Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2

Cell. 2019 Mar 7;176(6):1310-1324.e10. doi: 10.1016/j.cell.2019.01.045. Epub 2019 Feb 28.


DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes.

Keywords: CNVs; DNA repair; complex rearrangements; genomic characterization; genomic disorders; long-read sequencing; phasing.

Publication types

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

MeSH terms

  • Abnormalities, Multiple / genetics
  • Chromosome Breakpoints
  • Chromosome Disorders / genetics
  • Chromosome Duplication / genetics
  • Chromosomes, Human, Pair 17*
  • DNA Copy Number Variations
  • DNA Repair / genetics
  • DNA Replication
  • Gene Rearrangement
  • Genome, Human
  • Genomic Structural Variation
  • Humans
  • INDEL Mutation
  • Models, Genetic
  • Mutation*
  • Polymorphism, Single Nucleotide
  • Recombination, Genetic
  • Sequence Analysis, DNA / methods
  • Smith-Magenis Syndrome / genetics

Supplementary concepts

  • Potocki-Lupski syndrome