PDF(Pubmed)
Abstract：
The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
摘要：
重复三重复/反向重复（DUP-TRP/INV-DUP）结构是复杂的基因组重排（CGR）。尽管它已被确定为基因组疾病和癌症基因组中重要的致病性DNA突变特征，其架构仍未解决。这里,我们通过调查通过阵列比较基因组杂交(aCGH)鉴定的24例患者的DNA,研究了DUP-TRP/INV-DUP的基因组结构,我们在这些患者身上发现了4种预测结构变异(SV)单倍型中存在4种的证据.使用短阅读基因组测序（GS）的组合，长读GS,光学基因组作图，和单细胞DNA模板链测序(strand-seq)，在18个样本中解析了单倍型结构.4个样品中的模板转换点显示为反向重复序列对中100％核苷酸相似性的~2.2-5.5kb的片段。这些数据提供了反向低拷贝重复作为重组底物的实验证据。这种类型的CGR可以导致在易感剂量敏感基因座中产生多种SV单倍型的多个构象。
