Challenges and standards in integrating surveys of structural variation

Abstract

There has been an explosion of data describing newly recognized structural variants in the human genome. In the flurry of reporting, there has been no standard approach to collecting the data, assessing its quality or describing identified features. This risks becoming a rampant problem, in particular with respect to surveys of copy number variation and their application to disease studies. Here, we consider the challenges in characterizing and documenting genomic structural variants. From this, we derive recommendations for standards to be adopted, with the aim of ensuring the accurate presentation of this form of genetic variation to facilitate ongoing research.

Figure 1

Lexicon of genomic variation. Descriptors of variation began in the realm of cytogenetics, followed by those from the field of molecular genetics and, most recently, by technologies such as those described in this perspective, which bridge the gap for detection of genomic variants (sometimes called cytogenomics55). The designation of the category ‘1 kb to submicroscopic’ is somewhat arbitrary at both ends, but is used for operational definition. In a broad sense, structural variation has been used to refer to genomic segments both smaller and larger than the narrower operational definition, as illustrated by the large bracket. The focus of recent discoveries has been the subgroup in the midrange (indicated with strong highlighting), but the gradation of shading illustrates that the biological boundaries may really encompass some forms of variation previously recognized from either cytogenetic or molecular genetic approaches. At the molecular level, SNPs can be identified that are representative of the underlying haplotype structure (tagSNPs). As structural variation becomes better integrated with the existing SNP-based linkage disequilibrium maps, it is likely that presence or absence of many structural variants will simply be inferred by typing selected SNPs,,.