De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population

Abstract

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h²), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.

Keywords: Amish; de novo mutations; diversity; mutation rate; recombination.

Fig. 1.

Distribution of single-base and 3-mer mutation types across SNV DNM call set. (A) The distribution of single-base mutation type counts across our SNV DNM call set is shown. Colors represent mutation type, and stars represent associations with paternal age (red, P < 0.05 after Bonferroni correction). (B) The counts across our DNM call set for each of 96 3-mer mutation types is shown. Colors represent the center base mutation, and are the same as those in A. Stars represent associations with paternal age (red, P < 0.05 after Bonferroni correction).

Fig. 2.

City plot of rare variation, recombination rate, and DNM rate across the genome. The relationship between DNM rate (blue to red color range), rare variation (y axis, ranging from −5.83 to 9.06 z-scores), and recombination rate (z axis, ranging from 2.73 × 10⁻¹⁴ to 6.12 cM/Mb) across the genome (x axis, dotted vertical lines divide autosomes 1 to 22) is shown. In moving from low to high rare variation levels across the y axis, a blue to red gradient can be seen, which reflects the significant correlation between DNM rate and population-level rare variation. Furthermore, regions with high DNM rates and high variation levels generally have taller bars, which reflects the positive relationship between DNM rate, variation level, and recombination (a few exceptions to this can be seen as taller blueish bars). Regions with the highest variation levels in the genome, such as those on chromosomes 8 and 16, have the highest DNM rates.

Fig. 3.

DNM rates across diverse cohorts. DNM rates per individual show significant differences across cohort, which are driven by a reduction in the Amish.