Absence of heterozygosity due to template switching during replicative rearrangements.

TitleAbsence of heterozygosity due to template switching during replicative rearrangements.
Publication TypeJournal Article
Year of Publication2015
AuthorsCarvalho, CMB, Pfundt, R, King, DA, Lindsay, SJ, Zuccherato, LW, Macville, MVE, Liu, P, Johnson, D, Stankiewicz, P, Brown, CW, Shaw, CA, Hurles, ME, Ira, G, Hastings, PJ, Brunner, HG, Lupski, JR
Corporate AuthorsDDD Study
JournalAm J Hum Genet
Volume96
Issue4
Pagination555-64
Date Published2015 Apr 02
ISSN1537-6605
KeywordsBase Sequence, DNA Copy Number Variations, DNA Repair, DNA Replication, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Loss of Heterozygosity, Models, Genetic, Molecular Sequence Data, Netherlands, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Uniparental Disomy
Abstract

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.
DOI10.1016/j.ajhg.2015.01.021
Alternate JournalAm J Hum Genet
PubMed ID25799105
PubMed Central IDPMC4385179
Grant ListR01GM106373 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
R01GM080600 / GM / NIGMS NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
R01 GM080600 / GM / NIGMS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
/ / Wellcome Trust / United Kingdom

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