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Edited by John R. Roth, University of California, Davis, CA, and approved November 22, 2016 (received for review September 23, 2016)
Significance
Clustered genomic polymorphisms in DNA, such as microindels and stretches of nucleotide changes, play an important role in genome evolution. Here, we report a mutation mechanism responsible for such genomic polymorphisms where short, single-stranded DNA molecules invade double-stranded DNA and replace short genomic segments. We show, in a bacterial model organism, that the genomic replacements occur with very low levels of sequence identity (microhomologies). The invading DNA can be of intagenomic or foreign origin. Genotoxic stress, horizontally taken-up DNA, or lack of genome maintenance functions increase the mutation frequency up to 7,000-fold. Bioinformatic approaches suggest that this class of mutations is widespread in prokaryotes and eukaryotes and may have a role in tumorigenesis.
Abstract
In a screen for unexplained mutation events we identified a previously unrecognized mechanism generating clustered DNA polymorphisms such as microindels and cumulative SNPs. The mechanism, short-patch double illegitimate recombination (SPDIR), facilitates short single-stranded DNA molecules to invade and replace genomic DNA through two joint illegitimate recombination events. SPDIR is controlled by key components of the cellular genome maintenance machinery in the gram-negative bacterium Acinetobacter baylyi. The source DNA is primarily intragenomic but can also be acquired through horizontal gene transfer. The DNA replacements are nonreciprocal and locus independent. Bioinformatic approaches reveal occurrence of SPDIR events in the gram-positive human pathogen Streptococcus pneumoniae and in the human genome.
Footnotes
- ↵1To whom correspondence may be addressed. Email: klaus.harms{at}spdir.net, ewillerslev{at}snm.ku.dk, or paal.johnsen{at}uit.no.
Author contributions: K.H., K.M.N., E.W., and P.J.J. designed research; A.J.H. supervised pipeline building; K.H., A.L., N.H., T.M., L.V., C.P.A., P.M., and H.F. performed research; K.H., T.M., C.P.A., P.M., and P.J.J. analyzed data; and K.H., W.P.H., K.M.N., E.W., and P.J.J. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1615819114/-/DCSupplemental.
Freely available online through the PNAS open access option.
Clustered genomic polymorphisms
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