Figure 1: CNV infl uencing gene dosage and expression and disease. There are a number of mechanisms by which CNVs potentially could have an effect on gene expression and phenotypic traits. Well-documented examples involve regions with multiple genes deleted in microdeletion syndromes and microduplication syndromes (A), where there is a direct correlation between genotype and phenotype. Copy number polymorphisms where a gene is located entirely within a region that varies in copy number (B) have also been described to show a direct correlation between gene copy number and gene expression. Another mechanism by which CNVs may have an infl uence on disease phenotype is if the remaining copy harbors a risk allele that becomes apparent only in the hemizygous state (C). The opposite scenario may also occur, with an increased number of copies harboring a risk allele, causing a concurrent increase in disease susceptibility. It can also be hypothesized that CNVs may affect gene expression without directly changing the gene copy number. Gains or losses affecting the regulatory elements or promoter regions can also be important contributors to differences in gene expression. This could involve either loss of an element of transcriptional regulation (D and F) or a loss/gain changing the structural properties of DNA inhibiting enhancer interaction, chromatin structure or access of transcription factors to their binding sites (E). Interaction and additive models with any of these scenarios combined or in combination with any type of variation at other loci can be expected to be the cause of more complex genetic traits.