Copy number variants (CNVs) are genomic rearrangements implicated in numerous congenital and acquired diseases, including cancer. The appearance of culture-acquired CNVs in human pluripotent stem cells (PSCs) has prompted concerns for their use in regenerative medicine. A particular problem in PSC is the frequent occurrence of CNVs in the q11.21 region of chromosome 20. However, the exact mechanism of origin of this amplicon remains elusive due to the difficulty in delineating its sequence and breakpoints. Here, we have addressed this problem using long-read Nanopore sequencing of two examples of this CNV, present as duplication and as triplication. In both cases, the CNVs were arranged in a head-to-tail orientation, with microhomology sequences flanking or overlapping the proximal and distal breakpoints. These breakpoint signatures point to a mechanism of microhomology-mediated break-induced replication in CNV formation, with surrounding Alu sequences likely contributing to the instability of this genomic region.

中文翻译：

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纳米孔测序表明人类多能干细胞中染色体 20q11.21 的串联扩增是由断裂诱导复制驱动的

拷贝数变异 (CNV) 是涉及许多先天性和后天性疾病（包括癌症）的基因组重排。人类多能干细胞 (PSC) 中培养获得的 CNV 的出现引起了人们对其在再生医学中的使用的担忧。PSC 中的一个特殊问题是 CNV 在 20 号染色体的 q11.21 区域频繁出现。然而，由于难以描述其序列和断点，该扩增子的确切起源机制仍然难以捉摸。在这里，我们使用长读长纳米孔测序解决了这个问题，对这个 CNV 的两个例子进行了测序，呈现为重复和三次。在这两种情况下，CNV 都以头对尾的方向排列，微同源序列位于或重叠近端和远端断点。Alu序​​列可能导致该基因组区域的不稳定性。