Abstract
The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.
Highlights
The 22q11.2 Deletion Syndrome (22q11.2DS) is a congenital malformation disorder and the most frequent microdeletion syndrome in h umans[1]
Given that the families in the dataset consisted of probands with typical LCR22A to LCR22D deletions, we focused on LCR22A and LCR22D
Connecting LCR22A to LCR22D in one homolog was not possible in most genomes
Summary
The 22q11.2 Deletion Syndrome (22q11.2DS) is a congenital malformation disorder and the most frequent microdeletion syndrome in h umans[1]. The mechanism responsible for the deletion is non-allelic homologous recombination (NAHR) between surrounding chromosome 22-specific low copy repeats (LCR22s)[5,6]. The combination of large, near-identical segments makes the LCR22s substrates for NAHR, leading to genomic rearrangements These characteristics make the LCR22s difficult to sequence or to reliably identify rearrangement breakpoints in individuals with 22q11.2DS. There is no complete model of the 22q11.2DS NAHR mechanism Such a model would require complete resolution of contiguous LCR22 modules on each chromosome 22 homolog in the parent who transmits the recombination-generated deleted chromosome, along with the resulting 22q11.2 deletion-containing haplotype transmitted to this individual’s proband. Current sequencing technologies fail to correctly assemble the 22q11.2 region This has prevented an in-depth characterization of the haplotypes associated with NAHR and subsequent 22q11.2 deletions. In 22q11.2, the segmental duplications are significantly larger than any current sequencing technology’s read lengths but can be traversed by optical mapping’s ultra-long molecules
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