The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans

Abstract

James Lupski and colleagues provide evidence that a replication-based mechanism termed FoSTeS/MMBIR can mediate rearrangements in humans ranging in size from a few hundred base pairs to several megabases. They propose that FoSTeS/MMBIR could be an important mechanism for generating structural variation. We recently proposed a DNA replication–based mechanism of fork stalling and template switching (FoSTeS) to explain the complex genomic rearrangements associated with a dysmyelinating central nervous system disorder in humans1. The FoSTeS mechanism has been further generalized and molecular mechanistic details have been provided in the microhomology-mediated break-induced replication (MMBIR) model that may underlie many structural variations in genomes from all domains of life2. Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR. Furthermore, we show that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. The FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis3 and exon shuffling4, suggesting an important role in both genome and single-gene evolution.