TY - JOUR
T1 - Sequence variants affecting the genome-wide rate of germline microsatellite mutations
AU - Kristmundsdottir, Snaedis
AU - Jonsson, Hakon
AU - Hardarson, Marteinn T.
AU - Palsson, Gunnar
AU - Beyter, Doruk
AU - Eggertsson, Hannes P.
AU - Gylfason, Arnaldur
AU - Sveinbjornsson, Gardar
AU - Holley, Guillaume
AU - Stefansson, Olafur A.
AU - Halldorsson, Gisli H.
AU - Olafsson, Sigurgeir
AU - Arnadottir, Gudny A.
AU - Olason, Pall I.
AU - Eiriksson, Ogmundur
AU - Masson, Gisli
AU - Thorsteinsdottir, Unnur
AU - Rafnar, Thorunn
AU - Sulem, Patrick
AU - Helgason, Agnar
AU - Gudbjartsson, Daniel F.
AU - Halldorsson, Bjarni V.
AU - Stefansson, Kari
N1 - Funding Information: We thank our colleagues from deCODE genetics/Amgen Inc. We also thank all research participants who provided a biological sample to deCODE genetics and the UK Biobank. Publisher Copyright: © 2023, The Author(s).
PY - 2023/6/29
Y1 - 2023/6/29
N2 - 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.
AB - 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.
KW - Alleles
KW - DNA Mismatch Repair
KW - Germ Cells
KW - Germ-Line Mutation/genetics
KW - Humans
KW - Microsatellite Repeats/genetics
UR - https://www.scopus.com/pages/publications/85163792406
U2 - 10.1038/s41467-023-39547-6
DO - 10.1038/s41467-023-39547-6
M3 - Article
C2 - 37386006
SN - 2041-1723
VL - 14
SP - 3855
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3855
ER -