细胞遗传学检测到的倒位通常被认为是拷贝数和表型中性事件。虽然非等位基因同源重组被认为起主要作用,最近的数据表明,其他分子机制参与倒置形成。使用短阅读全基因组测序(WGS)的组合,10X基因组学铬WGS,液滴数字聚合酶链反应和阵列比较基因组杂交我们研究了18个大型独特的细胞遗传学检测染色体倒位的基因组结构,并实现了至少一个染色体倒位连接的13/18(72%)的核苷酸分辨率。令人惊讶的是,我们观察到,看似拷贝数中性反转可以伴随着高达350kb的拷贝数增加和局部基因组复杂性(3/18,17%)。在解析的反转中,突变特征与非同源末端连接(8/13,62%)或非同源介导的断裂诱导的复制(5/13,38%)一致.我们的研究表明,短读30x覆盖WGS可以检测到很大一部分染色体倒位。此外,这些事件中约有38%由基于复制的机制导致,这些事件导致相当大比例的倒位,而这些倒位实际上伴随着可能导致这些患者整体表型呈现的额外拷贝数变异.
Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short-read whole-genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy-number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end-joining (8/13, 62%) or microhomology-mediated break-induced replication (5/13, 38%). Our study indicates that short-read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication-based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy-number variation potentially contributing to the overall phenotypic presentation of those patients.