Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism

Karen E. Hermetz, Scott Newman, Karen N. Conneely, Christa L. Martin, Blake C. Ballif, Lisa G. Shaffer, Jannine D Cody, M. Katharine Rudd

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

Original languageEnglish (US)
Article numbere1004139
JournalPLoS Genetics
Volume10
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Human Genome
chromosome
genome
Chromosomes
disomics
fold
chromosomes
Sequence Inversion
Ring Chromosomes
Gene Amplification
gene amplification
Autistic Disorder
DNA Replication
Intellectual Disability
gene
Sequence Analysis
disability
DNA replication
breakage
tumor

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Hermetz, K. E., Newman, S., Conneely, K. N., Martin, C. L., Ballif, B. C., Shaffer, L. G., ... Rudd, M. K. (2014). Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism. PLoS Genetics, 10(1), [e1004139]. https://doi.org/10.1371/journal.pgen.1004139

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism. / Hermetz, Karen E.; Newman, Scott; Conneely, Karen N.; Martin, Christa L.; Ballif, Blake C.; Shaffer, Lisa G.; Cody, Jannine D; Rudd, M. Katharine.

In: PLoS Genetics, Vol. 10, No. 1, e1004139, 01.2014.

Research output: Contribution to journalArticle

Hermetz, KE, Newman, S, Conneely, KN, Martin, CL, Ballif, BC, Shaffer, LG, Cody, JD & Rudd, MK 2014, 'Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism', PLoS Genetics, vol. 10, no. 1, e1004139. https://doi.org/10.1371/journal.pgen.1004139
Hermetz KE, Newman S, Conneely KN, Martin CL, Ballif BC, Shaffer LG et al. Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism. PLoS Genetics. 2014 Jan;10(1). e1004139. https://doi.org/10.1371/journal.pgen.1004139
Hermetz, Karen E. ; Newman, Scott ; Conneely, Karen N. ; Martin, Christa L. ; Ballif, Blake C. ; Shaffer, Lisa G. ; Cody, Jannine D ; Rudd, M. Katharine. / Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism. In: PLoS Genetics. 2014 ; Vol. 10, No. 1.
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