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Research Article

Substitutions of short heterologous DNA segments of intragenomic or extragenomic origins produce clustered genomic polymorphisms

Klaus Harms, Asbjørn Lunnan, Nils Hülter, Tobias Mourier, Lasse Vinner, Cheryl P. Andam, Pekka Marttinen, Helena Fridholm, Anders Johannes Hansen, William P. Hanage, Kaare Magne Nielsen, Eske Willerslev, and Pål Jarle Johnsen
PNAS first published December 12, 2016; https://doi.org/10.1073/pnas.1615819114
Klaus Harms
aDepartment of Pharmacy, Faculty of Health Sciences, The Arctic University of Norway, 9037 Tromsø, Norway;
bCentre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark;
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  • For correspondence: klaus.harms@spdir.net ewillerslev@snm.ku.dk paal.johnsen@uit.no
Asbjørn Lunnan
aDepartment of Pharmacy, Faculty of Health Sciences, The Arctic University of Norway, 9037 Tromsø, Norway;
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Nils Hülter
cGenomic Microbiology, Institute of Microbiology, Christian-Albrechts-Universität zu Kiel, 24118 Kiel, Germany;
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Tobias Mourier
bCentre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark;
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Lasse Vinner
bCentre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark;
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Cheryl P. Andam
dDepartment of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115;
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Pekka Marttinen
eHelsinki Institute for Information Technology, Department of Computer Science, Aalto University, FIN-00076 Aalto, Finland;
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Helena Fridholm
bCentre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark;
fDepartment of Microbiological Diagnostics and Virology, Statens Serum Institut, 2300 Copenhagen S, Denmark;
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Anders Johannes Hansen
bCentre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark;
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William P. Hanage
dDepartment of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115;
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Kaare Magne Nielsen
gDepartment of Life Sciences and Health, Oslo and Akershus University College of Applied Sciences, 0130 Oslo, Norway;
hGenØk-Center for Biosafety, 9294 Tromsø, Norway
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Eske Willerslev
bCentre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark;
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  • For correspondence: klaus.harms@spdir.net ewillerslev@snm.ku.dk paal.johnsen@uit.no
Pål Jarle Johnsen
aDepartment of Pharmacy, Faculty of Health Sciences, The Arctic University of Norway, 9037 Tromsø, Norway;
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  • For correspondence: klaus.harms@spdir.net ewillerslev@snm.ku.dk paal.johnsen@uit.no
  1. Edited by John R. Roth, University of California, Davis, CA, and approved November 22, 2016 (received for review September 23, 2016)

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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.

  • illegitimate recombination
  • mutation
  • microindels

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.

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Clustered genomic polymorphisms
Klaus Harms, Asbjørn Lunnan, Nils Hülter, Tobias Mourier, Lasse Vinner, Cheryl P. Andam, Pekka Marttinen, Helena Fridholm, Anders Johannes Hansen, William P. Hanage, Kaare Magne Nielsen, Eske Willerslev, Pål Jarle Johnsen
Proceedings of the National Academy of Sciences Dec 2016, 201615819; DOI: 10.1073/pnas.1615819114

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Clustered genomic polymorphisms
Klaus Harms, Asbjørn Lunnan, Nils Hülter, Tobias Mourier, Lasse Vinner, Cheryl P. Andam, Pekka Marttinen, Helena Fridholm, Anders Johannes Hansen, William P. Hanage, Kaare Magne Nielsen, Eske Willerslev, Pål Jarle Johnsen
Proceedings of the National Academy of Sciences Dec 2016, 201615819; DOI: 10.1073/pnas.1615819114
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