A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

Álvarez-Prado, Á. F., Pérez-Durán, P., Pérez-García, A., Benguria, A., Torroja, C., de Yébenes, V. G. and Ramiro, A. R. (2018) A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets. Journal of Experimental Medicine, 215(3), pp. 761-771. (doi: 10.1084/jem.20171738) (PMID:29374026) (PMCID:PMC5839764)

Abstract

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth >1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Furthermore, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets. We also have found that base excision repair and mismatch repair back up each other to faithfully repair AID-induced lesions. Finally, our data establish a novel link between AID mutagenic activity and lymphomagenesis.

• Item Type: Articles
• Additional Information: A. Pérez-García was a fellow of the research training program funded by the Ministerio de Educación, Cultura y Deporte (grant FPU-AP2009-1732); A.F. Álvarez-Prado and A.R. Ramiro are supported by Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). This work was funded with the following grants to A.R. Ramiro from Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigación: Proyectos I+D+i 2016, Ministerio de Economía, Industria y Competitividad (MEIC; grants SAF2013-42767-R and SAF2016-75511-R). This work is cofunded by Fondo Europeo de Desarrollo Regional and the European Research Council Starting Grant program (grant BCLYM-207844). The CNIC is supported by the MEIC and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (MEIC award SEV-2015-0505).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Perez, Ms Arantxa
• Authors: Álvarez-Prado, Á. F., Pérez-Durán, P., Pérez-García, A., Benguria, A., Torroja, C., de Yébenes, V. G., and Ramiro, A. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Experimental Medicine
• Publisher: Rockefeller University Press
• ISSN: 0022-1007
• ISSN (Online): 1540-9538
• Published Online: 26 January 2018
• Copyright Holders: Copyright © 2018 Álvarez-Prado et al.
• First Published: First published in Journal of Experimental Medicine 215(3): 761-771
• Publisher Policy: Reproduced under a Creative Commons License