The impact of human copy number variation on gene expression

Abstract

Recent years have witnessed a flurry of important technological and methodological developments in the discovery and analysis of copy number variations (CNVs), which are increasingly enabling the systematic evaluation of their impact on a broad range of phenotypes from molecular-level (intermediate) traits to higher-order clinical phenotypes. Like single nucleotide variants in the human genome, CNVs have been linked to complex traits in humans, including disease and drug response. These recent developments underscore the importance of incorporating complex forms of genetic variation into disease mapping studies and promise to transform our understanding of genome function and the genetic basis of disease. Here we review some of the findings that have emerged from transcriptome studies of CNVs facilitated by the rapid advances in -omics technologies and corresponding methodologies.

Keywords: GWAS; copy number variation; eQTLs; gene expression; transcriptome.

Figure 1

CNVs may influence phenotype though several mechanisms. A gene duplication or deletion event can alter the expression of dosage-sensitive genes. CNVs that only partially overlap a dosage-sensitive gene can induce reduced expression, or by disrupting structure, lead to novel transcripts. CNVs can regulate normal flanking genes, often through a distal mechanism that can extend several megabases from the breakpoints, by modifying regulatory elements. CNVs can also regulate the expression of target genes through position effects (i.e. through the insertion or deletion of sequences leading to alterations in distance to regulatory elements). Green boxes represent exons. Blue boxes represent promoters while orange boxes represent distal enhancers. Triangles mark the breakpoints of CNVs. Circles represent transcription factors that may bind to regulatory elements. (A colour version of this figure is available online at: http://bfg.oxfordjournals.org)