Parental influence on human germline de novo mutations in 1,548 trios from Iceland
Abstract
The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies. 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…
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The paternally inherited variant p.Pro253Leu was detected together with the de novo variant p.Met1044Thr in individual 2; phasing was not possible, but it is more likely that the de novo variant is also located on the paternal allele (in cis).
“It should be noted that the paternally inherited variant p.Pro253Leu was detected together with the de novo variant p.Met1044Thr in individual 2. Unfortunately, phasing of the de novo variant was not possible, but it is more likely that this variant is also located on the paternal allele (i.e., in cis) (Jónsson et al. 2017).”
From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Jónsson et al. 2017
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“Unfortunately, phasing of the de novo variant was not possible, but it is more likely that this variant is also located on the paternal allele (i.e., in cis ) (Jónsson et al. 2017).”
Background
- Authors
- Jónsson, H., Sulem, P., Kehr, B., Kristmundsdottir, S., Zink, F., Hjartarson, E., Hardarson, M. T., Hjorleifsson, K. E., Eggertsson, H. P., Gudjonsson, S. A., Ward, L. D., Arnadottir, G. A., Helgason, E. A., Helgason, H., Gylfason, A., Jonasdottir, A., Jonasdottir, A., Rafnar, T., Frigge, M., Stacey, S. N., Th. Magnusson, O., Thorsteinsdottir, U., Masson, G., Kong, A., Halldorsson, B. V., Helgason, A., Gudbjartsson, D. F., & Stefansson, K.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- Corresponding author
- Gudbjartsson, Daniel F.
- ORCID
- Venue
- Nature
- Published
- 2017-09
- Volume
- 549
- Issue
- 7673
- Pages
- 519-522
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2756712855
- Cited by
- 561
- References
- 6
- Citations by year
- 2026: 47 · 2025: 73 · 2024: 72 · 2023: 57 · 2022: 80 · 2021: 70 · 2020: 62 · 2019: 50 · 2018: 37 · 2017: 6 · 2016: 6
- FWCI
- 28.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- de novo mutations, germline mutations, parental age, maternal age, paternal age, parent of origin, mutation rate, mutation spectrum, clustered mutations, indels, single nucleotide polymorphisms, mutational processes, Icelanders, parent-offspring trios, whole genome sequencing, mutational signatures, mutational hotspots
- MeSH terms
- Adolescent, Adult, Aged, Aging, Animals, Child, Pan troglodytes, Chromosomes, Human, Pair 8, Female, Gorilla gorilla, Humans, Iceland, Male, Maternal Age, Middle Aged, Parents, Paternal Age, Linkage Disequilibrium, Genome, Human, Mutagenesis, Germ-Line Mutation, Evolution, Molecular, Polymorphism, Single Nucleotide, GC Rich Sequence, INDEL Mutation, Young Adult, Pongo, Mutation Rate
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