Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

人类种系突变的生物学机制仍然很大程度上未知。我们使用体积正则化非负矩阵分解来统计分解沿基因组的突变率和谱的变化。测序数据集 (TOPMed) 的分析揭示了解释基因座之间突变特性变化的九个过程。我们为其中七个过程提供了生物学解释。我们将一种过程与大量 DNA 损伤联系起来，这些损伤在转录和复制方面是不对称解决的。两个进程分别跟踪复制叉的方向和复制计时。我们确定了主要作用于调控区域的主动去甲基化的诱变作用和长散布核元件的诱变作用。我们从群体测序数据中定位了卵母细胞特有的诱变过程。这个过程在转录上显得不对称。