Genome mapping resolves structural variation within segmental duplications associated with microdeletion/microduplication syndromes

Segmental duplications (SDs) are a class of long, repetitive DNA elements whose paralogs share a high level of sequence similarity with each other. SDs mediate chromosomal rearrangements that lead to structural variation in the general population as well as genomic disorders associated with multiple congenital anomalies, including the 7q11.23 (Williams-Beuren Syndrome, WBS), 15q13.3, and 16p12.2 microdeletion syndromes. These three genomic regions, and the SDs within them, have been previously analyzed in a small number of individuals. However, population-level studies have been lacking because most techniques used for analyzing these complex regions are both labor- and cost-intensive. In this study, we present a high-throughput technique to genotype complex structural variation using a single molecule, long-range optical mapping approach. We identified novel structural variants (SVs) at 7q11.23, 15q13.3 and 16p12.2 using optical mapping data from 154 phenotypically normal individuals from 26 populations comprising 5 super-populations. We detected several novel SVs for each locus, some of which had significantly different prevalence between populations. Additionally, we refined the microdeletion breakpoints located within complex SDs in two patients with WBS, one patient with 15q13.3, and one patient with 16p12.2 microdeletion syndromes. The population-level data presented here highlights the extreme diversity of large and complex SVs within SD-containing regions. The approach we outline will greatly facilitate the investigation of the role of inter-SD structural variation as a driver of chromosomal rearrangements and genomic disorders.