Inversion variants in the human genome: role in disease and genome architecture

Abstract

Significant advances have been made over the past 5 years in mapping and characterizing structural variation in the human genome. Despite this progress, our understanding of inversion variants is still very restricted. While unbalanced variants such as copy number variations can be mapped using array-based approaches, strategies for characterization of inversion variants have been limited and underdeveloped. Traditional cytogenetic approaches have long been able to identify microscopic inversion events, but discovery of submicroscopic events has remained elusive and largely ignored. With the advent of paired-end sequencing approaches, it is now possible to map inversions across the human genome. Based on the paired-end sequencing studies published to date, it is now feasible to make a first map of inversions across the human genome and to use this map to explore the characteristics and distribution of this form of variation. The current map of inversions indicates that many remain to be identified, especially in the smaller size ranges. This review provides an overview of the current knowledge about human inversions and their contribution to human phenotypes. Further characterization of inversions should be considered as an important step towards a deeper understanding of human variation and genome dynamics.

Figure 1

Overview of inversion discovery by paired-end mapping. The top part of the figure shows the alignment between the reference assembly and an individual carrying an inversion. When paired-end mapping is performed, the donor DNA is first sheared into several similarly sized DNA fragments. The ends of these fragments are then sequenced (fragments are depicted in blue and red, with the boxes at the ends showing the parts that are sequenced). The pairs of end-sequences are then mapped to the reference genome. The majority of these pairs will map in a plus(+)/minus(-) orientation, separated by the approximate distance expected from the fragment size (labeled A and D). End-pairs labeled B and C indicate mapping of fragment ends in a region containing an inversion compared to the reference assembly. Instead of the expected +/- orientation of the two end-sequences, the pairs spanning the inversion breakpoints map as +/+ and -/-, respectively. Clusters of such read pairs are indicative of an inversion. Only fragments spanning the inversion breakpoint will exhibit this pattern of alignment. Better clone coverage will yield better resolution and more accurate mapping of the breakpoints.

Figure 2

Distribution of inversion variants in the human genome. The blue lines in this ideogram show the human chromosomal distribution of the 479 non-redundant inversion variants reported in the Database of Genomic Variants.

Figure 3

Size distribution of inversions and copy number variants. The size distribution of inversions reported in the Database of Genomic Variants (a) shows that the majority of inversions reported to date are in the 10 to 100 kb size bin. The size distribution of inversions differs from that reported for copy number variants (CNVs) (b) The CNV data plotted here show the 11,700 non-redundant CNV events reported by Conrad et al. [13]. It is currently unclear whether the difference in size distribution between inversions and CNVs is due to ascertainment bias, or whether there is an actual biological difference in size distribution. Both cytogenetic data and evolutionary comparative genomic data indicate that large inversions are less detrimental than large deletions and duplications.