s trip to see David Balding at the University of Melbourne
I spent April 2015 visiting David Balding at the University of Melbourne, , and connecting with our Australian cousins. The first engagement I attended was a meeting of the Victoria Chapter of the Australian Academy of Forensic Sciences, where David gave a very interesting seminar on the weight of various lines of evidence for the bones of Richard III actually being who they were believed to be. This was followed by dinner where I had the opportunity to meet some of the members of the academy. I then presented my most recent work to the Mathematics and Computational Biology group. By good fortune, the month I was in Australia happened to coincide with a visit by Bob Carpenter, who is one of the main developers of STAN, a probabilistic programming language for Bayesian inference (think WinBUGS, but better). As a result I was able to attend monthly meetings of a STAN study group at the MCRI. I learnt a lot about STAN during these meetings, and it was interesting seeing all the other applications that people had applied STAN to. This all culminated in Bob Carpenter attending my last meeting, so I had some feedback on my attempted model from the very man himself!
On my last day in Melbourne, David and I gave a joint talk at the Victoria Police Forensic Centre. This was followed by a tour of the facility, complete with automotive shop, fake crime scene house, blood-spatter room (complete with Dexter poster on the door), drugs vault, gun collection and more expensive machines than you could count. My personal highlight was seeing WWI era German and British machine guns in the gun collection. Don't ask me how anyone would be able to commit a crime with those ancient pieces of kit!
Valentina’s visit to the Mexico-UK Genomics Workshop 2015 (24th-28th June, Oaxtepec, Morelos, Mexico
Dr. Valentina Cipriani has recently received a travel fellowship to take part in the Mexico-UK Genomics Workshop 2015 (24th-28th June, Oaxtepec, Morelos, Mexico). The workshop has been coordinated by Prof. Constantino López-Macías (Medical Research Unit on Immunochemistry of the Mexican Social Security Institute) and Dr. Antonio Berlanga-Taylor (Computational Genomics Analysis and Training Fellow at the University of Oxford) under the umbrella of the British Council Researcher Links Workshops initiative that promotes international collaborations and brings together researchers from the UK and partner countries. During the 5-day meeting, each participant had the opportunity to present a focus on their research interests and projects. Topics covered included computational genomics, immunity to bacteria and inflammatory response, immunogenomics, epidemiology and statistical genetics of infectious diseases. Valentina presented an overview of methods to integrate phenotypic and genomic data for rare disease gene discovery, with clinical examples from the field of rare retinal dystrophies. Last day was dedicated to discuss funding opportunities in both countries and how to take existing and new collaborations forward.
Valentina says: “I’m so glad I took part to this fellowship competition and I ended up in attending the Mexico-UK Genomics Workshop 2015. The formula of such meetings is quite different from other scientific conferences as all participants are specifically asked to attend with the intention to establish collaborations with the partner country. The organisation of the workshop was excellent with a very good balance between keynote lectures, participants’ talks and poster sessions and a wide range of social activities, including a visit to the “pueblo mágico” of Tepoztlán and the climbing to an impressive pyramid. Not to mention, the extra one week of holiday I took afterwards was amazing. Mexico with its warm and hospitable people, delicious food and so many different places to visit, including Mayan ruins, nature reserves and Caribbean beaches, was a beautiful discovery for me. Definitely worth establishing collaborations and going back!”.
UGI MSc courses
MSc Genetics of Human Disease and MSc Pharmacogenetics and Stratified Medicine
Our current students have completed the taught part of the programme and are now doing their research projects. Both programmes offer students an excellent list of research projects in the fields of Human Disease genetics and Pharmacogenetics from researchers working in various UCL research Institutes including UCL Genetics Institute, UCL Institute of Child Health, Centre for Neurology, Royal Free Hospital and UCL School of Pharmacy and others. Students have a choice of doing computer or lab-based projects. Students will be submitting their dissertations in the middle of August 2015 and will be giving short project presentations on 4th, 10th and 11th September 2015. The schedule of individual project presentations will be announced in August.
The MSc admissions are now underway and are going strong for both of our Masters. Deadlines for applications for both courses are 30th June 2015 for overseas applicants and 31st July 2015 for UK/EU students. Applications should be made on line by visiting the UCL website links:
We are always happy to hear from our former students and this time we got a wonderful message from Jamie Stafford, a 2013 graduate of the MSc Genetics of Human Disease. Currently Jamie is a PhD student at Wayne State University, Detroit, Michigan. Her research project investigates the genetics of hereditary ovarian cancer. “My time at UCL was short, but the amount of material I learned and skills I acquired was beyond what I could have imagined. Attending the MSc Genetics of Human Disease was the best decision I ever made,” wrote Jamie. We wish her every success in her PhD.
