Publication Date
7-10-2024
Journal
Cell Genomics
DOI
10.1016/j.xgen.2024.100590
PMID
38908378
PMCID
PMC11293582
PubMedCentral® Posted Date
6-21-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Haplotypes, Comparative Genomic Hybridization, Genomic Structural Variation, Genome, Human, Gene Duplication, copy-number variant, break-induced replication, recombination, Xq28, inversions, segmental duplication, MECP2 duplication syndrome, Mendelian diseases, MMBIR, template switching
Abstract
The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
Graphical Abstract
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Genetics and Genomics Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons
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