A comprehensive analysis of human spontaneous mutation has revealed a strong influence of paternal age, suggesting a link between an increasing number of older fathers and the rise in disorders such as autism. See Article p.471
Mutations are common on the scale of whole genomes, but rare on the scale of individual nucleotides. So until large-scale DNA sequencing became practical, measuring the rate at which novel mutations accumulate in a genome was a daunting task. Now, however, de novo mutations can be detected by a straightforward comparison of parent and offspring genotypes, making obsolete several ingenious methods that were previously used for this purpose. Such comparisons will rapidly produce reliable estimates of the parameters of spontaneous mutation in many species. On page 471 of this issue, Kong et al.1 report these figures for humans. They show that a newborn's genome sequence contains, on average, 60 new small-scale mutations, and that this number depends strongly on the age of the father at the time of conception.
Kong and colleagues' study is by far the largest of its kind yet conducted, involving 78 Icelandic parent–offspring trios. Their estimate of 60 new mutations per generation is in agreement with previous calculations2, but their data also reveal that, although a 20-year-old father transmits, on average, approximately 25 mutations to his child, a 40-year-old father transmits around 65. This means that every additional year of paternal age results in an average of two extra mutations in human offspring. By contrast, the authors found that the number of de novo mutations transmitted by the mother is always roughly 15, regardless of her age.
That the male parent makes a disproportionate contribution to mammalian mutation has been described previously3, as has an effect of paternal age on the number of mutations in an offspring4. These findings are easily explained by the fact that, in mammals, male germ cells (sperm) are continually produced, so they go through many more cell divisions over the course of a generation than do female germ cells (eggs), which are not actively dividing in individuals of reproductive age. However, Kong and colleagues' estimates of the effect of these differences on mutation rates are the most precise and definite that we have so far.
In humans, as many as 10% of point mutations are deleterious5, so Kong and colleagues' findings suggest that an average newborn carries six new deleterious mutations. Although most of these mutations will, on their own, have only mild effects, collectively they could have a substantial impact on health. Perhaps most immediately pertinent to the authors' findings are data showing that the prevalence of several single-gene and multifactorial diseases increases with paternal age4. Although in some cases this increase is due to selection pressures exerted on germ-line cells6, there is little doubt that its main cause is the effect of paternal age on the number of new mutations in the offspring's genome. For example, a causal role of de novo mutations has recently been demonstrated in autism7. It seems that multifactorial disorders that result from impaired brain function, such as autism, schizophrenia, dyslexia and reduced intelligence, are particularly susceptible to the paternal-age effect8. This is consistent with the fact that more genes are expressed in the brain than in any other organ, meaning that the fraction of new mutations that will affect its functions is the highest.
Kong and colleagues' findings suggest that the difference in health between children of fathers younger than 20 years and those of fathers older than 40 years (with all other factors being equal) is equivalent to about half the average decline in human health that results from the free accumulation of spontaneous mutations with each generation. Modern human populations are subject to many fewer selection pressures than has been the case throughout human evolutionary history. Because deleterious mutations are much more common than beneficial ones, evolution under this relaxed selection will inevitably lead to a decline in the mean fitness of the population. Indeed, data obtained from Drosophila fruitflies in experimental situations of relaxed selection suggest that this decline can be quite rapid9. It is therefore reasonable to assume that the ongoing increase in the incidence and prevalence of autism in many human populations10 could be due, at least in part, to the accumulation of mutations resulting from relaxed selection and a higher average paternal age — and not only to better recognition of cases.
A valuable opportunity to further study the impact of de novo mutations on human health may be provided by mutator alleles — defective versions of genes involved in DNA replication or repair that cause an increase in the mutation rate. For example, a type of colorectal cancer is caused by a mutation that results in the loss of function of one copy of a gene encoding a protein involved in DNA mismatch repair (a process whereby erroneous DNA sequences are fixed during replication). In rats, the presence of such a mutation in both gene copies increases the spontaneous mutation rate by a factor of 30 (ref. 11) and reduces lifespan. In humans, a complete lack of DNA mismatch repair function leads to multiple childhood cancers, and patients do not live to reproductive age12. Even single-copy mutations in DNA repair genes can substantially increase the mutation rate. A detailed evaluation of children of individuals who carry such mutator alleles might allow us to assess the impact of several generations of unchecked accumulation of de novo mutations.
If the paternal-age effect on the de novo mutation rate does lead to substantially impaired health in the children of older fathers, then collecting the sperm of young adult men and cold-storing it for later use4 could be a wise individual decision. It might also be valuable for public health, as such action could, according to Kong and colleagues' findings, substantially reduce the rate of deterioration of the gene pool in human populations under relaxed selection. By contrast, any attempt to reduce mutation accumulation in our gene pool by restoring selection pressures would probably be much more controversial and painful. Thus, Kong et al. have certainly provided food for thought, on both an individual and a population level.
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Scientific Reports (2017)