Origins and Impacts of Structural Mutations Image Professor Colin Semple - Group leader and Head of Bioinformatics Research in a Nutshell The emergence of widespread whole genome sequencing has revealed a vast layer of structural mutations: deletions, duplications and other rearrangements of the human genome. These structural alterations affect more of the genome than the short variants that are more familiar but their effects on gene function are poorly understood. We study these alterations in the germline and early embryo, where they can disrupt developmental expression patterns, and also in tumours where complex structural rearrangements can drive cancer progression. We have a particular focus on the chaotic mutational landscapes that evolve in many cancers of unmet need (such as ovarian cancer, glioblastoma and mesothelioma) where tumour genomes become dramatically rearranged. With our clinical collaborators we explore the consequences of these rearrangements for tumour biology and cancer patient outcomes; motivated by four questions. What are the origins of structural mutations? How do they impact gene function? How does structural complexity drive disease progression? How do the diverse constellations of mutations evolving at different scales in tumours combine to create adaptations and vulnerabilities? Group External Website People Professor Colin Semple Group leader and Head of Bioinformatics Dr Stuart Aitken Bioinformatician Dr Vera Kaiser Bioinformatician Dr Devin Bendixsen Bioinformatician Matthew Brown PhD student Ryan Silk PhD student Scott Pirrie PhD student Simon Timmins PhD Student Alhafidz Hamdan ECAT fellow Edward Esiri-Bloom CRUK TRACC Fellow Bioinformatics Analysis Core Dr Jing Su Institute of Genetics and Cancer Bioinformatics Analysis Core Manager Dr Philippe Gautier Bioinformatician Mr Graeme Grimes Bioinformatician Dr Mihail Halachev NHS/Institute of Genetics and Cancer Translational Bioinformatician Kevin Donnelly Bioinformatician Murray Wham Bioinformatician Steve Fox Institute of Genetics and Cancer Data Manager Hywel Dunn-Davies Institute of Genetics and Cancer Statistician Contact Colin.Semple@ed.ac.uk Publications Kaiser VB, Talmane L, Kumar Y, Semple F, MacLennan M, DDD Study, FitzPatrick DR, Taylor MS*, Semple CA*. (2021) Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome. Genome Research 31: 1-14. Ewing A, Meynert A, Churchman M, Grimes GR, Hollis RL, Herrington CS, Rye T, Bartos C, Croy I, Ferguson M, Lennie M, McGoldrick T, McPhail N, Siddiqui N, Dowson S, Glasspool R, Mackean M, Nussey F, McDade B, Ennis D, McMahon L, Matakidou A, Dougherty B, March R, Barrett JC, McNeish IA, SGP, Biankin AV, Roxburgh P, Gourley C*, Semple CA*. (2021) Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma. Clinical Cancer Research 27: 3201-3214. Aitken SA, Anderson CJ, Connor F, Pich O, Sundaram V, Feig C, Rayner TF, Lukk M, Aitken S, Luft J, Kentepozidou E, Arnedo-Pac C, Beentjes S, Davies SE, Drews RM, Ewing A, Kaiser VB, Khamseh A, Lopez-Arribillaga E, Redmond AM, Santoyo-Lopez J, Sentis I, Talmane L, Yates AD, Semple CA, Lopez- Bigas N, Flicek P, Odom DT, Taylor MS. (2020) Pervasive lesion segregation shapes cancer genome evolution. Nature 583: 265-270. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. (2020) Pan-cancer analysis of whole genomes. Nature 578: 82-93. Ballinger TJ, Bouwman BAM, Mirzazadeh R, Garnerone S, Crosetto N, Semple CA. (2019) Modeling double strand break susceptibility to interrogate structural variation in cancer. Genome Biology 20:28. Full publication list can be found on Research Explorer: Colin Semple — University of Edinburgh Research Explorer Collaborations Professor Wendy Bickmore, MRC Human Genetics Unit Professor Malcolm Dunlop, MRC Human Genetics Unit Professor David Fitzpatrick, MRC Human Genetics Unit Professor Chris Haley, MRC Human Genetics Unit Professor Martin Taylor, MRC Human Genetics Unit Dr Nicola Crosetto, Karolinska Institute, Sweden Professor Charlie Gourley, Cancer Research UK Edinburgh Centre Professor Piero Carninci, RIKEN Center for Life Science Technologies, Japan Partners and Funders Medical Research Council Chief Scientist Office Scientific Themes Medical Genomics, Bioinformatics, Transcriptomics, Epigenomics Technology Expertise Computational Biology This article was published on 2024-09-23
