Mechanisms of change in gene copy number

Abstract

Copy number variants (CNVs) arise by homologous recombination (HR) between repeated sequences (recurrent CNVs) or by non-homologous recombination mechanisms that occur throughout the genome (non-recurrent CNVs). Non-recurrent CNVs frequently show microhomology at their end-points, and can have a complex structure. The locus-specific mutation frequencies for copy number variation and other structural changes are two to four orders of magnitude greater than for point mutations. HR mechanisms generally achieve accurate repair of DNA damage. Double-stranded breaks are repaired by HR or by end-joining mechanisms, which can be non-homologous. Broken replication forks with single double-stranded ends are also repaired by HR. There is evidence that repair of broken replication forks underlies some non-homologous recombination. Repair of broken forks in stressed cells could cause non-homologous repair because of a downregulation of HR proteins induced by stress. Models are presented for mechanisms by which stress might induce non-homologous events leading to copy number variation.