Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis

Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently muta...

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Detalles Bibliográficos
Autores: López Bigas, Núria, Demajo, Santiago, Muiños Ballester, Ferran, Grau López, Miguel, Ramis Zaldívar, Joan Enric, Andrianova, Maria, González Pérez, Abel
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/211861
Acceso en línea:https://hdl.handle.net/2445/211861
Access Level:acceso abierto
Palabra clave:Mutació (Biologia)
Hematopoiesi
Mutation (Biology)
Hematopoiesis
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spelling Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation MutagenesisLópez Bigas, NúriaDemajo, SantiagoMuiños Ballester, FerranGrau López, MiguelRamis Zaldívar, Joan EnricAndrianova, MariaGonzález Pérez, AbelMutació (Biologia)HematopoiesiMutation (Biology)HematopoiesisClonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. In this study, we trained machine learning models for 12 of the most recurrent CH genes to identify their driver mutations. These models outperform expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals.American Association for Cancer Research2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/211861Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1158/2159-8290.CD-23-1416Cancer Discovery, 2024https://doi.org/10.1158/2159-8290.CD-23-1416cc by-nc-nd (c) López Bigas, Núria et al, 2024http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2118612026-05-27T06:46:51Z
dc.title.none.fl_str_mv Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
title Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
spellingShingle Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
López Bigas, Núria
Mutació (Biologia)
Hematopoiesi
Mutation (Biology)
Hematopoiesis
title_short Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
title_full Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
title_fullStr Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
title_full_unstemmed Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
title_sort Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
dc.creator.none.fl_str_mv López Bigas, Núria
Demajo, Santiago
Muiños Ballester, Ferran
Grau López, Miguel
Ramis Zaldívar, Joan Enric
Andrianova, Maria
González Pérez, Abel
author López Bigas, Núria
author_facet López Bigas, Núria
Demajo, Santiago
Muiños Ballester, Ferran
Grau López, Miguel
Ramis Zaldívar, Joan Enric
Andrianova, Maria
González Pérez, Abel
author_role author
author2 Demajo, Santiago
Muiños Ballester, Ferran
Grau López, Miguel
Ramis Zaldívar, Joan Enric
Andrianova, Maria
González Pérez, Abel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Mutació (Biologia)
Hematopoiesi
Mutation (Biology)
Hematopoiesis
topic Mutació (Biologia)
Hematopoiesi
Mutation (Biology)
Hematopoiesis
description Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. In this study, we trained machine learning models for 12 of the most recurrent CH genes to identify their driver mutations. These models outperform expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/211861
url https://hdl.handle.net/2445/211861
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1158/2159-8290.CD-23-1416
Cancer Discovery, 2024
https://doi.org/10.1158/2159-8290.CD-23-1416
dc.rights.none.fl_str_mv cc by-nc-nd (c) López Bigas, Núria et al, 2024
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) López Bigas, Núria et al, 2024
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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