Comprehensive in�vivo interrogation reveals ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
Comprehensive in�vivo interrogation reveals phenotypic impact of human enhancer variants
Auteur(s) :
Kvon, Evgeny Z. [Auteur]
Zhu, Yiwen [Auteur]
Kelman, Guy [Auteur]
Novak, Catherine S. [Auteur]
Plajzer-Frick, Ingrid [Auteur]
Kato, Momoe [Auteur]
Garvin, Tyler H. [Auteur]
Pham, Quan [Auteur]
Harrington, Anne N. [Auteur]
Hunter, Riana D. [Auteur]
Godoy, Janeth [Auteur]
Meky, Eman M. [Auteur]
Akiyama, Jennifer A. [Auteur]
Afzal, Veena [Auteur]
Tran, Stella [Auteur]
Escande, Fabienne [Auteur]
Gilbert-Dussardier, Brigitte [Auteur]
Jean-Marcais, Nolwenn [Auteur]
Hudaiberdiev, Sanjarbek [Auteur]
Ovcharenko, Ivan [Auteur]
Dobbs, Matthew B. [Auteur]
Gurnett, Christina A. [Auteur]
Manouvrier, Sylvie [Auteur]
Petit, Florence [Auteur]
Visel, Axel [Auteur]
Dickel, Diane E. [Auteur]
Pennacchio, Len A. [Auteur]
Zhu, Yiwen [Auteur]
Kelman, Guy [Auteur]
Novak, Catherine S. [Auteur]
Plajzer-Frick, Ingrid [Auteur]
Kato, Momoe [Auteur]
Garvin, Tyler H. [Auteur]
Pham, Quan [Auteur]
Harrington, Anne N. [Auteur]
Hunter, Riana D. [Auteur]
Godoy, Janeth [Auteur]
Meky, Eman M. [Auteur]
Akiyama, Jennifer A. [Auteur]
Afzal, Veena [Auteur]
Tran, Stella [Auteur]
Escande, Fabienne [Auteur]
Gilbert-Dussardier, Brigitte [Auteur]
Jean-Marcais, Nolwenn [Auteur]
Hudaiberdiev, Sanjarbek [Auteur]
Ovcharenko, Ivan [Auteur]
Dobbs, Matthew B. [Auteur]
Gurnett, Christina A. [Auteur]
Manouvrier, Sylvie [Auteur]
Petit, Florence [Auteur]
Visel, Axel [Auteur]
Dickel, Diane E. [Auteur]
Pennacchio, Len A. [Auteur]
Titre de la revue :
Cell
Nom court de la revue :
Cell
Date de publication :
2020-03-06
ISSN :
1097-4172
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer ...
Lire la suite >Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.Lire moins >
Lire la suite >Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
Collections :
Date de dépôt :
2021-09-02T07:01:35Z