Disease-Causing Genetic Mutations In Sperm Increase With Men's Age

"It makes sense that the mutations causing these diseases would occur more frequently in older men, and indeed that's what we saw for Apert syndrome," says Ethylin Jabs, M.D., director of the Center for Craniofacial Development and Disorders at Johns Hopkins.

Importantly, disorders linked to advancing paternal age begin to increase rapidly at about the same time as maternal risks increase -- age 33 to 35.

To obtain the first genetic explanation for these effects, the scientists studied sperm from about 60 men of various ages and looked for two genetic changes responsible for 99 percent of the cases of Apert syndrome. They found that men over 50 were, on average, three times as likely as men under 30 to have sperm with at least one of these changes. The mutations were not more common in blood samples as men aged.

The scientists say it's likely that the number of cell divisions that go into making a sperm plays a large role in the link between Apert syndrome and paternal age, and represents a fundamental difference between how aging egg and sperm can impact the health of a child.

"In the men we studied, these mutations had not been inherited, but rather collected over time in the reservoir of primitive cells that become sperm," says first author Rivka Glaser, a graduate student in human genetics at the Johns Hopkins School of Medicine.

Cells that mature into eggs are essentially frozen in time from puberty until the time the egg is signaled to develop. Because of the stage at which they are "frozen," the most likely error in an egg is to have an abnormal partitioning of chromosomes, producing an egg with an extra copy or a missing copy, Glaser says. For example, in Down syndrome, an extra copy of chromosome 21 is inherited from the mother.

Sperm, on the other hand, are continually produced throughout a male's lifetime from a reservoir of primitive cells. These primitive cells, like other kinds of so-called stem cells, can either replicate themselves or take a step closer to becoming a sperm, a process called differentiation. All told, these cells divide every 21 days after puberty, and at each cell division the opportunity exists for an error in copying the DNA.

"Literally hundreds of millions of sperm are made in each batch, so in most cases there are still many normal sperm available," says Jabs, also a professor of pediatrics. Their study showed that "high levels" of mutations among men who had no children with Apert syndrome amounted to roughly 3 sperm with the mutation among 100,000 sperm.

If an error is made in any of the steps toward becoming a sperm, the only cells affected are the resulting sperm for that batch. However, if an error appears in a primitive cell as it replicates itself and the mistake isn't fixed, the mutation will continue to be passed on to all of its progeny, including subsequent primitive cells and other batches of semen.

As men age, more of these primitive cells have collected mutations that cause Apert syndrome, leading to more sperm with the mutations in each batch of semen, the scientists suggest. The risk of having a child with Apert is about six times higher for a man age 52 than for someone who's 27.


Authors on the study are Glaser, Jabs, and Rebecca Schulman, of Johns Hopkins School of Medicine, and Karl Broman, of the Johns Hopkins Bloomberg School of Public Health.

Like 35 and Down Syndrome for Women

Old fathers raise risk of brain disorder
By Jacqueline Maley
October 23, 2004
There is a "strong association" between men who become fathers after the age of 50 and of schizophrenia in their children, a study has found.

Swedish research that tracked over 700,000 young people found 15 per cent of schizophrenia cases could be attributed to older fathers. Researchers believe the link may be due to sperm mutations, which accumulate as men get older.

Compared with men who become fathers between 21 and 24, those who father children at the age of 50 or older have four to five times the chance of their offspring developing schizophrenia. The link was stronger if there was no family history of the disorder.

The link between schizophrenia and older paternity had been made before, but this was the first large study to look at a range of factors that could confound the results, said Professor John McGrath, a psychiatric epidemiologist at the Queensland Centre for Mental Health Research.

"If all babies had fathers less than 30, the paper suggests, the incidence of schizophrenia would reduce by 15 per cent," he said.

In the 1970s it was commonly believed that mothers caused their children's schizophrenia, Professor McGrath said. "There is now an interesting new lead looking at father's age, and this study adds weight to that.

"Schizophrenia is a group of brain disorders, and we're struggling to find out what causes them. This study ... will help to tease apart the causal pathway."

In Australia about 1 per cent of people develop schizophrenia. A study published in 2002 in People and Place, a Monash University journal, found consecutive generations of Australian men were becoming parents later.

In 2002 the average age of fathers was 32, compared with an average age of 29 in 1982, according to data from the Australian Bureau of Statistics.

The executive director of the mental health lobby group SANE Australia, Barbara Hocking, said the Swedish research, published in the British medical journal BMJ, was "major, major stuff".

She likened the research to the link between mothers over 35 and an increased risk of Down syndrome in their children. "It helps people understand what risk factors may be, so you can take action to reduce them."

Paternal Age Explains between 1/4 and 1/3 of all Schizophrenia

Dr. Dolores Malaspina interviewed by Dr. Norman Sussman


"The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children. In the 1960s, an excess of schizophrenia in last-born children was also reported."

http://www.schizophreniaforum.org/for/curr/Malaspina/default.asp




Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the

fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.
genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the

fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.