Rate of de novo mutations and the importance of father’s age to disease risk
Open accessAbstract
Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.
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The observed SNP heritability for autistic carriers reflects autism rather than factors associated with the generation of germline mutations.
“suggesting that the observed SNP heritability for autistic carriers reflects autism rather than factors associated with the generation of germline mutations57,58.”
From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [58]
Advanced paternal age correlates with increased rates of germline mutation in offspring.
“We and others have demonstrated that advanced paternal age correlates with increased rates of germline mutation in offspring28–30”
From A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex (2022) · cites this paper as [29]
ASD is often caused by newly arising CNVs or rare germline mutations, particularly in sperm of older fathers.
“ASD is often due to newly arising gene copy number variants (CNVs) — such as a deletion or duplication of a region of a chromosome — or a rare mutation that arises in the germ cell, particularly in sperm of older fathers5–10.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [10]
De novo mutations arising in the germline are a significant cause of ASD.
“Recent evidence suggests that de novo mutations that arise in the germline are a significant cause of ASD, although it is important to keep in mind that the genetic aetiology of about 70% of the forms of ASD is unknown and it remains perplexing why ASD is at least four times more prevalent in males than in females.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [10]
References 7-10 used exome and whole-genome sequencing to show the importance of rare mutations in ASD and to identify new genetic mutations linked to ASD.
“References 7– 10 use exome and entire genome sequencing to demonstrate the importance of rare mutations in ASD and identify new genetic mutations associated with ASD.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [10]
Those studies show that new sequencing technologies can greatly advance knowledge of the genetic basis of ASD.
“These studies demonstrate the ability of new sequencing technologies to significantly advance our understanding of the genetic basis of ASD.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [10]
About 70% of de novo mutations are paternal, and the total new mutation rate in offspring increases by 1-2 mutations per year with paternal age.
“Thus, a majority (70%) of de novo mutations originate from the father and total rate of new mutations in offspring increase by 1–2 mutations per year with his age (Kong et al., 2012; Michaelson et al., 2012).”
From Getting to the cores of autism (2019) · cites this paper as Kong et al., 2012
In Icelandic trio de novo mutations, TCC to TTC and GGA to GAA rank 20th and 18th.
“In the Icelandic trios, TCC → TTC and GGA → GAA are ranked 20th and 18th.”
From Evidence for recent, population-specific evolution of the human mutation rate (2015) · cites this paper as [10]
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- Authors
- Kong, A., Frigge, M. L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S. A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Wong, W. S. W., Sigurdsson, G., Walters, G. B., Steinberg, S., Helgason, H., Thorleifsson, G., Gudbjartsson, D. F., Helgason, A., Magnusson, O. T., Thorsteinsdottir, U., & Stefansson, K.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- Illumina (United Kingdom) (GB)
- Corresponding author
- Kong, Augustine
- ORCID
- Venue
- Nature
- Published
- 2012-08
- Volume
- 488
- Issue
- 7412
- Pages
- 471-475
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3548427
- OpenAlex
- W2020331089
- Cited by
- 2,134
- References
- 27
- Citations by year
- 2026: 83 · 2025: 95 · 2024: 113 · 2023: 109 · 2022: 128 · 2021: 147 · 2020: 175 · 2019: 154 · 2018: 149 · 2017: 167 · 2016: 180 · 2015: 186 · 2014: 209 · 2013: 188 · 2012: 46
- FWCI
- 120.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH071425, MH071425)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- de novo mutations, mutation rate, paternal age, single nucleotide polymorphisms, parent-offspring trios, schizophrenia, autism spectrum disorder, disease risk, demographic transition, Icelandic population
- MeSH terms
- Adult, Autistic Disorder, Chromosomes, Human, Female, Humans, Iceland, Male, Middle Aged, Mothers, Ovum, Paternal Age, Pedigree, Risk Factors, Schizophrenia, Selection, Genetic, Spermatozoa, Genome, Human, Sequence Analysis, DNA, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Young Adult, Mutation Rate
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