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Review
. 2014 Apr:25:93-100.
doi: 10.1016/j.gde.2013.11.022. Epub 2014 Mar 2.

Complex correlations: replication timing and mutational landscapes during cancer and genome evolution

Jiao Sima  1 , David M Gilbert  2
Affiliations
Review

Complex correlations: replication timing and mutational landscapes during cancer and genome evolution

Jiao Sima et al. Curr Opin Genet Dev. 2014 Apr.

Abstract

A recent flurry of reports correlates replication timing (RT) with mutation rates during both evolution and cancer. Specifically, point mutations and copy number losses correlate with late replication, while copy number gains and other rearrangements correlate with early replication. In some cases, plausible mechanisms have been proposed. Point mutation rates may reflect temporal variation in repair mechanisms. Transcription-induced double-strand breaks are expected to occur in transcriptionally active early replicating chromatin. Fusion partners are generally in close proximity, and chromatin in close proximity replicates at similar times. However, temporal enrichment of copy number gains and losses remains an enigma. Moreover, many conclusions are compromised by a lack of matched RT and sequence datasets, the filtering out of developmental variation in RT, and the use of somatic cell lines to make inferences about germline evolution.

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Figures

Figure 1
Figure 1. Complex relationship between replication timing and genome variation
In the G1-nucleus, heterochromatin, localized to the periphery of the nucleus, may form a first defense line for invading mutagens, increasing point mutation rates in late replicating chromatin. Higher levels of transcription in the interior euchromatin could facilitate transcription-coupled nucleotide excision repair (lowering point mutation rates), but could also promote DSBs leading to translocations. In early S phase, collisions between replication and transcription machineries could increase rates of translocations or duplications, which develop either within a domain (observed during reprogramming) or between domains (observed in cancers). In late-S phase, error-prone repair mechanisms cause accumulation of point mutations.
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