Genomic Rearrangement Mechanisms.

<p>For the gene deletions in patient 1, gene rearrangements exhibiting deletions due to non-homologous end-joining (NHEJ) were thought to have occurred, since repeated two base sequences of TA were observed at both ends of the gene (1a, 1b). In patient 2, it was hypothesized that rearrangement might have occurred through a mechanism involving a combination of fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR). A three base repeat sequence of AAT prone to cause changes in copy number or sequence swaps was observed in a discontinuous end of the lagging strand during DNA replication. This formed a loop by binding to TTA on its complementary strand with replication slippage occurring (2a). At the discontinuous end, the lagging strand with the loop formed had a six base microhomology of AGGTAT and dissociated. The dissociated end subsequently bound to the ATACCT found at the duplication front of the leading strand. Synthesis and extension of the leading strand then occurred originating from the binding site (2b). The gene synthesized on the leading strand is hypothesized to cause structural abnormalities leading to duplications of the DNA strand subsequent to the DNA strand deletion by returning to the lagging strand after the end of duplication and the binding of the end that has finished duplication to the starting end of the normal gene on the lagging strand by DNA ligase (2c).