Fig. 2

Replication-based mechanism model for the generation of DUP-TRP/INV-DUP rearrangement followed by isoUPD detected in the present case. a The event probably occurred involving parental homolog chromosomes, P1 and P2. The first template switch (template switch 1) have been triggered by a stalled or collapsed replication fork (fork collapse 1), and used a complementary strand to resume replication through using microhomology in the complementary strand at the annealing site (jct1, Fig. 1c) to prime DNA synthesis, resulting in the production of a segment with the inverse orientation compared with the reference genome. Two putative jct1 sites, jct1 between c and d_c (left) and jct1 between d and c_c, (right) are predicted, because the same sequence result can be obtained in both cases (see Fig. 1c). Then, a new fork stalling or collapsing event (fork collapse 2) have released a free 3’ end that can be resolved by the second template switching (template switch 2) through using the microhomology in the homologous chromosome at the annealing site (jct2, Fig. 1c) to prime and resume DNA synthesis, resulting in the generation of jct2 as well as isoUPD. a–d, representative chromosome alleles in P1 chromosome; a_c–e_c, complementary chromosome alleles in P1 chromosome; A–E: corresponding homologous chromosome alleles in the P2 chromosome. b Top: different genomic structures are predicted to be generated depending on the location of the selected annealing site (jct1) to prime DNA synthesis in the first template switch event. isoUPD will result if the unidirectional replication fork continues until the telomere. Bottom: predicted segmental CNV in a simulated CMA. Note that the small size of the telomeric duplication between fork collapse 1 and jct1 led to the evasion of CMA detection (Fig. 1a), because the region was too small to be detected by Affymetrix Cytoscan HD array