The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics1,2 and to evolutionary studies3. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32–0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45–1.57). The number of clustered mutations increases faster with the mother’s age than with the father’s, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19–0.33%) decrease in cytosine–phosphate–guanine to thymine–phosphate–guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28–0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.
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We thank all the participants in this study. This study was performed in collaboration with Illumina.
All of the authors are employees of deCODE Genetics/Amgen, Inc.
Reviewer Information Nature thanks S. Sunyaev and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
a, b, Fraction of DNMs from father per proband. c, d, Fraction of DNMs from father per proband against parental age difference at conception (father’s age − mother’s age). e, f, Paternal age at conception against maternal age at conception. In b, d, and f, all probands with phased DNMs were used; meanwhile, in a, c, and e, the analysis was restricted to 225 three-generation probands. The vertical bars in c and d represent 95% confidence intervals using a normal approximation.
a, Phased DNMs from both parents. b, DNMs from mothers. The mutations were aggregated per year, and parent age groups with only one proband were excluded. The numbers of probands per aggregate year were used as weights for linear regression. We restricted results to 225 three-generation probands for this figure. The y axes are different for a and b. The grey areas in a and b represent 95% confidence intervals using a normal approximation.
a, The maternal DNM enrichment in genome-wide context. We contrasted the local DNM sex ratio in each 2-Mb window against the genome-wide average, using a binomial test. The 2-Mb window number is depicted after the chromosome. The vertical line corresponds to log10(0.05/1352). b, DNMs of paternal origin. c, DNMs of maternal origin. The dotted horizontal line is the genome-wide average. All phased DNMs (42,961) were used for this figure.
a, Excluding regions (10,000 bp) with average coverage of <12× or >120× (2-Mb windows). b, Excluding regions (100,000 bp) with false negative rate above 5% (2-Mb windows). c, Restricting to DNMs phased with the three-generation approach (15,746 DNMs, 3Mb windows).
Extended Data Figure 5 The number of maternal DNMs per 2-Mb window without DNMs in segmental duplications or repeat regions.
a, Without DNMs in annotated segmental duplications. b, Without DNMs in annotated repeat regions.
a, Rare variants (<1%). b, Common variants (≥1%). The dotted horizontal line is the genome-wide average.
a, Span of multi-nucleotide events in base pairs. b, The concordance of C or G reference bases within multi-nucleotide events as a function of span length. c, Same as b except restricted to C>G DNMs. The vertical bars in b and c represent 95% confidence intervals using a normal approximation.
a, The concordance ratio. b, The absolute concordance counts.
This figure corresponds to Fig. 4c–e for all of the autosomes. a, The C>G divergence between baboon and human, normalized by the C>G divergence between baboon and chimpanzee (db,h/db,c, 1-Mb windows). b, Same as a except the gorilla is used instead of the chimpanzee (db,h/db,g). c, Same as b except the orangutan is used instead of the chimpanzee (db,h/db,o).
Extended Data Figure 10 The phylogenetic context of the dependence of C>G and T>A relative divergence on the rate in the Icelandic dataset.
a, C>G relative divergence against C>G rate. b, T>A relative divergence against T>A rate. The dependency of the relative divergence (C>G or T>A) was modelled against the rate (C>G or T>A) in Icelandic dataset with a linear model. The coefficients of the slopes are reported in the blue rectangles with 95% confidence intervals below the estimates. The dependency of the C>G relative divergence on the C>G SNP patterns in humans reaches its minimum in the ancestral lineage of great apes.
This file contains Supplementary Text and Data, Supplementary Tables 1-3, 5-11, 13-20 and Supplementary References. (PDF 605 kb)
This zipped file contains a gzipped tar archive of the DNMs with proband identifiers. The positions correspond to build hg38 of the human genome. (ZIP 3911 kb)
This file contains the C>G enriched regions in 1Mb windows. The columns are the following: chromosome, the window number (1Mb) and region. One in the region column correspond to a C>G enriched region. (TXT 24 kb)
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Jónsson, H., Sulem, P., Kehr, B. et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature 549, 519–522 (2017). https://doi.org/10.1038/nature24018
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