Older fathers and new genetics

[This piece appeared in the October edition of Marshwood Vale Magazine]

Pablo Picasso and children, Claude and Paloma. Their mother was Francoise Gilot.

Couples contemplating childbirth have conventionally focussed on the age of the mother as a risk factor for disorders such as Down’s syndrome.  There has been a growing feeling, however, that the age of the father, previously disregarded, could influence the occurrence of autism and schizophrenia.  A recent study sheds light on the mechanism of this effect as well as showcasing the power of the new genetics. 

The new genetics – the Genome revealed

About ten years ago, the sequence of the Human Genome was reported.  Let’s look at what this means.  Most cells in the body contain a set of instructions that allows new cells to be built.  These instructions, found in the chromosomes, are written in the form of strings of molecules of DNA (DeoxyRibonucleic Acid).  The DNA molecules are organised in to chunks called genes and each gene contains the instructions for making one protein building block.  The Human Genome is made up of about 21,000 of these genes as well as very large stretches of DNA encoding molecules that regulate expression of the genes.  Ten years ago, the sequence of all the DNA molecules (~ 3 billion) in the Genome was determined.  This was a heroic technical and intellectual effort. The Human Genome sequence was called the “blueprint for life” and was expected to lead to huge advances in human health.

The new genetics – the reality

Expansive predictions were made about the effect of the Genome sequence on clinical medicine.  Predictive genetic tests for common diseases such as cancer and heart disease would be available within ten years and new therapies would follow.  None of this has proven to be true.  It had been expected that the genetic basis of these diseases would reside in a handful of changes in the DNA sequence, or mutations as they are called, allowing predictive genetic tests to be developed.  The reality is that many mutations have been identified, each conferring only a small risk for the disease.  Many of the mutations are also in the regulatory part of the DNA, which is not well understood, although it is under intense study.   

The new genetics – whole genome sequencing

Map of Iceland

It became clear that to exploit the power of the new genetics fully, it would be necessary to sequence complete genomes from many people.  Until recently this was impossible for financial and technical reasons.  Now this is going ahead and one of the leaders in this field has been a company deCODE, based in Iceland where it is taking advantage of some of the unique features of this small country.  Iceland has a small population (about 275,000) who are genetically rather similar. This means that mutations in the Genome will stand out from the background variation more clearly than in populations with greater genetic diversity.  Iceland holds genealogical information dating back more than 1000 years allowing inheritance to be tracked between families.  It also holds comprehensive medical records on all its citizens allowing diseases to be followed in the population.  deCODE has so far sequenced the genomes of more than 2000 people and is comparing the sequences from healthy people and those suffering from certain conditions to try to identify disease-causing mutations and has already made important discoveries in stroke, schizophrenia, osteoarthritis and diabetes.

The age of the father at conception

The company has recently compared the genomes of 78 family “trios” of father/mother/child.  The genome of a child contains contributions from both the father and mother and this study examined how maternal and paternal DNA had been changed when it was incorporated in the child’s genome.  The surprising result was that the maternal DNA in the child’s genome contained about 14 new mutations independently of the age of the mother at conception.  The paternal contribution to the child’s DNA, however, contained more mutations and the number increased with increasing age of the father; 20-year old and 40-year old fathers transmitted 25 and 65 mutations respectively.  A woman receives her complement of eggs at birth so it is not surprising that there are few new mutations in maternal DNA.  Sperm, however, result from continuous division of precursor cells; this repeated division, together with environmental insults, results in mistakes (mutations) when the DNA is copied.  In older fathers the sperm precursors will have undergone more divisions with increased risk of mutations compared to younger fathers.

The implications

We now know that the age of the father at conception is the major determinant of new mutations in his child’s DNA.  This surprising finding raises many issues.  First, does the increased number of mutations have any consequence for human health?  The answer here is possibly.  It has been shown in the Icelandic population that as the father’s age at conception increases so does the risk of schizophrenia or autistic spectrum disorder (ASD).  Older fathers transmit more new mutations to their children.   Most of these mutations are harmless, but some may confer increased risk of schizophrenia or ASD.  The risks are still very low but given that age of fathers at conception in the UK has increased from 31.5 in 1998 to 32.4 a decade later, these findings on paternal age are worthy of  discussion more widely in society.  The age of the mother is still an important factor in the occurrence of abnormalities like Down’s syndrome where extra chromosomes are present rather than new mutations.  

Some commentators have wondered if men will now be mindful of ticking biological clocks in the same way women are.  Would young men be sprinting to the sperm bank to preserve their precious non-mutated treasures?  It had always been thought that men were immune to reproductive ageing.  This may now be a myth and we might look differently on the next craggy-faced rock star fathering children in his sixties.

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