Copy number variants, diseases and gene expression

Abstract

Copy number variation (CNV) has recently gained considerable interest as a source of genetic variation likely to play a role in phenotypic diversity and evolution. Much effort has been put into the identification and mapping of regions that vary in copy number among seemingly normal individuals in humans and a number of model organisms, using bioinformatics or hybridization-based methods. These have allowed uncovering associations between copy number changes and complex diseases in whole-genome association studies, as well as identify new genomic disorders. At the genome-wide scale, however, the functional impact of CNV remains poorly studied. Here we review the current catalogs of CNVs, their association with diseases and how they link genotype and phenotype. We describe initial evidence which revealed that genes in CNV regions are expressed at lower and more variable levels than genes mapping elsewhere, and also that CNV not only affects the expression of genes varying in copy number, but also have a global influence on the transcriptome. Further studies are warranted for complete cataloguing and fine mapping of CNVs, as well as to elucidate the different mechanisms by which they influence gene expression.

Genetic Variants Contribute to Gene Expression Variability in Humans

“…However, this assumption cannot be used to explain the negative correlations between gene copy number and expression level. Schlattl et al (2011) found that $20% of associations of CNVs displayed the unexpected negative correlations, including several instances that had been previously observed (Stranger et al 2007a;Henrichsen et al 2009). …”

Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia

“…Deletions, in the presence of other schizophrenia genetic risk factors, may be directly interrupting one or more of these systems resulting in reduced neural efficiency and dysfunctional connectivity, leading to greater cognitive dysfunction. However, CNVs may also be affecting the expression and regulation of genes other than those directly affected by the CNV itself [91]. Further In sum, the current study replicated previous findings concerning the relationship between rare deletions and general cognition and extended the findings, identifying grey-matter volume differences in the striatum and right superior temporal gyrus and functional connectivity differences in cognitive control and default mode resting state networks.…”

Insight into the Genomics of Premature Ovarian Failure

“…Identification of deletions and translocations in POF1 and POF2 regions has suggested several POF-candidate genes, such as [36][37][38], although very few mutations have actually been detected in these loci [39,40].…”

“…The CNV, defined as regions of DNA larger than 1 kb that display copy number differences in the normal population, contribute to genetic variation associated with diseases or susceptibility to diseases [40]. Indeed, CNV can influence transcriptional and translational levels of overlapping or nearby genes [91].…”