Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):E5765-74. doi: 10.1073/pnas.1603241113. Epub 2016 Sep 14.

Inevitability and containment of replication errors for eukaryotic genome lengths spanning megabase to gigabase.

Author information

1
Division of Computational Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK;
2
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
3
Division of Computational Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK; T.Newman@dundee.ac.uk.

Abstract

The replication of DNA is initiated at particular sites on the genome called replication origins (ROs). Understanding the constraints that regulate the distribution of ROs across different organisms is fundamental for quantifying the degree of replication errors and their downstream consequences. Using a simple probabilistic model, we generate a set of predictions on the extreme sensitivity of error rates to the distribution of ROs, and how this distribution must therefore be tuned for genomes of vastly different sizes. As genome size changes from megabases to gigabases, we predict that regularity of RO spacing is lost, that large gaps between ROs dominate error rates but are heavily constrained by the mean stalling distance of replication forks, and that, for genomes spanning ∼100 megabases to ∼10 gigabases, errors become increasingly inevitable but their number remains very small (three or less). Our theory predicts that the number of errors becomes significantly higher for genome sizes greater than ∼10 gigabases. We test these predictions against datasets in yeast, Arabidopsis, Drosophila, and human, and also through direct experimentation on two different human cell lines. Agreement of theoretical predictions with experiment and datasets is found in all cases, resulting in a picture of great simplicity, whereby the density and positioning of ROs explain the replication error rates for the entire range of eukaryotes for which data are available. The theory highlights three domains of error rates: negligible (yeast), tolerable (metazoan), and high (some plants), with the human genome at the extreme end of the middle domain.

KEYWORDS:

Poisson distribution; eukaryotes; genome length; mathematical modeling; replication error

PMID:
27630194
PMCID:
PMC5047159
DOI:
10.1073/pnas.1603241113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center