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Intronic CNVs and gene expression variation in human populations

Lookup NU author(s): Dr Daniel Rico RodriguezORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Introns can be extraordinarily large and they account for the majority of the DNA sequence in human genes. However, little is known about their population patterns of structural variation and their functional implication. By combining the most extensive maps of CNVs in human populations, we have found that intronic losses are the most frequent copy number variants (CNVs) in protein-coding genes in human, with 12,986 intronic deletions, affecting 4,147 genes (including 1,154 essential genes and 1,638 disease-related genes). This intronic length variation results in dozens of genes showing extreme population variability in size, with 40 genes with 10 or more different sizes and up to 150 allelic sizes. Intronic losses are frequent in evolutionarily ancient genes that are highly conserved at the protein sequence level. This result contrasts with losses overlapping exons, which are observed less often than expected by chance and almost exclusively affect primate-specific genes. An integrated analysis of CNVs and RNA-seq data showed that intronic loss can be associated with significant differences in gene expression levels in the population (CNV-eQTLs). These intronic CNV-eQTLs regions are enriched for intronic enhancers and can be associated with expression differences of other genes showing long distance intron-promoter 3D interactions. Our data suggests that intronic structural variation of protein-coding genes makes an important contribution to the variability of gene expression and splicing in human populations.

Publication metadata

Author(s): Rigau M, Juan D, Valencia A, Rico D

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2019

Volume: 15

Issue: 1

Online publication date: 24/01/2019

Acceptance date: 17/12/2018

Date deposited: 02/12/2019

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science


DOI: 10.1371/journal.pgen.1007902

PubMed id: 30677042


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Funder referenceFunder name
206103/Z/17/ZWellcome Trust
European Regional Development Fund (ERDF)
Project Retos BFU2015-71241-R Spanish Ministry of Economy, Industry and Competiveness (MEIC)