Unstable DNA repair genes shaped by their own sequence modifying phenotypes

Daniel S. Falster, Sigve Nakken, Marie Bergem-Ohr, Einar Andreas Rødland, Jarle Breivik*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)
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Abstract

The question of whether natural selection favors genetic stability or genetic variability is a fundamental problem in evolutionary biology. Bioinformatic analyses demonstrate that selection favors genetic stability by avoiding unstable nucleotide sequences in protein encoding DNA. Yet, such unstable sequences are maintained in several DNA repair genes, thereby promoting breakdown of repair and destabilizing the genome. Several studies have therefore argued that selection favors genetic variability at the expense of stability. Here we propose a new evolutionary mechanism, with supporting bioinformatic evidence, that resolves this paradox. Combining the concepts of gene-dependent mutation biases and meiotic recombination, we argue that unstable sequences in the DNA mismatch repair (MMR) genes are maintained by their own phenotype. In particular, we predict that human MMR maintains an overrepresentation of mononucleotide repeats (monorepeats) within and around the MMR genes. In support of this hypothesis, we report a 31% excess in monorepeats in 250 kb regions surrounding the seven MMR genes compared to all other RefSeq genes (1.75 vs. 1.34%, P = 0.0047), with a particularly high content in PMS2 (2.41%, P = 0.0047) and MSH6 (2.07%, P = 0.043). Based on a mathematical model of monorepeat frequency, we argue that the proposed mechanism may suffice to explain the observed excess of repeats around MMR genes. Our findings thus indicate that unstable sequences in MMR genes are maintained through evolution by the MMR mechanism. The evolutionary paradox of genetically unstable DNA repair genes may thus be explained by an equilibrium in which the phenotype acts back on its own genotype.

Original languageEnglish
Pages (from-to)266-274
Number of pages9
JournalJournal of Molecular Evolution
Volume70
Issue number3
DOIs
Publication statusPublished - Mar 2010

Bibliographical note

Copyright the Author(s) 2010. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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    Falster, D. S., Nakken, S., Bergem-Ohr, M., Rødland, E. A., & Breivik, J. (2010). Unstable DNA repair genes shaped by their own sequence modifying phenotypes. Journal of Molecular Evolution, 70(3), 266-274. https://doi.org/10.1007/s00239-010-9328-0