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Genomic copy number variation (CNV) plays a major role in various human diseases as well as in normal phenotypic variability. For some recurrent disease-causing CNVs that convey genomic disorders, the causative mechanism is meiotic, non-allelic, homologous recombination between breakpoint regions exhibiting extensive sequence homology (e.g. low-copy repeats). For the majority of recently identified rare pathogenic CNVs, however, the mechanism is unknown. Recently, a model for CNV formation implicated mitotic replication-based mechanisms, such as (alternative) non-homologous end joining and fork stalling and template switching, in the etiology of human pathogenic CNVs. The extent to which such mitotic mechanisms contribute to rare pathogenic CNVs remains to be determined. In addition, it is unexplored whether genomic architectural features such as repetitive elements or sequence motifs associated with DNA breakage stimulate the formation of rare pathogenic CNVs. To this end, we have sequenced breakpoint junctions of 30 rare pathogenic microdeletions and eight tandem duplications, representing the largest series of such CNVs examined to date in this much detail. Our results demonstrate the presence of (micro)homology ranging from 2 to over 75 bp, in 79% of the breakpoint junctions. This indicates that microhomology-mediated repair mechanisms, including the recently reported fork stalling and template switching and/or microhomology-mediated break-induced replication, prevail in rare pathogenic CNVs. In addition, we found that the vast majority of all breakpoints (81%) were associated with at least one of the genomic architectural features evaluated. Moreover, 75% of tandem duplication breakpoints were associated with the presence of one of two novel sequence motifs. These data suggest that rare pathogenic microdeletions and tandem duplications do not occur at random genome sequences, but are stimulated and potentially catalyzed by various genomic architectural features.

Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture