Sequence variants affecting the genome-wide rate of germline microsatellite mutations

Snaedis Kristmundsdottir, Hakon Jonsson, Marteinn T. Hardarson, Gunnar Palsson, Doruk Beyter, Hannes P. Eggertsson, Arnaldur Gylfason, Gardar Sveinbjornsson, Guillaume Holley, Olafur A. Stefansson, Gisli H. Halldorsson, Sigurgeir Olafsson, Gudny. A. Arnadottir, Pall I. Olason, Ogmundur Eiriksson, Gisli Masson, Unnur Thorsteinsdottir, Thorunn Rafnar, Patrick Sulem, Agnar Helgason, Daniel F. Gudbjartsson, Bjarni V. Halldorsson () and Kari Stefansson ()
Additional contact information
Snaedis Kristmundsdottir: deCODE genetics / Amgen Inc.
Hakon Jonsson: deCODE genetics / Amgen Inc.
Marteinn T. Hardarson: deCODE genetics / Amgen Inc.
Gunnar Palsson: deCODE genetics / Amgen Inc.
Doruk Beyter: deCODE genetics / Amgen Inc.
Hannes P. Eggertsson: deCODE genetics / Amgen Inc.
Arnaldur Gylfason: deCODE genetics / Amgen Inc.
Gardar Sveinbjornsson: deCODE genetics / Amgen Inc.
Guillaume Holley: deCODE genetics / Amgen Inc.
Olafur A. Stefansson: deCODE genetics / Amgen Inc.
Gisli H. Halldorsson: deCODE genetics / Amgen Inc.
Sigurgeir Olafsson: deCODE genetics / Amgen Inc.
Gudny. A. Arnadottir: deCODE genetics / Amgen Inc.
Pall I. Olason: deCODE genetics / Amgen Inc.
Ogmundur Eiriksson: deCODE genetics / Amgen Inc.
Gisli Masson: deCODE genetics / Amgen Inc.
Unnur Thorsteinsdottir: deCODE genetics / Amgen Inc.
Thorunn Rafnar: deCODE genetics / Amgen Inc.
Patrick Sulem: deCODE genetics / Amgen Inc.
Agnar Helgason: deCODE genetics / Amgen Inc.
Daniel F. Gudbjartsson: deCODE genetics / Amgen Inc.
Bjarni V. Halldorsson: deCODE genetics / Amgen Inc.
Kari Stefansson: deCODE genetics / Amgen Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Microsatellites are polymorphic tracts of short tandem repeats with one to six base-pair (bp) motifs and are some of the most polymorphic variants in the genome. Using 6084 Icelandic parent-offspring trios we estimate 63.7 (95% CI: 61.9–65.4) microsatellite de novo mutations (mDNMs) per offspring per generation, excluding one bp repeats motifs (homopolymers) the estimate is 48.2 mDNMs (95% CI: 46.7–49.6). Paternal mDNMs occur at longer repeats than maternal ones, which are in turn larger with a mean size of 3.4 bp vs 3.1 bp for paternal ones. mDNMs increase by 0.97 (95% CI: 0.90–1.04) and 0.31 (95% CI: 0.25–0.37) per year of father’s and mother’s age at conception, respectively. Here, we find two independent coding variants that associate with the number of mDNMs transmitted to offspring; The minor allele of a missense variant (allele frequency (AF) = 1.9%) in MSH2, a mismatch repair gene, increases transmitted mDNMs from both parents (effect: 13.1 paternal and 7.8 maternal mDNMs). A synonymous variant (AF = 20.3%) in NEIL2, a DNA damage repair gene, increases paternally transmitted mDNMs (effect: 4.4 mDNMs). Thus, the microsatellite mutation rate in humans is in part under genetic control.

Date: 2023
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DOI: 10.1038/s41467-023-39547-6

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