Sequence variants affecting the genome-wide rate of germline microsatellite mutations
Snædís Kristmundsdóttir, Hákon Jónsson, Marteinn T. Hardarson, Gunnar Pálsson, Doruk Beyter, Hannes P. Eggertsson, Arnaldur Gylfason, Garðar Sveinbjörnsson, Guillaume Holley, Ólafur Andri Stefánsson, Gísli H. Halldórsson, Sigurgeir Ólafsson, Gudny A. Arnadottir, Pall I. Olason, Ögmundur Eiríksson, Gísli Másson, Unnur Þorsteinsdóttir, Þórunn Rafnar, Patrick Sulem, Agnar Helgason, Daníel F. Guðbjartsson, Bjarni V. Halldórsson, Kāri Stefánsson
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.