Disclosing the Hidden Structure and Underlying Mutational Mechanism of a Novel Type of Duplication CNV Responsible for Hereditary Multiple Osteochondromas

作者：Su, Peiqiang; Wang, Ye; Cooper, David N.; Zhu, Wenjuan; Huang, Dongsheng; Ferec, Claude; Wang, Yiming; Chen, Jian-Min^*

来源：Human Mutation, 2015, 36(8): 758-763.

DOI：10.1002/humu.22815

• Alu-mediated recombination
• break-induced replication
• hereditary multiple osteochondromas
• whole-genome sequencing

The additional mutational complexity associated with copy number variation (CNV) can provide important clues as to the underlying mechanisms of CNV formation. Correct annotation of the additional mutational complexity is, however, a prerequisite for establishing the mutational mechanism. We illustrate this point through the characterization of a novel approximate to 230 kb EXT1 duplication CNV causing autosomal dominant hereditary multiple osteochondromas. Whole-genome sequencing initially identified the CNV as having a 22-bp insertion at the breakpoint junction and, unprecedentedly, multiple breakpoint-flanking micromutations on both sides of the duplication. Further investigation revealed that this genomic rearrangement had a duplication-inverted triplication-duplication structure, the inverted triplication being a 41-bp sequence synthesized from a nearby template. This permitted the identification of the sequence determinants of both the initiation (an inverted Alu repeat) and termination (a triplex-forming sequence) of break-induced replication and suggested a possible model for the repair of replication-associated double-strand breaks.

• 出版日期2015-8
• 单位中国科学院北京基因组研究所; 河北医科大学; 深圳华大生命科学研究院; 中山大学