Content area
Full Text
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.
Structural variations of the human genome, including copy number variations (CNVs) and balanced inversions generated by genomic rearrangements, represent a significant source of genetic variation5-12. Rearrangements of the human genome can be categorized into two major groups on the basis of breakpoint analysis: recurrent rearrangements, occurring in multiple unrelated individuals with clustering of breakpoints and sharing a common rearrangement interval and size, and nonrecurrent rearrangements, with variable breakpoints13. The major mechanism underlying the former is nonallelic homologous recombination (NAHR)13,14; however, the mechanism(s) for nonrecurrent rearrangements are less well established. Nonhomologous end joining (NHEJ) is a candidate recombination-based mechanism to explain some nonrecurrent rearrangements13,15.
Using high-density oligonucleotide array comparative genomic hybridization (aCGH) to study the nonrecurrent PLP1 duplication rearrangements on the human X chromosome causing Pelizaeus- Merzbacher disease (PMD; MIM312080), we recently reported a high frequency of complex rearrangements1. These complexities were not revealed by previous assays including FISH, PFGE (pulsed-field gel electrophoresis) and BAC aCGH1. The findings were inconsistent with a simple recombination-based mechanism such as NAHR or NHEJ. We proposed a new DNA replication-based mechanism termed FoSTeS to parsimoniously explain the generation of these complex rearrangements in the human genome1.
According to the FoSTeS model1, during DNA replication, the active replication fork can stall and switch templates using complementary template microhomology to anneal and prime DNA replication. The involved forks can be separated by sizeable linear distances but may be adjacent or in close proximity in...