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Multifactorial heterogeneity of the human mutation landscape related to DNA replication dynamics

Mutations do not occur uniformly across genomes but instead show biased associations with various genomic features, most notably late replication timing. However, it remains contested which mutation types in human cells relate to DNA replication dynamics and to what extents. Previous studies have been limited by the absence of cell-type-specific replication timing profiles and lack of consideration of inter-individual variation. To overcome these limitations, we performed high-resolution comparisons of mutational landscapes between and within lymphoblastoid cell lines from 1662 individuals, 151 chronic lymphocytic leukemia patients, and three colon adenocarcinoma cell lines including two with mismatch repair deficiency. Using cell type-matched replication timing profiles, we demonstrate how mutational pathways can exhibit heterogeneous replication timing associations. We further identified global mutation load as a novel, pervasive determinant of mutational landscape heterogeneity across individuals. Specifically, elevated mutation load corresponded to increased late replication timing bias as well as replicative strand asymmetries of clock-like mutations and off-target somatic hypermutation. The association of somatic hypermutation with DNA replication timing was further influenced by mutational clustering. Considering these multivariate factors, and by incorporating mutation phasing at an unprecedented scale, we identified a unique mutational landscape on the inactive X-chromosome. Overall, we report underappreciated complexity of mutational pathways and their relationship to replication timing and identify specific factors underlying differential mutation landscapes among cell types and individuals.