DNA replication initiation shapes the mutational landscape and expression of the human genome

Murat, Pierre, Perez, Consuelo, Crisp, Alastair, van Eijk, Patrick ORCID: https://orcid.org/0000-0001-9549-555X, Reed, Simon H. ORCID: https://orcid.org/0000-0002-4711-0560, Guilbaud, Guillaume and Sale, Julian E. 2022. DNA replication initiation shapes the mutational landscape and expression of the human genome. Science Advances 8 (45) 10.1126/sciadv.add3686

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (1MB) | Preview

Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2375-2548
Date of First Compliant Deposit:	21 December 2022
Date of Acceptance:	21 September 2022
Last Modified:	18 May 2023 11:51
URI:	https://orca.cardiff.ac.uk/id/eprint/155086

Actions (repository staff only)

Edit Item