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Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease

It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many...

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Autores principales: Fu, Alexander Xi, Lui, Kathy Nga-Chu, Tang, Clara Sze-Man, Ng, Ray Kit, Lai, Frank Pui-Ling, Lau, Sin-Ting, Li, Zhixin, Garcia-Barcelo, Maria-Mercè, Sham, Pak-Chung, Tam, Paul Kwong-Hang, Ngan, Elly Sau-Wai, Yip, Kevin Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605255/
https://www.ncbi.nlm.nih.gov/pubmed/32948616
http://dx.doi.org/10.1101/gr.264473.120
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author Fu, Alexander Xi
Lui, Kathy Nga-Chu
Tang, Clara Sze-Man
Ng, Ray Kit
Lai, Frank Pui-Ling
Lau, Sin-Ting
Li, Zhixin
Garcia-Barcelo, Maria-Mercè
Sham, Pak-Chung
Tam, Paul Kwong-Hang
Ngan, Elly Sau-Wai
Yip, Kevin Y.
author_facet Fu, Alexander Xi
Lui, Kathy Nga-Chu
Tang, Clara Sze-Man
Ng, Ray Kit
Lai, Frank Pui-Ling
Lau, Sin-Ting
Li, Zhixin
Garcia-Barcelo, Maria-Mercè
Sham, Pak-Chung
Tam, Paul Kwong-Hang
Ngan, Elly Sau-Wai
Yip, Kevin Y.
author_sort Fu, Alexander Xi
collection PubMed
description It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage–specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.
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spelling pubmed-76052552021-05-01 Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease Fu, Alexander Xi Lui, Kathy Nga-Chu Tang, Clara Sze-Man Ng, Ray Kit Lai, Frank Pui-Ling Lau, Sin-Ting Li, Zhixin Garcia-Barcelo, Maria-Mercè Sham, Pak-Chung Tam, Paul Kwong-Hang Ngan, Elly Sau-Wai Yip, Kevin Y. Genome Res Method It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage–specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain. Cold Spring Harbor Laboratory Press 2020-11 /pmc/articles/PMC7605255/ /pubmed/32948616 http://dx.doi.org/10.1101/gr.264473.120 Text en © 2020 Fu et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Method
Fu, Alexander Xi
Lui, Kathy Nga-Chu
Tang, Clara Sze-Man
Ng, Ray Kit
Lai, Frank Pui-Ling
Lau, Sin-Ting
Li, Zhixin
Garcia-Barcelo, Maria-Mercè
Sham, Pak-Chung
Tam, Paul Kwong-Hang
Ngan, Elly Sau-Wai
Yip, Kevin Y.
Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
title Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
title_full Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
title_fullStr Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
title_full_unstemmed Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
title_short Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
title_sort whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with hirschsprung disease
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605255/
https://www.ncbi.nlm.nih.gov/pubmed/32948616
http://dx.doi.org/10.1101/gr.264473.120
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