Papers of the week – Copy Number Variations

Dennis' paper of the weekVariations on Copy Numbers. In the third issue of our series on the papers of the week I will focus on the detection and annotation of the most common form of structural variation encountered in genomes. Deletions, duplications and inversions are frequent events, which are surprisingly hard to deal with using sequencing-based tools. Hence, this is an area of active development.

Annotation. The idea of this post came from a collaborator who asked for a list of tools which will help him to interpret his CNV list. I sent him a list of really old webpages and told him that I am not aware about a really helpful tool that was usable by non-experts out of the box. But then you google. In their new paper, Zhao & Zhao present CNVannotator, a user-friendly web server that annotates all kinds of functional information to a list of CNVs. I tested it and think it’s a cool tool to explore the genomic region covered by a CNV (or a batch of CNVs) in more detail.

Gheldorf et al. (2013) PLoS ONE by CC-BY

Gheldorf et al. (2013) PLoS ONE by CC-BY

Exploring the “neighboring effect”. Can large CNVs lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype? Gheldof and colleagues present some evidence for this. The causative variation of genes in the epilepsy associated recurrent CNVs are still not identified. Shouldn’t we study 3D chromatin interactions?

Inversions. Standard cytogenetic, arrays as well as Multiplex Ligation-dependent Probe Amplification (MPLA) approaches detect deletions or duplications but not balanced structural aberrations such as inversions and translocations. In addition, onversions may escape detection although interruptions of genes may result in haploinsufficiency. Check out InvFEST, a database presented in a paper by Martínez-Fundichely, combining multiple sources of information to generate a complete catalogue of non-redundant human polymorphic inversions.

Comparative-high resolution melting. Rare non-recurrent small CNVs have been found to be associated with neurodevelopmental diseases on several occasions in the last years. In contrast to large recurrent CNVs, small CNVs often turn out to be false positives, especially when detected by sequencing technologies. The costs for validating these CNVs are high due to their heterogeneity at a given locus. Borun and collaborators present a novel technique which allows for a quick and cost-effective CNV detection.

Principles and challenges in CNV calling by NGS platforms. Do I need an array or is a exome enough to detect gene-affecting CNVs? Liu and collegues reviewed NGS data types used for CNV detection, the principles for data preprocessing, and interpretation with special focus on somatic CNV detection, although the depth of your pockets might play the most substantial role.

Missed the latest on CNVs related to idiopathic epilepsies? Join our presentations at the Young Researchers in Epileptology Meeting in Sde Boker, Israel next month.