Structural Variants in Health and Disease
Genomic disorders often occur as a result of structural variants (SVs) that are caused by rearrangements in unstable regions of the human genome. These types of rearrangements can lead to the loss or gain of dosage-sensitive genes. The rearrangement breakpoints often localize to segmental duplications (SDs), a class of low copy repeats, which mediate the rearrangements. These SD-mediated rearrangements can cause recurrent copy number variations (CNVs) resulting from microdeletion or microduplication of relatively large segments of DNA (>500 Kb). The 7q11.23 microdeletions associated with Williams-Beuren syndrome (WBS), and 22q11.2 microdeletions associated with the 22q11.2. Deletion syndrome (22q11.2 DS) are some well-studied examples of disorders resulting from SD-mediated rearrangements. Several studies have suggested that SD-containing regions vary within the human population. There is evidence that the chromosomes of the transmitting parent of patients with WBS have inversions potentially acting as predisposing SD configurations. Resolving these predisposing SD configurations can further our understanding of microdeletion breakpoints, their impact on the stability of the human genome and pinpoint potential hotspots. However, current techniques used to characterize genomic regions, such as short-read sequencing limited regarding the accurate alignment of the highly-identical sequences of paralogous copies of SDs. Therefore, the structure and content of SD-containing regions remain uncharacterized. We characterized 7q11.2 and 22q11.2 SD-containing regions in a large number of individuals including patients with these microdeletion syndrome and controls from the general population, by using Bionano Genomics optical mapping. Our results revealed unprecedented level of variation in SD-containing regions, between individuals and across different populations. The 22q11.2 SD configurations that we identified, provide the most comprehensive map of the variation at this locus in the human reference sequence. Additionally, we identified novel SVs within the SDs in 7q11.2, 15q13.3 and 16p12.2. These new findings may be useful in prenatal testing, to identify potential predisposing chromosomal configurations in parental samples. Also, methods that we develop during this study can be applied to many other SD containing regions in the genome to identify SVs within SDs and characterize SD configurations.