Copy number variation and susceptibility to complex traits

Abstract

Copy number variations (CNV) within the genome are extremely abundant. In this closeup, Canales and Walz discuss how CNV are associated with normal variation, genomic disorders, genome evolution, adaptive traits and how the use of a novel screen described by Ermakova et al in this issue that is designed to identify human diseaserelevant phenotypes associated with CNV in the mouse can help elucidating susceptibility or predisposition to diseases loci.

Figure 1. Copy number variations (CNV) result in subtle differences in genomic background, which can lead to phenotypic variability

The presence of CNV (first hit) can determine sensitized backgrounds, which set different thresholds for disease development. Not only a genetic second hit can trigger a phenotype, also environmental ‘second hits’ or challenges can activate a set of phenotypes and complex traits.

1. Environmental second hit: an individual carries a CNV, which predisposes to obesity under certain environmental conditions. The phenotype is only revealed after challenge (high fat diet).

2. Genetic second hit: an individual carries a CNV, which predisposes for the development of a cardiovascular disease. Both individuals have a mutated allele for a gene that predisposes them to a cardiovascular disease, but only the one with the two genetic modifications will develop a cardiovascular phenotype.