Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
Cell. 2019 Mar 7;176(6):1310-1324.e10. doi: 10.1016/j.cell.2019.01.045. Epub 2019 Feb 28.
DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes.
导致人类基因组结构变异 (SV) 的 DNA 重排是由多种突变机制引起的。我们使用长读和短读测序技术来研究新发生的 17p11.2 染色体重排的终产物，并探究反复出现和非反复出现事件背后的分子机制。在非反复出现的重排中，发现顺式聚集单核苷酸变异 (SNV) 突变的速率增加。插入缺失和 SNV 的形成与 17p11.2 的拷贝数增益和缺失都有关，发生在断裂点连接点约 1Mb 之外，并且有利于 C > G 颠换取代；结果表明，在 SV 的产生过程中形成了单链 DNA，并为 SV 形成的微同源介导的断裂诱导复制 (MMBIR) 机制提供了强有力的支持。我们的数据显示了 MMBIR 的额外突变负担，包括局限于该基因座的超突变，表现为 SNVs 和主要在基因内的插入缺失。
