Chromosomal breaks at the origin of small tandem DNA duplications

Abstract

Small tandem DNA duplications in the range of 15 to 300 base‐pairs play an important role in the aetiology of human disease and contribute to genome diversity. Here, we discuss different proposed mechanisms for their occurrence and argue that this type of structural variation mainly results from mutagenic repair of chromosomal breaks. This hypothesis is supported by both bioinformatical analysis of insertions occurring in the genome of different species and disease alleles, as well as by CRISPR/Cas9‐based experimental data from different model systems. Recent work points to fill‐in synthesis at double‐stranded DNA breaks with complementary sequences, regulated by end‐joining mechanisms, to account for small tandem duplications. We will review the prevalence of small tandem duplications in the population, and we will speculate on the potential sources of DNA damage that could give rise to this mutational signature. With the development of novel algorithms to analyse sequencing data, small tandem duplications are now more frequently detected in the human genome and identified as oncogenic gain‐of‐function mutations. Understanding their origin could lead to optimized treatment regimens to prevent therapy‐induced activation of oncogenes and might expose novel vulnerabilities in cancer.

CRISPR/Cas9-induced double-strand breaks in huntingtin locus lead to CAG repeat contraction through the extensive DNA end resection and homology-mediated repair

“…A substantial group of reads comprises sequences resulting from the deletion of the CAG repeat region between short microhomologous sequences, most frequently CC:GG (see Supplementary File 1). Additionally, a portion of the products contained duplicated sequences from the upstream flank of the CAG repeats, potentially indicating the activity of polymerase theta [32,33].…”

DNA replication initiation drives focal mutagenesis and rearrangements in human cancers

“…Although we observed distinctive signatures in SVs and CNVs at origins, the origins of these events remain speculative. It is noteworthy that double-stranded DNA breaks with protruding ends, such as those that may arise following polymerase stalling at G4s near origins, are known to trigger small tandem duplications following overhang gap filling and end-joining (reviewed in 39 ). In this context, the size of tandem duplication events would be controlled by the location of the breaks and the site where DNA synthesis is initiated.…”