Causal variants and mechanisms in complex traits and diseases Image Professor Chris Ponting - Section Head: Biomedical Genomics, Chair of Medical Bioinformatics Research in a Nutshell The challenge in genomics is to pinpoint DNA variants that alter individuals’ risk to common disease; the challenge in genetics is to determine how these changes alter genetic mechanisms; and, the challenge in cell biology is to find out how these altered mechanisms affect development, cells and organs. Our research uses cutting-edge analytical approaches in genomics, transcriptomics, and cell biology to trace the causal links relating DNA variation to physiological outcome. Our research intersects disease genomics, computational biology, machine learning and molecular mechanism. We are currently pursuing two major research projects: Pinpointing DNA variants that alter complex disease risk. What are the causal contributions to disease risk made by DNA variants that alter transcription factor-binding affinity? For this, we used data from 6,017 ChIP-seq samples, 558 TFs and 46 genotyped cell lines to identify nearly 16,000 DNA variants that alter transcription factor binding. We are now interrogating these variants for their association with human diseases and traits using TarGene, a new algorithm developed with colleagues Sjoerd Beentjes, Ava Khamseh and Olivier Labayle Pabet. Inferring cell states in single cell RNA-seq data. We have developed Stator, a novel method, workflow and app that reveals cell types, subtypes and states without relying on local proximity of cells in gene expression space. Stator is now being applied in many different biomedical contexts. This is an interdisciplinary project with colleagues Sjoerd Beentjes, Ava Khamseh, Abel Jansma and Luigi Del Debbio. ME/CFS Genetics. DecodeME is a £3.2m NIHR and MRC-funded strategic grant running until August 2025. With 18,000 DNA participants, this is the world’s largest genetic study into ME/CFS. An initial genome-wide association analysis (using matched UK Biobank individuals as controls) will occur late in 2024. DecodeME is a co-production with people with lived experience of ME/CFS that adheres to UK PPI Standards. PhD students also work in the group on ME/CFS genetics funded by Action for ME or by ME Research UK. We support Action for ME’s vision to establish the UK’s first Genetics Centre of Excellence, a virtual network of ME researchers who, with the ME community, will build on the genetic insights gained through DecodeME and other studies. Please get in touch (chris.ponting@ed.ac.uk) if you would like to undertake a personal Fellowship, postdoctoral post or studentship with us! Research Programme People Professor Chris Ponting Group Leader Tom Baker Data Manager, DecodeME Thibaud Boutin DecodeME Research Fellow Diana Garcia DecodeME Project Manager Cristina Martin X-net Project Manager Gosia Clyde DecodeME Admin Manager Anne Connolly DecodeME Communications and Engagement Manager Breeshey Roskams-Hieter PhD Student Gemma Samms PhD Student Julia Oakley PhD Student Artur Miralles Méharon PhD Student Veronique Vitart DecodeME Co-Investigator Audrey Ryback Action for M.E. Research Fellow Andrew Bretherick Senior Clinical Research Fellow Esther Ewaoluwagbemiga Statistical Geneticist Alina Kumukova Cross-disciplinary Fellow Andrii Iakovliev Cross-disciplinary Fellow Yavor Novev Cross-disciplinary Fellow Luciana Luque Cross-disciplinary Fellow (with CRUK Scotland Institute) Maria Delgado-Ortet Cross-disciplinary Fellow Rodrigo García-Tejera Cross-disciplinary Fellow Svitlana Braichenko Cross-disciplinary Fellow Contact Chris.Ponting@ed.ac.uk Publications Baran-Gale J, Morgan MD, Maio S, Dhalla F, Calvo-Asensio I, Deadman ME, Handel AE, Maynard A, Chen S, Green F, Sit RV, Neff NF, Darmanis S, Tan W, May AP, Marioni JC, Ponting CP*, Holländer GA*. (2020) Ageing compromises mouse thymus function and remodels epithelial cell differentiation. eLife 9:e56221 Dhalla F, Baran-Gale J, Maio S, Chappell L, Holländer GA*, Ponting CP*. (2020) Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells. EMBO J 39:e101828 Sirey TM*, Roberts K, Haerty W, Bedoya-Reina O, Rogatti-Granados S, Tan JY, Li N, Heather LC, Carter RN, Cooper S, Finch AJ, Wills J, Morton NM, Marques AC, Ponting CP*. (2019) The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity. eLife 8:e45051 Bretherick, A.D., Canela-Xandri, O., Joshi, P.K., Clark, D.W., Rawlik, K., Boutin, T.S., Zeng, Y., Amador, C., Navarro, P., Rudan, I., Wright, A.F., Campbell, H., Vitart, V., Hayward, C., Wilson, J.F., Tenesa, A., Ponting, C.P., Baillie, J.K., Haley, C. (2020) Linking protein to phenotype with Mendelian Randomisation detects 38 proteins with causal roles in human diseases and traits. PLoS Genet. 16: e1008785. Kousathanas, A., Pairo-Castineira, E. et al. (including Ponting, C.P.) Caulfield, M.J., Baillie, J.K. Whole-genome sequencing reveals host factors underlying critical COVID-19. (2022) Nature Full publication list can be found on Research Explorer: Chris Ponting — University of Edinburgh Research Explorer Collaborations Professor Georg Hollander, University of Oxford Dr Ava Khamseh & Dr Sjoerd Beentjes, University of Edinburgh Partners and Funders MRC Wellcome NIHR Action for ME/ Chief Scientist's Office, Scotland ME Research UK Scientific Themes Population genomics, ME/CFS genetics, molecular mechanisms in complex disease. Technology Expertise Single cell biology This article was published on 2024-09-23
