Rate of de novo mutations and the importance of father’s age to disease risk

• Published in: Nature (London) Vol. 488; no. 7412; pp. 471 - 475
• Main Authors: Kong, Augustine, Frigge, Michael L., Masson, Gisli, Besenbacher, Soren, Sulem, Patrick, Magnusson, Gisli, Gudjonsson, Sigurjon A., Sigurdsson, Asgeir, Jonasdottir, Aslaug, Jonasdottir, Adalbjorg, Wong, Wendy S. W., Sigurdsson, Gunnar, Walters, G. Bragi, Steinberg, Stacy, Helgason, Hannes, Thorleifsson, Gudmar, Gudbjartsson, Daniel F., Helgason, Agnar, Magnusson, Olafur Th, Thorsteinsdottir, Unnur, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.08.2012; Nature Publishing Group
• Subjects: 631/181/2474; 631/208/737; 692/499; 692/700/478/174; Adult; Age (Biology); Autism; Autistic Disorder - epidemiology; Autistic Disorder - etiology; Autistic Disorder - genetics; Biological and medical sciences; Chromosomes, Human - genetics; Classical genetics, quantitative genetics, hybrids; Confidence intervals; Demographic aspects; Demographics; Father-child relations; Fathers; Female; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human - genetics; Genomes; Haplotypes; Health aspects; Health risks; Human; Humanities and Social Sciences; Humans; Iceland - epidemiology; Male; Mental disorders; Middle Aged; Mothers; multidisciplinary; Mutation; Mutation Rate; Offspring; Ovum - metabolism; Paternal Age; Pedigree; Polymorphism, Single Nucleotide - genetics; Risk Factors; Risk factors (Health); Schizophrenia; Schizophrenia - epidemiology; Schizophrenia - etiology; Schizophrenia - genetics; Science; Selection, Genetic - genetics; Sequence Analysis, DNA; Spermatozoa - metabolism; Young Adult; Atlantic Ocean Islands; Scandinavia; Europe; Iceland; Denmark; United Kingdom; Human; Risk; Mutation; Father; Age; De novo
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11396

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. Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia. Fathers' ages linked to disease risk De novo mutations are important both as sources of diversity in evolution and for their immediate impact on diseases. Scientists at deCODE genetics and their colleagues have used whole-genome sequencing data from 78 Icelandic parent–offspring trios to study mutation rates in humans at the genome-wide level. They find that diversity in the mutation rate of single nucleotide polymorphisms is dominated by the age of the father at the time a child is conceived. For each year increase in the father's age at conception, the number of mutations increases by about two, and once the effects of random variation are accounted for the father's age is estimated to explain almost all of the remaining variation in the de novo mutation counts. Furthermore, the results show that demographic transitions that affect the age at which males reproduce can have a considerable effect on the rate of mutations, and consequently on the risk of diseases such as schizophrenia and autism.