Copy-Number Variations, Noncoding Sequences, and Human Phenotypes

Whereas single-nucleotide polymorphisms and their role in predisposition to disease have been studied extensively, the analysis of structural variants—genomic changes such as insertions, deletions, inversions, duplications, and translocations—is still in its infancy. Changes in copy number, also known as copy-number variations (CNVs), constitute one such group of these structural variants. CNVs are structural genomic variants that arise from deletions (loss) or duplications (gain), and as a consequence result in a copy-number change of the respective genomic region. CNVs may include entire genes or regions of transcribed sequence, or, indeed, comprise only nontranscribed sequences. Whereas the duplication or deletion of a gene can be expected to have an effect on gene dosage, the consequences of CNVs in nontranscribed sequences are less obvious. Here we review CNVs that involve regulatory nontranscribed regions of the genome, describe the associated human phenotypes, and discuss possible disease mechanisms.