Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution

The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the function...

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Autores principales: Kircher, Martin, Xiong, Chenling, Martin, Beth, Schubach, Max, Inoue, Fumitaka, Bell, Robert J. A., Costello, Joseph F., Shendure, Jay, Ahituv, Nadav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687891/
https://www.ncbi.nlm.nih.gov/pubmed/31395865
http://dx.doi.org/10.1038/s41467-019-11526-w
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author Kircher, Martin
Xiong, Chenling
Martin, Beth
Schubach, Max
Inoue, Fumitaka
Bell, Robert J. A.
Costello, Joseph F.
Shendure, Jay
Ahituv, Nadav
author_facet Kircher, Martin
Xiong, Chenling
Martin, Beth
Schubach, Max
Inoue, Fumitaka
Bell, Robert J. A.
Costello, Joseph F.
Shendure, Jay
Ahituv, Nadav
author_sort Kircher, Martin
collection PubMed
description The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we perform saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitutions and deletions. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and comprise a rich dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.
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spelling pubmed-66878912019-08-12 Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution Kircher, Martin Xiong, Chenling Martin, Beth Schubach, Max Inoue, Fumitaka Bell, Robert J. A. Costello, Joseph F. Shendure, Jay Ahituv, Nadav Nat Commun Article The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we perform saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitutions and deletions. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and comprise a rich dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations. Nature Publishing Group UK 2019-08-08 /pmc/articles/PMC6687891/ /pubmed/31395865 http://dx.doi.org/10.1038/s41467-019-11526-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kircher, Martin
Xiong, Chenling
Martin, Beth
Schubach, Max
Inoue, Fumitaka
Bell, Robert J. A.
Costello, Joseph F.
Shendure, Jay
Ahituv, Nadav
Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
title Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
title_full Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
title_fullStr Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
title_full_unstemmed Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
title_short Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
title_sort saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687891/
https://www.ncbi.nlm.nih.gov/pubmed/31395865
http://dx.doi.org/10.1038/s41467-019-11526-w
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