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

Abstract

Microsatellites are polymorphic tracts of short tandem repeats (STRs) with one to six base-pair (bp) motifs and are some of the most polymorphic markers in the genome. Using 6,084 Icelandic parent-offspring trios we estimate 63.7 (95% CI: 61.9–65.4) microsatellite de novo mutations (mDNMs) per offspring per generation. Paternal mDNMs occur at longer repeats, while maternal mDNMs affect more bp. 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. We found two independent coding variants associated with an increased number of mDNMs transmitted to offspring; 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.

High-fidelity, Large-scale Targeted Profiling of Microsatellites

“…Red circle: threshold value chosen for final filtering settings. Red line: approximate expected microsatellite de novo mutation rate (i.e., Mendelian discordance rate) based on prior studies (Weber and Wong 1993; Huang et al 2002; Sun et al 2012; Kristmundsdottir et al 2023). Note that individual parameter filters do not achieve the expected discordance rate, and the final filter settings utilize an optimized combination of filters to achieve the expected discordance rate ( Methods ).…”

“…We similarly optimized the order of which callers to prioritize in the ensemble genotyping process. Specifically, the filter optimization process identified a set of parameters that produced the expected Mendelian discordance rate based on prior estimates of microsatellite de novo mutation rates (∼ 1 in 10,000 loci) (Weber and Wong 1993; Huang et al 2002; Sun et al 2012; Kristmundsdottir et al 2023) and that maximized the number of “fully genotyped” loci. We used Family 1100 for this initial optimization because it was a trio of blood samples, and we expected blood samples to have a lower discordance rate than LCLs due to the possibility of microsatellite mutations occurring during cell culture.…”

“…If the genotype of the offspring does match Mendelian inheritance patterns, that locus is considered concordant. A true discordant locus indicates the presence of a de novo mutation in the offspring, so the rate of discordance should match the microsatellite de novo mutation rate, which prior studies have estimated to be ∼ 1 x 10 -4 mutations per locus per generation (Weber and Wong 1993; Huang et al 2002; Sun et al 2012; Kristmundsdottir et al 2023). In addition to optimizing our filters to achieve this discordance rate, we also optimized them to maximize the number of loci that were genotyped (i.e., that passed filters).…”

“…Red circle: threshold value chosen for final filtering settings. Red line: approximate expected microsatellite de novo mutation rate (i.e., Mendelian discordance rate) based on prior studies (Weber and Wong 1993; Huang et al 2002; Sun et al 2012; Kristmundsdottir et al 2023). A. HipSTR: minimum mean quality score across all samples.…”

The impact of ancestral, environmental and genetic influences on germlinede novomutation rates and spectra

“…Rare variants in DNA repair genes are well-known modifiers of somatic mutation rates and spectra 8–10 , and have been shown to contribute to elevated rates of germline mutation 4,10 . Certain common variants are associated with the rates of germline mutations at microsatellites 11 , and common variants that decrease age of menopause, many of which implicate DNA repair genes, are associated with increased rates of de novo point mutations in the female germline 12 . Human polymorphism data indicate that mutation spectra have varied over time and between human populations 13,14 , and a variety of genetic and environmental causes have been proposed for this 15 .…”