Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication

Area of Science:

• Genetics
• Genomic Rearrangement
• Molecular Biology

Background:

• Inverted repeats (IRs) are known hotspots for genomic rearrangements.
• Complex structural variations, such as duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) events, have been associated with MECP2 duplication syndrome and Pelizaeus-Merzbacher disease (PMD).

Purpose of the Study:

• To investigate the mechanism behind DUP-TRP/INV-DUP rearrangements in PMD patients.
• To identify the role of inverted repeats in facilitating complex genomic rearrangements.

Main Methods:

• Analysis of 17 unrelated PMD subjects with copy number gains at the PLP1 locus.
• Characterization of structural variation products, including DUP-TRP/INV-DUP rearrangements.

Main Results:

• 16 out of 17 PMD subjects exhibited DUP-TRP/INV-DUP rearrangement products.
• An inverted repeat distal to the PLP1 gene was identified as a key facilitator of DUP-TRP/INV-DUP formation and inversions.
• Evidence suggests homology-driven DNA repair mechanisms mediate template switching within microhomology regions.

Conclusions:

• Inverted repeats play a crucial role in the formation of complex structural variations like DUP-TRP/INV-DUP rearrangements in PMD.
• The microhomology-mediated break-induced replication (MMBIR) model can explain the formation of quadruplications and higher-order amplifications through rolling circle amplification.