August 22, 2012

expert reaction to mutations in sperm of older fathers

Children of older fathers have a higher rate of new mutations according to a large genome-sequencing study published in Nature.

Dr. Allan Pacey, Senior Lecturer in Andrology at the University of Sheffield and Chairman of the British Fertility Society, said:

“We have known for some time that children of older fathers have a higher risk of being born with a range of genetically linked diseases such as achondroplasia, Down’s syndrome, schizophrenia and autism spectrum disorders among others. There is also evidence that as men get older their partner is at increased risk of infertility and miscarriage because of genetic changes which are evident in his sperm. It is for these reasons that in the UK we recommend that men should be under the age of 40 years old if they wish to be a sperm donor.

“What we have not understood to date, is the cellular and molecular events that lead to these epidemiological observations. Therefore for this reason today’s paper is very interesting. It is a surprise to find that men transmit a higher number of mutations to their children than do women. Whilst not wanting to scare the children of older fathers, information like this is important to understand and should remind us that nature designed us to have our children at a young age and if at all possible men and women should not delay parenthood if they are in a position not to.”

Prof Darren Griffin, Professor of Genetics, University of Kent, said:

“The study by Kong is a fascinating one. It is the first to correlate directly the act of the father with possible mutations in the offspring and sheds much needed insight into the ageing process and the damage it has on our DNA. The associated effect observed in studies of families with Autism and Schizophrenia confirms previously established population studies.

“The observed effect is a significant one but not one necessarily to cause great worry among prospective older fathers. There are three billion of letters in the DNA code of humans and the numbers of mutations detected in this study are in the dozens. The observed approximate doubling of mutation rate between the ages of 20 and 40 (when most fathers are actively reproducing) is certainly clinically noteworthy but not realistically likely to deter more mature fathers from having children

“It is also important to consider the work in a global context of parental age effects. This study only considered single DNA letter changes however overall DNA damage in the sperm as well as more gross genomic (chromosomal) age-related changes on the egg should be considered. The maternal age effect on chromosomal abnormalities (that could lead to Down syndrome, more serious congenital disorders or pregnancy loss) is a far more potent and measurable.

“It is also interesting to speculate on the mechanism by which these mutations arise. The production of human sperm is a process particularly prone to DNA damage and the older we get, the more likely that such damage may occur. The study by Kong and colleagues opens up a number of very promising avenues of new research avenues that will be exploited in the coming years by reproductive biologists.”

Prof Richard Sharpe, MRC Centre for Reproductive Health, University of Edinburgh, said:

“Of the many contrasts between men and women, perhaps the least appreciated is that which applies to their germ cells (from which our children derive). In women, germ cell (oocytes or eggs) number is fixed in fetal life and no further proliferation occurs, whereas in men the opposite is true and germ cells continue to proliferate throughout life to enable continuous sperm production (100-200 million/day!) through to old age. One consequence of this difference is that women run out of germ cells/oocytes, which triggers the menopause, whereas men remain fertile into old age. Much as this might seem like a positive for older men, there is a price to pay. As the paper in Nature demonstrates, the price is paid by their children because the older your father at conception the greater the number of gene mutations you inherit from him; in contrast, gene mutations inherited from your mother are unaffected by her age at conception.

“There is a very simple explanation for this difference. New gene mutations usually only occur when a cell proliferates/multiplies, as this is when all of the genes need to be copied, and there is a (low) chance that this copying will be imperfect; if it is imperfect, we call it a mutation. So, it is simple maths – the more times a cell replicates the greater will be the number of mutations; female germ cells in women stop replicating in fetal life, germ cells in men replicate continuously into old age. Most gene mutations are harmless (ie do not result in disease), but some are not. Therefore, children fathered by older men are more likely to inherit a harmful mutation than if their father was a younger man.

“The new study in Nature has accurately counted the number of new mutations according to the father’s age. On average two new mutations occur per year or, put another way, every 16.5 years the number of gene mutations will have doubled. This is continuous, there is no cut-off starting age, mutations increase with each advancing year.

“Today, couples are starting families at much later ages than in the past. Because female fertility declines beyond age 25, concerns have been focussed on the increased chance of her failure to conceive with aging. However, the same scenario also means that fathers are generally older, and therefore their sperm will have acquired more mutations than when they were younger, which will increase the chance of children they father inheriting a disease-producing mutation. The risk is small, but it is increased proportionately with the father’s age at conception.

“Although maternal age may not affect the transmission of gene mutations to her children, it does substantially increase the risk of transmitting chromosomal abnormalities (eg Downs syndrome) which, unlike gene mutations, always has major health consequences.”

Prof Christopher Barratt, Professor of Reproductive Medicine, University of Dundee, said:

“This is a very important high quality study pointing out the potential long term consequences of men fathering children at advanced age. This study provides experimental data using comprehensive sequencing of children and parents. The authors report a noticeable increase in the number of spontaneous mutations with age of father at conception which translates into a doubling of mutations every 16.5 years. The findings may be even more significant as only one man in the current study was over 40 years old.

“The accompanying News and Views article suggests than younger men consider sperm banking to reduce the health risks to the child. Whilst sperm banking is technically feasible more data would be required to recommend this policy as a routine.

“Previously studies had reported (1) higher incidence of some disorders with increasing paternal age e.g. autism, schizophrenia. (2) Decreased fertility in men of older age – using a large data set of 8515 planned pregnancies Ford and colleagues showed significantly reduced fertility rate in men 35-39 (50% compared to men less than 25) (Ford et al., 2000). (3) Higher levels of compromised nuclear quality in the sperm of older men (Wyrobeck et al., 2006).

“There is a widespread worldwide trend for an increasing use of assisted conception (ART) to treat sub fertile couples. Recent data from ESHRE indicate 4.6% of national births are the result of ART. Advanced paternal age is an important factors in these couples and the Kong study has important implications for the health of children of the increasing use of ART in older in men.”

‘Rate of de novo mutations and the importance of father’s age to disease risk’ by Kong et al., published in Nature on Wednesday 22nd August.