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There is a higher incidence of new genetic mutations in the offspring of older parents, especially fathers, report scientists in a new study in Nature.
Prof. Darren Griffin, Professor of Genetics, University of Kent, said:
“This is a paper that is impressive in its scope, size and thoroughness. The key finding that de-novo mutation rate increases as the father ages reflects the nature of susceptibility of the gametes themselves to DNA damage. Sperm are produced continually throughout a man’s life, there are more divisions overall, and their ability to repair DNA damage become compromised once they differentiate. By contrast, the eggs are more prone to whole chromosome errors as the woman ages. This fits with work already published for several years however this is probably the most comprehensive overview to date. In terms of a direct comparison of the difference between males and females in this regard and the magnitude of that difference, this is a first as far as I am aware. The evolutionary aspect of this is also interesting: the mechanisms described appear to be unique to humans and their nearest relatives.”
Prof. Martin Taylor, MRC Human Genetics Unit, Institute of Genetics & Molecular Medicine, University of Edinburgh, said:
“It is often assumed that mutations in our DNA occur randomly, they don’t, it’s a loaded dice. What this work convincingly shows is that the dice is loaded differently in mothers and fathers.
“Although the majority of new mutations reported in this study have come from the fathers, the most striking new insights are from the extra mutations that occur in the eggs of older mothers.
“Because DNA is continually replicated to produce sperm, it has been speculated for decades and known convincingly for several years that mutation rate goes up with the father’s age. More recently it has been shown that there is a similar but less dramatic effect with mother’s age. This is surprising as the DNA replication in a woman’s eggs occurred back when she was in her mother’s womb and doesn’t generally get copied any more as she gets older. This new paper shows that many, and perhaps even most, of those extra mutations from older mothers occur in groups on the same DNA strand at the same time.
“It seems that when a chromosome breaks in an egg, it can sometimes be repaired, avoiding a chromosomal catastrophe but leaving a scar of small mutations. A handful of chromosome regions have far more of these scars than can be explained by chance, suggesting they may be particularly prone to breaking there, or unusually efficiently patched-up by error prone repair.
“A key question raised by this work is what process is generating the clusters of C to G changes on damaged chromosomes in the egg? The APOBEC enzymes, the obvious candidates appear to be out of the frame.
“While the vast majority of these new mutations will have no medical impact, this study represents an important resource with which to understand the patterns and processes that give rise to new mutations. Comparing the patterns of new mutations to more common DNA changes in the population is an important approach for working out the type of mutations that do have a medical impact.
“It is important to remember that the mutations observed in this study aren’t quite representative of the mutations that occurred. Any mutations that stopped an egg from maturing, a sperm from growing or an embryo developing would never have been seen. Capturing these is one of the next frontiers in the study of human germline mutations.
“Intriguingly the site on chromosome 8 that shows the highest rate of these mutation clusters (scars) is immediately next to a large region of DNA that is frequently re-ordered and arranged through human generations and highly variable in the population (beta-defensin locus). Such regions can cause problems for chromosome segregation and could trigger breaks.
“One technical limitation is that such segmentally repetitive and polymorphic regions could cause problems for read mapping – so the authors couldn’t be completely confident in identifying the different mutations. The authors have addressed this as well as possible with the sequencing technology used, and the fact that the effect is much more pronounced in maternally rather than paternally inherited mutations suggests that the mutation cluster is not an artefact related to mutation identification.”
Prof. Allan Pacey, Professor of Andrology, University of Sheffield, said:
“This is a very interesting study which shows that there is a striking relationship between the number of de novo (spontaneous) mutations in a person’s DNA and the age of their father and mother when they were conceived. What is even more striking is that the number of these mutations is higher, and seems to increase at a faster rate, as the father gets older in comparison to the mother.
“This is elegant work, but should come as no real surprise. We have known for many years that the risk of having a child with a medical condition of genetic origin, increases noticeably with the father’s age at conception. It is for this reason that there is a recommended upper age limit for sperm donors (currently 40 years) in the UK. Put simply, the genetic quality of sperm from younger men (in terms of de novo mutations) is generally much better than that of older men.
“It’s likely that the difference in risk of de novo mutations in children according to the ages of their mother or father at conception, is explained by the different ways in which sperm and eggs are produced. For example, in women all of the eggs are produced at the same time and very early in her life (mostly before she was born) and hence there is little opportunity for spontaneous mutations caused by cell division to occur. However, in men, the production of sperm is a continuous process (from puberty until death), and therefore there is probably more opportunity for genetic errors to creep into the process of cell division that underpins the production of sperm.
“The study will be important for our understanding of human evolution and for our understanding of some rare diseases. However, for me, it simply reminds me of why we should always encourage men and women to have their children as early in their lives as possible.”
Prof. John Hardy, Professor of Molecular Neuroscience, UCL, said:
“This is a very interesting piece of work which leverages the fact that DeCode have got DNA sequence information and genealogy on the whole population of Iceland. The effects are small on an individual basis (so no particular need for elderly parents to be unduly concerned), but clearly of interest and importance on a population level. DeCode have developed an amazing pipeline for genetic discovery and have been the first in many areas: they are limited by the small size of the Icelandic population. One hopes that the NHS UK Biobank initiative can, using the UK’s far greater population, also make important discoveries of this type.”
* ‘Parental influence on human germline de novo mutations in 1,548 trios from Iceland’ by Hákon Jónsson et al. published in Nature on Wednesday 20 September 2017.
Declared interests
Prof. Darren Griffin: “Prof Griffin is Director of the Centre for Interdisciplinary Studies of Reproduction (CISoR) http://www.kent.ac.uk/cisor”
Prof. Martin Taylor: “I have no real or reasonably perceived conflict of interest with this published work. I am likely to use the results of this manuscript in my own subsequent work.”
Prof. Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid). Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (paid consultancy with all monies going to University of Sheffield). Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).”
Prof. John Hardy: “No relevant conflicts.”