Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

Autor:	Grochowski CM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Bengtsson JD; Pacific Northwest Research Institute, Seattle, WA 98122, USA., Du H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Gandhi M; Pacific Northwest Research Institute, Seattle, WA 98122, USA., Lun MY; Pacific Northwest Research Institute, Seattle, WA 98122, USA., Mehaffey MG; Pacific Northwest Research Institute, Seattle, WA 98122, USA., Park K; Pacific Northwest Research Institute, Seattle, WA 98122, USA., Höps W; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Benito E; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Hasenfeld P; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Korbel JO; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Mahmoud M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Paulin LF; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Hwang JP; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Bhamidipati SV; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Muzny DM; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Fatih JM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Gibbs RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Pendleton M; Oxford Nanopore Technologies, New York, NY 10013, USA., Harrington E; Oxford Nanopore Technologies, New York, NY 10013, USA., Juul S; Oxford Nanopore Technologies, New York, NY 10013, USA., Lindstrand A; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Clinical Genetics and Genomics, Karolinska University Hospital, 171 76 Stockholm, Sweden., Sedlazeck FJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Computer Science, Rice University, Houston TX 77030, USA., Pehlivan D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA., Carvalho CMB; Pacific Northwest Research Institute, Seattle, WA 98122, USA. Electronic address: ccarvalho@pnri.org.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2024 Jul 10; Vol. 4 (7), pp. 100590. Date of Electronic Publication: 2024 Jun 21.
DOI:	10.1016/j.xgen.2024.100590
Abstrakt:	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. Competing Interests: Declaration of interests Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of BG, which performs clinical microarray analysis, clinical ES, and clinical biochemical studies. J.R.L. serves on the scientific advisory board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Genomics International, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. E.H. and S.J. are employees of ONT and shareholders and/or share option holders of ONT. D.P. provides consulting services for Ionis Pharmaceuticals. F.J.S. receives research support from Genetech, Illumina, Pacbio, and ONT. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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