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Somatic mutation hotspots correlate with DNA polymerase η error spectrum

Abstract

Mutational spectra analysis of 15 immunoglobulin genes suggested that consensus motifs RGYW and WA were universal descriptors of somatic hypermutation. Highly mutable sites, “hotspots”, that matched WA were preferentially found in one DNA strand and RGYW hotspots were found in both strands. Analysis of base-substitution hotspots in DNA polymerase error spectra showed that 33 of 36 hotspots in the human polymerase η spectrum conformed to the WA consensus. This and four other characteristics of polymerase η substitution specificity suggest that errors introduced by this enzyme during synthesis of the nontranscribed DNA strand in variable regions may contribute to strand-specific somatic hypermutagenesis of immunoglobulin genes at A-T base pairs.

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Figure 1: Somatic hypermutation spectrum in the mouse κ light chain transgene MM_TR_K1.

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Acknowledgements

Partly supported by RFFR (grant No. 99-04-49535). We thank V. K. Nguyen, B. A. Rogozin, E. V. Koonin, J. Drake, A. Aksenova and W. C. Copeland for helpful discussion and comments on the manuscript.

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Correspondence to Thomas A. Kunkel.

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Rogozin, I., Pavlov, Y., Bebenek, K. et al. Somatic mutation hotspots correlate with DNA polymerase η error spectrum. Nat Immunol 2, 530–536 (2001). https://doi.org/10.1038/88732

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