Bloomsbury Centre for Genetics Epidemiology and Statistics (BCGES)
The Centre held its Annual Scientific Meeting on 30th June at UCL’s Darwin Lecture Theatre. The theme this year was Genetics & the Brain. The plenary speaker was our Research Director who gave a brilliant overview on the Genetics of Parkinson’s disease spanning his career to date and discussing the merits of the various methods entailed over the years and the outcomes. We were also thrilled to hear talks from BCGES researchers on topics ranging from the dopamine neurotransmitter system (Iroise Dumontheil), apolipoprotien E (Ghazaleh Fatemifar) and learning disabilities and serious mental illness (Andrew McQullin). The afternoon was mainly external speakers Prof Marcus Munafo, University of Bristol[SRD1] spoke about cigarettes and coffee – the impact on mental health – with Cathryn Lewis dissecting phenotypes to genotypes in depression and stroke. Stephen Sawcer updated us on Multiple Sclerosis genetics and finally Silvia Paracchini speaking about handedness and dyslexia.
The Centre will run two short courses in September 2015
Course 1: Introduction to Genetic Epidemiology in the GWAS era
(1 – 4 September 2015)
Genetic epidemiology holds great potential for personalised medicine and improved biological knowledge of disease processes. This course provides an introduction to the design, analysis and interpretation of genetic studies of disease, with a focus on state of the art analysis of genomewide association scans. Throughout the course participants will gain practical experience of analysing genetic data in population and family studies. By the end of the course participants will have an understanding of the fundamental concepts of genetic epidemiology, will have a working knowledge of the terminology and current status of the field, and will be able to perform many basic analyses of genetic data.
Course 2: High throughput sequencing in disease studies
(midday 7 – midday 11 September 2015)
Rapidly developing technologies now allow genomes to be sequenced more quickly and cheaply than ever before. This course will cover state of the art methods and applications of next generation sequencing. The course runs over 4 days and participants will be introduced to tools for analysing high throughput sequence data, including methods for measuring copy number variants and allele-specific expression, and conducting disease association analysis with sequence data. There will be considerable opportunities to gain practical experience with new data types such as whole genome sequence, RNA- and ChIP-seq data. By the end of the course participants will have a broad knowledge of the state of the art and will be well equipped to analyse their own data.
For further information and to book your place visit BCGES website.
If you would like to join the e-mail list that will announce future seminars in statistical genetics and genetic epidemiology and other related events of broad interest, you can subscribe here.
Four decades of transmission of amultidrug-resistant Mycobacterium tuberculosis outbreak strain - Vegard Eldholm, Johana Monteserin, Adrien Rieux, Beatriz Lopez, Benjamin Sobkowiak, Viviana Ritacco & Francois Balloux Four decades of transmission of amultidrug-resistant Mycobacterium tuberculosis outbreak strain
Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression p-values 2×10-8 to 3×10-14). Four traits are associated with a functional variant in the EctodysplasinA receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1) and we confirm that rs17023457 alters in-vitro binding of CART1.
Recursive splicing in long vertebrate genes - Christopher R. Sibley, Warren Emmett, Lorea Blazquez, Ana Faro,Nejc Haberman, Michael Briese, Daniah Trabzuni, Mina Ryten, Michael E. Weale, John Hardy, Miha Modic, Tomaž Curk, Stephen W. Wilson, Vincent Plagnol & Jernej Ule
Bayesian mixture analysis for metagenomic community profiling - Sofia Morfopoulou and Vincent Plagnol
Previous reports have described the widespread prevalence of "yin yang" haplotypes of SNPs. In a pair of yin yang haplotypes alleles differ at each locus and what is surprising is that intermediate haplotypes, such as would be expected to occur as a result of sequential mutations, are observed relatively rarely or are completely absent. This study reports that such yin yang haplotype pairs occur not only with common SNPs extending over long regions but can also be seen with rare coding variants within single genes. An example is given of a perfect yin yang haplotype of 8 variants within ABCA13 which always occur together. This haplotype is widely distributed geographically. The mechanism whereby such haplotypes are produced is unknown. The study of yin yang haplotypes may throw light on mechanisms whereby polymorphisms arise and they may prove useful in studying the history of human populations. The fact that rare variants can exhibit complete linkage disequilibrium also has implications for devising methods to analyse sequence data, for example when exploring the relationship between such variants and risk of developing a disease.
Given that schizophrenia is disabling and markedly reduces reproductive fitness, it may seem surprising that it is both highly heritable and not particularly rare. One possible explanation is that recessive effects contribute to risk and this study sought to identify genes with an excess of coding variants occurring either as homozygotes or compound heterozygotes. Whole exome sequence data from 2545 controls and 2545 cases were investigated using a variety of methods. This approach revealed a number of difficulties which can occur when attempting to detect recessive effects using next generation sequence data. These relate to the fact that artefacts can occur through problems with variant calling and with phasing algorithms and that strong linkage disequilibrium between variants can make it difficult to reliably identify compound heterozygotes when unphased data are studied. No genes were identified in which recessive effects were statistically significant, implying either that heterogeneity is too marked, that the methods and sample sizes used were inadequate or that such effects do not in fact make a substantial contribution to the risk of developing schizophrenia.
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