Father's Age Affects Mutation Rate

The number of new gene mutations in children rises dramatically with the age of their father at conception.

Aug 22, 2012
Hayley Dunning

Estimates of overall human de novo mutation rate—the appearance of new gene mutations—have been largely carried out using indirect methods, such as extrapolating mutation rates from disease states or from the record of divergence of species. But whole genome sequencing is changing that, providing a way to map de novo mutations arising in family lines. Now, in a huge study that sequenced the genomes of 219 individuals consisting of 78 trios (father, mother, and child) and some multi-generational families, the rate of human mutations is clearer than ever, and surprisingly lower than previously estimated. However, according to the study, published today (August 22) in Nature, the number of mutations originating from the father rises with the age, so that the number of mutations doubles for every 16.5 years older the father is, raising the potential for detrimental mutations to occur and cause disease.

The results “are substantial and exciting given that this is the largest whole genome sequencing study of trios, relatives, or multigenerational pedigrees to date," said geneticist Philip Awadalla of the University of Montreal, who was not involved in the study, by email. The sequencing was carried out by deCODE Genetics in Iceland, as part of a larger project aimed at understanding the contributions of the genome to human diversity, which has already sequenced the genomes of around 2,500 Icelanders. Iceland's small population and impeccable records of genealogy make it ideal for population studies, and deCODE has also already genotyped 120,000 individuals.

The families sequenced for this study consisted of both disease-free children and children with disorders resulting from mutations, particularly autism spectrum disorder (ASD) and schizophrenia. While do novo mutations are random, the more mutations that accrue, the more likely one will be detrimental. Mutations were identified by comparing the genomes of the parents and their offspring, and although Awadalla is concerned that relatively few mutations were subject to experimental validation, he believes the potential for false positives doesn't change the conclusions about human mutation rate and the link to father's age.

Indirect approaches have estimated that the father's contributions will be more mutated than the mother's because of the difference between production of the sperm and ova. Sperm are generated and proliferate throughout a man's life, whereas ova are likely all present from birth. The estimated difference in mutation rates between the sexes has been variable, but high, at around 4-7 times faster in males. This new study confirms that the variance is high, but that the father's contribution of mutations is likely no more than two times greater than the mother's.

The dependence on father's age on mutation rate, however, is a "terribly novel" finding according to Awadalla. "The age dependence with respect to mutation rates in fathers is robust and the first direct observation from substantial numbers in humans without reliance on indirect approaches," he said. "The observation is striking particularly for autism and schizophrenia 'families'." The risk of ASD and schizophrenia increased significantly with father's age at conception, which the authors say is consistent with epidemiological studies in Iceland. Children with ASD in this study had no close genetic relatives with the disease, meaning the incidence of ASD is likely to be solely as a result of de novo mutations.

Factoring in father's age over Iceland's history, it appears the average age of fathers has been rising lately, from around 27 in the 1970s to 33 today. "Perhaps a sizeable portion of the increase in the diagnoses of autism over the past few years is rooted in the increasing age of fathers," said deCODE CEO Kari Stefansson.

The determination of the human mutation rate overall also brings up new questions in human evolution. This study confirms the mounting evidence that mutation rate has likely been two or three times slower than previously estimated. The result is "fairly important as the rate of mutation is used to calibrate split times between species," said Awadalla. "It appears that divergence times between humans and other primates is almost double that which was previously inferred from fossil records or phylogenetic approaches." The rate at which species branch off could therefore be slower than previously estimated, shifting the timescales of human evolution.

A. Kong et al., "Rate of de novo mutations and the importance of father’s age to disease risk," Nature, 488: 471–475, 2012.