Abstract
Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication—inverted triplication—duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals—16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology—or homeology—driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.
Highlights
Inverted repeats (IRs) are a common architectural feature within the human genome and can predispose loci to rearrangement [1,2,3]
We described a complex genomic rearrangements (CGR) product at the MECP2 locus with an unusual pattern consisting of an inverted triplicated segment flanked by duplicated segments of the genome
This complex CGR is facilitated by inverted repeats in a process that mechanistically could occur by two template switches mediated by replicative DNA repair
Summary
Inverted repeats (IRs) are a common architectural feature within the human genome and can predispose loci to rearrangement [1,2,3]. An IR-mediated inversion that disrupts the Factor VIII gene causes ~45% of severe hemophilia A cases [4]. The abundance of inverted low copy repeats (LCRs) or segmental duplications genome-wide suggests that ~12% of the genome may be susceptible to inversion mediated by IRs [2]. Earlier work provided experimental evidence for genome-wide inversions and suggested these can occur somatically and with aging [9]. Inverted repetitive regions that are smaller than conventional LCRs, designated self-chains, are associated with genomic instability furthering the impact of IRs on both structural human differences and phenotypes [3]
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