Absence of heterozygosity due to template switching during replicative rearrangements

Am J Hum Genet. 2015 Apr 2;96(4):555-64. doi: 10.1016/j.ajhg.2015.01.021. Epub 2015 Mar 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA Copy Number Variations / genetics*
  • DNA Repair / genetics*
  • DNA Replication / genetics*
  • Gene Rearrangement / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Loss of Heterozygosity / genetics*
  • Models, Genetic*
  • Molecular Sequence Data
  • Netherlands
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide / genetics
  • Sequence Analysis, DNA
  • Uniparental Disomy / genetics*

Associated data

  • GEO/GSE65113
  • GEO/GSE65379