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Genetic Linkage

Older Dads Have More Mutations

As a genetic counselor, I hate telling a woman over 35 that she’s of “advanced maternal age,” which raises the risk of conceiving a child who has an extra chromosome. Now older men are in the reproductive spotlight too.

Since the nineteenth century, physicians have noted that Down syndrome babies tend to be the youngest children in large families. At first the blame went to syphilis, thyroid disease, tuberculosis, alcoholism, or emotional distress. After a study of 350 large families with Down syndrome found an unusually high number of older mothers, doctors blamed “maternal reproductive exhaustion.”

In 1930 researchers attributed the increased risk of having a baby with an extra chromosome to the mother’s age, which involved more than just general decrepitude following unceasing pregnancy and nursing. “Advanced maternal age” is associated with sending too many or too few chromosomes into an immature egg, like a square dance generating a single and a trio amidst the couples. Trig Palin, who has trisomy 21 Down syndrome, and Bella Santorum, who has trisomy 18 Edwards syndrome, fit the pattern, each the youngest in a large family and each getting an extra chromosome.

But wait! Two new papers explain the less well known “paternal age effect” (PAE) disorders.

Yes, aged sperm run into problems too, and they tend to cause dominant single-gene diseases in offspring, unlike the chromosome imbalances traced to older mothers. Both types of conditions, springing forth suddenly in developing sperm or eggs, are spontaneous and new – they don’t continue a family history of the illness. The reason why men introduce single-gene conditions while women originate chromosome imbalances arises from meiosis, which is how we make eggs and sperm.

Meiosis has two cell divisions. In females, eggs-to-be arrest on the brink of that second chromosomal pairing-and-parting in a five-week fetus. The process completes just after a sperm enters the egg, hopefully a few decades later. So a chromosomal mistake either happened before a pregnant woman was herself born, or by being exposed to environmental dangers (such as viruses and radiation) during the years that her immature eggs awaited ovulation.

In the male, however, stem cells in the testis divide, every 16 days, from puberty on. And each time, DNA replication can run afoul, causing a disease if that unfortunate sperm hits its mark.

Anne Goriely and Andrew Wilkie discuss several such PAE conditions in The American Journal of Human Genetics. They include a form of dwarfism; premature fusion of an infant’s skull bones; the rare Noonan, Costello, Apert, Crouzon, and Pfeiffer syndromes; and multiple endocrine neoplasia, which causes glandular cancers. More common conditions may also be traced to older men with mutations.

Geneticists think that mutations arise in stem cells in the testes that make them divide faster than neighboring stem cells, which stick to the 16-day schedule. To see this, Norman Arnheim and co-workers at USC viewed sperm stem cells in “human biomaterials” from the National Disease Research Interchange -- from men who had donated their bodies to science.

“Each testis was cut into 6 slices and each slice into 32 pieces of approximately equal size,” they write in PLoS Genetics. Then the researchers cataloged the DNA representing the genes behind multiple endocrine neoplasia in each testicle piece. And they found that some sectors had more mutations than others. Plus, the older the man, the more mutations.

So now in addition to women over 35 worrying that they are obstetrically elderly, pregnant women of any age with older husbands will have to worry. And amniocentesis won’t help them, because it checks only chromosomes. They’ll need a test panel to detect the dad-disorder mutations in amniotic fluid. Are you listening, biotech companies?

My next post will address yet another aspect of masculinity in genetics news – the restored image of the Y chromosome. Stay tuned.

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