Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Broken String Biosciences Ltd., BioData Innovation Centre, Unit AB3-03, Level 3, Wellcome Genome Campus, Hinxton, Cambridge CB10 1DR, UK.
Sci Adv. 2022 Nov 11;8(45):eadd3686. doi: 10.1126/sciadv.add3686. Epub 2022 Nov 9.
The interplay between active biological processes and DNA repair is central to mutagenesis. Here, we show that the ubiquitous process of replication initiation is mutagenic, leaving a specific mutational footprint at thousands of early and efficient replication origins. The observed mutational pattern is consistent with two distinct mechanisms, reflecting the two-step process of origin activation, triggering the formation of DNA breaks at the center of origins and local error-prone DNA synthesis in their immediate vicinity. We demonstrate that these replication initiation-dependent mutational processes exert an influence on phenotypic diversity in humans that is disproportionate to the origins' genomic size: By increasing mutational loads at gene promoters and splice junctions, the presence of an origin significantly influences both gene expression and mRNA isoform usage. Last, we show that mutagenesis at origins not only drives the evolution of origin sequences but also contributes to sculpting regulatory domains of the human genome.
活性生物过程和 DNA 修复之间的相互作用是诱变的核心。在这里，我们表明普遍存在的复制起始过程具有诱变作用，在数千个早期和有效的复制起点留下特定的突变足迹。观察到的突变模式与两种不同的机制一致，反映了起源激活的两步过程，在起源的中心触发 DNA 断裂的形成，并在其附近进行局部易错 DNA 合成。我们证明，这些依赖于复制起始的突变过程对人类表型多样性的影响与其基因组大小不成比例：通过增加基因启动子和剪接接头处的突变负荷，起源的存在显著影响基因表达和 mRNA 异构体的使用。最后，我们表明，起源处的诱变不仅驱动了起源序列的进化，而且有助于塑造人类基因组的调控域。
