PDF(Pubmed)
Abstract：
Replication errors and various genotoxins cause DNA double-strand breaks (DSBs) where error-prone repair creates genomic mutations, most frequently focal deletions, and defective repair may lead to neurodegeneration. Despite its pathophysiological importance, the extent to which faulty DSB repair alters the genome, and the mechanisms by which mutations arise, have not been systematically examined reflecting ineffective methods. Here, we develop PhaseDel, a computational method to detect focal deletions and characterize underlying mechanisms in single-cell whole genome sequences (scWGS). We analyzed high-coverage scWGS of 107 single neurons from 18 neurotypical individuals of various ages, and found that somatic deletions increased with age and in highly expressed genes in human brain. Our analysis of 50 single neurons from DNA repair-deficient diseases with progressive neurodegeneration (Cockayne syndrome, Xeroderma pigmentosum, and Ataxia telangiectasia) reveals elevated somatic deletions compared to age-matched controls. Distinctive mechanistic signatures and transcriptional associations suggest roles for somatic deletions in neurodegeneration.
摘要：
复制错误和各种基因毒素会导致DNA双链断裂（DSB），其中易错修复会产生基因组突变，最常见的局灶性缺失，修复缺陷可能导致神经变性。尽管它的病理生理重要性，错误的DSB修复改变基因组的程度，以及突变产生的机制，没有经过系统的检查，反映出无效的方法。这里,我们开发了PhaseDel,一种检测局灶性缺失和表征单细胞全基因组序列（scWGS）潜在机制的计算方法。我们分析了来自不同年龄的18个神经典型个体的107个单神经元的高覆盖率scWGS，并发现体细胞缺失随着年龄和人脑中高表达基因的增长而增加。我们分析了50个来自DNA修复缺陷疾病的进行性神经变性（Cockayne综合征，着色性干皮病,与年龄匹配的对照相比，共济失调毛细血管扩张）显示出体细胞缺失升高。独特的机制特征和转录关联表明体细胞缺失在神经变性中的作用。
