Germline DNA replication timing shapes mammalian genome composition

Abstract

Mammalian DNA replication is a highly organized and regulated process. Large, Mb-sized regions are replicated at defined times along S-phase. Replication Timing (RT) is thought to play a role in shaping the mammalian genome by affecting mutation rates. Previous analyses relied on somatic RT profiles. However, only germline mutations are passed on to offspring and affect genomic composition. Therefore, germ cell RT information is necessary to evaluate the influences of RT on the mammalian genome. We adapted the RT mapping technique for limited amounts of cells, and measured RT from two stages in the mouse germline - primordial germ cells (PGCs) and spermatogonial stem cells (SSCs). RT in germline cells exhibited stronger correlations to both mutation rate and recombination hotspots density than those of RT in somatic tissues, emphasizing the importance of using correct tissues-of-origin for RT profiling. Germline RT maps exhibited stronger correlations to additional genetic features including GC-content, transposable elements (SINEs and LINEs), and gene density. GC content stratification and multiple regression analysis revealed independent contributions of RT to SINE, gene, mutation, and recombination hotspot densities. Together, our results establish a central role for RT in shaping multiple levels of mammalian genome composition.

Genome size variation and species diversity in salamanders

“…Bengtsson noted that the “properties characteristic of stable or unstable karyotypes may indicate that the cytological factors of importance for karyotype evolution are all of a sub‐microscopic nature (Bengtsson, ).” As a hypothesis for future investigation, we propose that C‐value, as it relates to the amount of noncoding DNA in the genome—and more specifically to a yet uncharacterized cellular system sensitive to variation in noncoding DNA content—influences speciation rates. Such a system, operating in the germline and interacting with recombination rates, would necessarily regulate genome organization and stability (Ohno, ; Yehuda et al., ) and consequently would also act to influence genetic diversity at the molecular level both developmentally and over evolutionary time. The eukaryotic DNA damage response system (DDR), which regulates genome stability, has been proposed to play a role in modulating mutation rates and speciation rates (Herrick, ), and might therefore account for the sub‐microscopic system hypothesized by Bengtsson.…”

Chromosomal Mcm2-7 distribution is the primary driver of the genome replication program in species from yeast to humans

“…Eukaryotes organize the replication of their genomes according to programs that ensure that certain regions of the genome complete replication earlier in S phase than others (Bleichert, Botchan, & Berger, 2017;Dileep & Gilbert, 2018;Fragkos, Ganier, Coulombe, & Mechali, 2015;Rhind & Gilbert, 2013;Riera et al, 2017). Differences in replication timing can have significant consequences, as late replication is associated with higher frequencies of mutation and genome rearrangement (Chen et al, 2010;Koren et al, 2012;Lang & Murray, 2011;Stamatoyannopoulos et al, 2009;Weber, Pink, & Hurst, 2012;Yehuda et al, 2018). The importance of replication timing is underscored by the observation that it is sometimes modulated according to the utility of the region being replicated: For example, some chromosomal regions containing developmentally regulated genes replicate early only during those developmental phases during which they are activated (Hiratani et al, 2010;Rivera-Mulia et al, 2015;Siefert, Georgescu, Wren, Koren, & Sansam, 2017).…”

Insights into the Link between the Organization of DNA Replication and the Mutational Landscape

“…Meiotic recombination provides genetic variation, and hotspots of recombination have been identified in numerous organisms. Comparison of the mouse meiotic recombination landscape with replication profiles indicated that early-replicating regions harbor a higher density of such hotspots [27]. A similar correlation was observed in human genomes in a study of crossover recombination in parent–child pairs [41].…”

“…Mutations serve as substrates for selection and evolution, and it has long been known that they do not accumulate randomly across a genome. A remarkable correlation between replication timing, mutation frequency, and mutation spectrum has emerged from work on a variety of organisms [24,25,26,27]. These connections indicate that the replication program may be a crucial input that affects the types and distributions of genetic alterations that arise in different genomic regions.…”

“…Along the same lines, work in mammalian systems provided evidence for a correspondence between the replication timing of genomic regions and their associated mutation rates. Indeed, comparisons of evolutionary divergence and nucleotide diversity in human and mouse genome sequencing datasets [24,30], as well as of different human cell lines [26,27], indicate that mutation rate is significantly increased in late-replicating regions. This is also the case in cancer cells, where mutation frequencies are two- to three-fold higher in late- vs. early-replicating areas [31,32,33,34].…”