Older fathers have more risk of having diseased children

Tick tock, tick tock. The clock is ticking for women. They can’t have children forever. But, although men produce sperm until late in life, in the light of accumulating evidence that the risk to have a child with a disease is higher for older men, they might want to reconsider taking all the time on their hands before becoming fathers.

It’s no news that the father’s age can affect the child’s health. In 1912 already it was noticed that achondroplasia, a form of dwarfism, was more common in last born children, the cause of which was shown in 1955 to be the age of the father. In 1998 a study demonstrated that of the 40 cases of achondroplasia it analyzed all mutations occured in the father. Nowadays it is known that mutations causing several diseases, amongst which schizophrenia and autism, arise exclusively or predominantly in fathers and that there exists a link between these diseases and advanced paternal age.

Because the mutations causing these diseases are de novo mutations, that is the differences in nucleotide emerged in the sperm or the ovule as they are absent in both parents but present in the child. And men and women are not equal when it comes to de novo mutations. The difference probably comes from the distinct biology of male and female reproduction. Cells that give rise to sperm cells continuously divide throughout a man’s life while cells that develop into ovules stop replicating when the woman is still a fetus. Consequently, an ovule at any time of a woman’s life will have gone through 24 cell divisions while sperm will be at about 200 divisions in a 20 year old man and up to 600 in a man of 40 years. When cells divide, they replicate their DNA to transmit a copy of the genome to each daughter cell but this replication is not 100% accurate. With each division mutations creep in the DNA so the more divisions a cell goes through, the more mutations it accumulates. Add to this that the fidelity of DNA replication and the efficiency of cells to repair mistakes in the DNA decreases as we get older and that could well explain why de novo mutations are more often transmitted by fathers than mothers and why the probability to transmit such mutations increases with the father’s age.

These mutations won’t all have detrimental effects on the child’s health. Some mutations have no consequence as they don’t change the identity of the amino acid in the protein. Even among those mutations that modify the protein, some will have no or little effect. Typically, two humans taken at random have 3 million nucleotide differences between them and they’re not feeling worse for all these differences. But some mutations will cause diseases and as the number of de novo mutations transmitted increases so does the probability that one of these mutations will cause health problems, hence the association between paternal age and certain diseases.

Image credit: Vera Kratochvil via Wikimedia Commons

What’s new, however, is the sequencing technologies that allow faster and cheaper sequencing of whole genomes, which makes more extensive studies of these mutations possible. Researchers recently sequenced the genomes of 78 parents-child trios from Iceland and analyzed de novo mutations consisting in differences of a single nucleotide. The results show that fathers pass on to their children about 4 times more de novo mutations than mothers. On average 55.4 mutations are paternal in origin compared to 14.2 mutations coming from maternal DNA. They confirm the number of mutations increases with the father’s age. Estimates calculate it doubles every 16.5 years and increases by 8-fold in 50 years. The data also provide additional evidence that the risk of schizophrenia and autism grows with advanced paternal age.

These findings are not restricted to single nucleotide mutations. DNA sequences of several million nucleotides can be duplicated or deleted from chromosomes. The resulting differences in the number of copies of these sequences are another type of mutation called copy number variation. De novo copy number variants associated with intellectual disability were also found to be more frequently inherited from fathers and to increase in numbers with the father’s age.

It’s also possible that older fathers transmit altered epigenetic marks to their children. Epigenetic marks are chemical modifications of the DNA itself or of the proteins it is wrapped around that determine which genes are expressed and which ones are not. A study in mice has shown that offspring from older fathers had more DNA methylation, which is one type of epigenetic mark, than those from younger fathers, and consequently the expression of their genes could be modified.

However, there are not only downsides to men reproducing at a later age. Chromosomes end in repetitive DNA sequences called telomeres. The way the DNA is replicated, the ends of chromosomes cannot be copied so chromosomes loose some DNA at each cell division. Telomeres are here to take the blow, they are the ones being shortened instead of sequences containing essential genes. But telomeres are not infinite. Once they become too short, cells die rather than loosing important genes, which explains why telomeres length is linked to longevity. Studies have observed that elderly people with shorter telomeres have a higher mortality.

And it turns out children from older fathers have longer telomeres. The effect is even seen across several generations. Children whose grandfather was older when their own father was born also have longer telomeres, no matter how old their own father was at the time of their birth. And if their own father was older, the effect adds up. The body of an older person has known more cell divisions than a younger one so for most tissues telomeres become shorter with age. Except sperm, probably because of the higher activity in testis of a protein that extends telomeres. Older men have longer sperm telomeres, which could account for their children’s longer telomeres. In one year, sperm telomeres increase of the same length that other tissues telomeres shorten.  After several generations of men reproducing at an advanced age, it is possible that humans might start living longer.

Furthermore, mutations are the raw material natural selection works on. Mutations can be beneficial and selected for with the consequence that more individuals in the population will have these advantageous mutations. As mutations accumulate, the population becomes different and that’s how new species arise. Without mutations we wouldn’t know the rich diversity of life forms that inhabit Earth today. Without mutations we wouldn’t be here. So maybe men’s egoes will be flattered to know that they have been playing and are still playing a bigger role in human evolution.

ResearchBlogging.org

Kong et al. (2012). Rate of de novo mutations and the importance of father’s age to disease risk. Nature, 488, 471-475 DOI: 10.1038/nature11396

Eisenberg DTA, Hayes MG, Kuzawa CW (2012). Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. PNAS DOI: 10.1073/pnas.1202092109

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