The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
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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“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]
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“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]
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In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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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Citations
Cites
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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
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“Applying (5) eliminated 1,285 candidate mutations (Supplementary Information).”
InfluentialDe novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734
Estimate of the Mutation Rate per Nucleotide in Humans
Nachman, M. W., & Crowell, S. L. (2000) · Genetics · doi:10.1093/genetics/156.1.297 · Cited by 1,226
Molecular basis of base substitution hotspots in Escherichia coli
Coulondre, C., Miller, J. H., Farabaugh, P. J., & Gilbert, W. (1978) · Nature · doi:10.1038/274775a0 · Cited by 1,193
Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing
Roach, J. C., Glusman, G., Smit, A. F. A., Huff, C. D., Hubley, R., Shannon, P. T., Rowen, L., Pant, K. P., Goodman, N., Bamshad, M., et al. (2010) · Science · doi:10.1126/science.1186802 · Cited by 1,084
The origins, patterns and implications of human spontaneous mutation
Crow, J. F. (2000) · Nature Reviews Genetics · doi:10.1038/35049558 · Cited by 928
Rate, molecular spectrum, and consequences of human mutation
Lynch, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912629107 · Cited by 792
Cited by
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Rare copy number variation in extremely impulsively violent males
Vevera, J., Zarrei, M., Hartmannová, H., Jedličková, I., Mušálková, D., Přistoupilová, A., Oliveriusová, P., Trešlová, H., Nosková, L., Hodaňová, K., et al. (2019) · Genes, Brain and Behavior · doi:10.1111/gbb.12536 · Cited by 15
Woodley of Menie, M. A., Fernandes, H. B. F., Kanazawa, S., & Dutton, E. (2018) · HOMO · doi:10.1016/j.jchb.2018.06.003 · Cited by 9
Geier, D. A., Hooker, B. S., Kern, J. K., Sykes, L. K., & Geier, M. R. (2016) · Journal of Child Neurology · doi:10.1177/0883073814541478 · Cited by 7
Metadata
- 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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