James F. Crow Professor Emeritus Population Genetics University of Wisconsin

Genetic Mutations Tied To Father in Most Cases


An excellent article from 1994


By NATALIE ANGIER
Published: May 17, 1994

Some excerpts ................................
"WHEN it comes to parceling out blame for birth defects and genetic disorders, women have historically shouldered most of the burden, particularly older mothers who supposedly risked their offspring's well-being by letting their eggs sit around growing progressively more stale and chromosomally unstable.

By contrast, men have been seen as eternally fertile, able to father healthy children well into their dotage.

But growing evidence suggests that men, rather than women, may be the source of most new genetic mutations in the population, and thus may be responsible for the majority of congenital diseases that seem to come from nowhere. In addition, the older the man gets, the more likely his sperm is to carry genetic mutations.

The new view is based largely on studies of individual cells, and scientists emphasized that they have much to learn about the source of genetic mutations. Nor do they have any idea how often a minor variation in the genetic blueprint for a human being translates into a birth defect. The overwhelming majority of genetic alterations that appear in the course of generating sex cells are likely to be harmless. Nevertheless, some researchers said it was time to take a closer look at the inherent fallibility of sperm cells.

"This is a subject that has not received as much attention as it should," said Dr. James F. Crow, a geneticist at the University of Wisconsin in Madison.

As long as half a century ago, J. B. S. Haldane, the great Scottish geneticist, proposed that new cases of hemophilia not associated with a family history of the disease were much more likely to be the result of a genetic glitch originating with the male's sperm rather than with the female's egg. Scientists realized that while a woman's eggs are fully formed during fetal development and undergo no further cell division after birth, the progenitor sex cells that give rise to a man's sperm continue to divide throughout his life. And the greater the number of cell divisions, the greater the odds that minor errors called point mutations can occur while the chromosomes are being copied.

More recently, scientists have shown that genes on the Y chromosome -- the sole province of the male -- do indeed mutate at a faster rate than genes on the X chromosome, which is essentially though not exclusively a female chromosome. Using these and other new findings, scientists estimate that the overall genetic mutation rate in sperm cells is six times greater than it is in eggs. The Aging Factor

That discrepancy only widens with age. The older a man is, the more times his progenitor sperm cells have divided, and so the higher the number of possible point mutations that may have piled up in the chromosomes.

At 13, when a boy typically begins making sperm, his sex cells have divided about 36 times, and they divide about 23 times a year thereafter. By age 20, the cells have replicated about 200 times; by 30, about 430 times; and by 45, about 770 times.

Statistical evidence supports the premise that an older father is likelier to sire a child with a birth defect than is a younger man, Dr. Crow said. On average, fathers of children who have a new dominant genetic disorder -- a disease caused by a single genetic defect not known to run in the family -- are six years older than fathers of children without an illness. For example, older fathers have an elevated risk of giving birth to children with achondroplastic dwarfism, Marfan syndrome and myositis ossificans, a disease of bony tissue."............................




"I think we could eliminate quite a bit of human mutation if males either reproduced at a young age, or stored their youthful sperm on nitrogen for use later in life," he said.

James F. Crow's paper the High Rate of Spontaneous Mutation:Is it a health risk? Is very important work to read if you can.