THE ROLE OF DNA REPLICATION TIMING IN GERMLINE MUTATION ACCUMULATION

Abstract

DNA replication timing is a highly regulated, cell type-specific process that is associated with mutation accumulation. The developmental plasticity of replication timing complicates this relationship, however. In this work, I analyzed the locations of germline mutations in relation to replication timing profiles at five developmental stages in zebrafish to investigate how replication timing plasticity relates to germline mutation accumulation. Single nucleotide polymorphisms (SNPs) were enriched within regions of developmentally-stable replication timing, while copy number variants (CNVs) were enriched within regions with progressively later replication timing throughout development. CNVs with developmentallyplastic replication timing were also enriched within the protocadherin gene clusters, suggesting that replication timing plasticity, not just the replication timing at one developmental stage, may play a role in mutation accumulation bias and permit mutation accumulation within evolutionarily-advantageous regions.