Downstream transcription promotes human recurrent CNV associated AT-rich sequence mediated genome rearrangements in...

AT-rich sequence can cause structure variants such as translocations and its instability can be accelerated by replication stresses. When human 16p11.2 or 22q11.2 recurrent copy number variant (reCNV) associated AT-rich sequence was inserted upstream GAL1 promoter in yeast genome, we found that downstream transcription could promote AT-rich forming cruciform structure and mediate gross genome rearrangements. When genes were flanked with direct repeats containing AT-rich sequence, copy number loss of these genes would be stimulated. Transcription-mediated AT-rich instability can be alleviated by disrupting MUS81 or YEN1 and exacerbated by disrupting RAD1/10. Deletion of homologous recombination-associated genes can not only increase AT-rich fragility but also alter the breakpoint positions. AT-rich stability was also affected by DNA topoisomerase poisons. Our results reveal that transcription can promote AT-rich-mediated de novo genome rearrangement, which might be helpful for understanding the mechanism of reCNV formation in humans.