Relating CNVs to transcriptome data at fine-resolution: Assessment of the effect of variant size, type, and overlap with functional regions
- ↵* Corresponding author; email: korbel{at}embl.de
Abstract
Copy-number variants (CNVs) form an abundant class of genetic variation with a presumed widespread impact on individual traits. While recent advances, such as the population-scale sequencing of human genomes, facilitated the fine-scale mapping of CNVs, the phenotypic impact of most of these CNVs remains unclear. By relating copy-number genotypes to transcriptome sequencing data, we have evaluated the impact of CNVs, mapped at fine-scale, on gene expression. Based on data from 129 individuals with ancestry from two populations, we identified CNVs associated with the expression of 110 genes, with 13% of the associations involving complex, multi-allelic CNVs. Categorization of CNVs according to variant type, size and gene overlap enabled us to examine the impact of different CNV classes on expression variation. While many small (<4kb) CNVs were associated with expression variation, overall we observed an enrichment of large duplications and deletions, including large intergenic CNVs, relative to the entire set of expression-associated CNVs. Furthermore, the copy-number of genes intersecting with CNVs typically correlated positively with the genes′ expression, and also was more strongly correlated with expression than nearby single nucleotide polymorphisms, suggesting a frequent causal role of CNVs in expression quantitative trait loci (eQTLs). We also elucidated unexpected cases of negative correlations between copy-number and expression by assessing the CNVs′ effects on the structure and regulation of genes. Finally, we examined dosage compensation of transcript levels. Our results suggest that association-studies can gain in resolution and power by including fine-scale CNV information, such as those obtained from population-scale sequencing.
- Received February 28, 2011.
- Accepted August 8, 2011.
- Copyright © 2011, Cold Spring Harbor Laboratory Press
