Department of Molecular Biology and Genetics, Cornell University.
Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation.
Genome Biol Evol. 2019 Jun 1;11(6):1663-1678. doi: 10.1093/gbe/evz098.
The DNA replication timing program is modulated throughout development and is also one of the main factors influencing the distribution of mutation rates across the genome. However, the relationship between the mutagenic influence of replication timing and its developmental plasticity remains unexplored. Here, we studied the distribution of copy number variations (CNVs) and single nucleotide polymorphisms across the zebrafish genome in relation to changes in DNA replication timing during embryonic development in this model vertebrate species. We show that CNV sites exhibit strong replication timing plasticity during development, replicating significantly early during early development but significantly late during more advanced developmental stages. Reciprocally, genomic regions that changed their replication timing during development contained a higher proportion of CNVs than developmentally constant regions. Developmentally plastic CNV sites, in particular those that become delayed in their replication timing, were enriched for the clustered protocadherins, a set of genes important for neuronal development that have undergone extensive genetic and epigenetic diversification during zebrafish evolution. In contrast, single nucleotide polymorphism sites replicated consistently early throughout embryonic development, highlighting a unique aspect of the zebrafish genome. Our results uncover a hitherto unrecognized interface between development and evolution.
DNA 复制时间程序在整个发育过程中被调节，也是影响基因组突变率分布的主要因素之一。然而，复制时间的诱变影响与其发育可塑性之间的关系仍未被探索。在这里，我们研究了斑马鱼胚胎发育过程中 DNA 复制时间变化与基因组中拷贝数变异 (CNVs) 和单核苷酸多态性 (SNPs) 分布之间的关系。我们表明，CNV 位点在发育过程中表现出强烈的复制时间可塑性，在早期发育中显著提前复制，但在更高级的发育阶段显著延迟复制。相反，在发育过程中改变复制时间的基因组区域比发育恒定区域包含更高比例的 CNVs。发育可塑性的 CNV 位点，特别是那些复制时间延迟的位点，富含聚类原钙黏蛋白，这是一组对神经元发育很重要的基因，在斑马鱼进化过程中经历了广泛的遗传和表观遗传多样化。相比之下，SNP 位点在整个胚胎发育过程中始终较早复制，突出了斑马鱼基因组的一个独特方面。我们的结果揭示了发育和进化之间一个以前未被认识到的界面。
