Am J Hum Genet. 1955 March; 7(1): 21–27.

Two different mutations of the X-chromosome causing diabetes insipidus
Hans Forssman

Familial genetic defects plus late paternal age make for a horrendous combination

Vol. 39 No. 10, October 1982 Archives
• Online Features



Familial schizophrenia. A predictor of neuromotor and attentional abnormalities in schizophrenia
E. Walker and J. Shaye


Family history of psychopathology may have a role in schizophrenics' attentional and neuromotor functions. Twelve schizophrenics with a schizophrenic biological parent (SFH), 12 schizophrenics with no history of schizophrenia in first- or second-degree relatives (SNFH), 12 psychiatric controls, and 12 normal controls were given brief neuromotor examinations and the continuous performance test (CPT). Statistical analyses indicated that SFH manifested significantly more neuromotor abnormalities than did normal controls. On the CPT, SFH had significantly more errors than SNFH and psychiatric controls and slower reaction times than psychiatric controls

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

© 1994 Oxford University Press

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RESEARCH-ARTICLE


Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells
Judith Pratt Rosslter, Michele Young1, Michelle L. Kimberland, Pierre Hutter1, Rhett P. Ketterling2, Jane Gitschier3, Jürgen Horst4, Michael A. Morris1, Daniel J. Schaid5, Phillppe de Moerloose6, Steve S. Sommer2, Haig H. Kazazian, Jr.* and Styllanos E. Antonarakis1,*
Center for Medical Genetics, The Johns Hopkins University School of Medicine 600 N.Wolfe Street, Baltimore, MD 21287, USA 1Division of Medical Genetics, University of Geneva Medical School &Cantonal Hospital Geneva, Switzerland 2Department of Biochemistry and Molecular Biology, Mayo Clinic/Foundation Rochester, MN 3Howard Hughes Medical Institute and Department of Medicine, University of California San Francisco, CA, USA 4Institut fur Humangenetik der UniSwitzerland Munster, Germany 5Section of Biostatistics, Department of Health Sciences Research, Mayo Clinic/Foundation Rochester, MN, USA 6Hemostasis and Thrombosis Unit, Cantonal Hospital Geneva, Switzerland

*To whom correspondence should be addressed

Received March 22, 1994; Revised May 13, 1994; Accepted May 13, 1994

The factor VIII gene, which is defective In hemophilia A, is located in the last megabase of the long arm of the X chromosome. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of all cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the Inversion process, and that, therefore, the event originates predominantly in male germ cells. In all 20 informative cases In which the inversion originated in a maternal grandparent, DNA polymorphism analysis determined that it occurred in the male germline. In addition, all but one of 50 mothers of sporadic cases due to an Inversion were carriers. Thus, these data support the hypothesis and Indicate that factor VIII gene inversions leading to severe hemophilia A occur almost exclusively In male germ cells.

Study Confirms Paternal Age Past 40 and Increase Breast Cancer Risk

Born in Jerusalem


Eur J Cancer Prev. 2007 Dec;16(6):549-54.
Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.Weiss-Salz I, Harlap S, Friedlander Y, Kaduri L, Levy-Lahad E, Yanetz R, Deutsch L, Hochner H, Paltiel O.
Department of Health Services Research, Ministry of Health, Jerusalem, Isreal. gilsalz@012.net.il

To study the risk factors associated with breast cancer in women younger than 40 years, a cohort study (The Jerusalem Perinatal Study) of 42 822 female offspring born in hospitals in West Jerusalem during 1964-1976 was carried out. Hazard ratios of potential parental and perinatal risk factors for early breast cancer were measured. The overall incidence of breast cancer was 5.2/100 000 person-years. The highest incidence was found among Jewish women of West Asian ancestry (8.6/100 000 person-years), specifically those whose maternal grandfathers were born in Iraq, Iran or Afghanistan (9.5/100 000 person-years). Using Cox models we found independent risk factors for early breast cancer to be paternal age (relative risk/year=1.06, 95% confidence interval=1.02-1.10, P=0.005), and ancestry from Iraq/Iran/Afghanistan (relative risk=3.1, 95% confidence interval=1.50-6.52, P=0.002). The study confirms a previously observed effect of advanced paternal age on the occurrence of early breast cancer and identifies a novel population group at increased risk for the disease. The excess risk of early breast cancer associated with ancestry from Iraq, Iran and Afghanistan suggests involvement of genetic determinants, environmental exposures and/or lifestyle factors and mandates further investigation.

Paternal Age and Epigenetics Why One Twin Can Be Affected and Not the Other

Geneticists have also been unable to explain why identical twins sometimes aren't. Born of the same egg and sperm, the twins' genetic blueprints couldn't be more similar. Yet physicians have known for decades that one twin can become chronically ill while the other carries on in perfect health. If one identical twin is autistic, for example, the other often is, too, but only in 60 percent of the cases. For people with schizophrenia and bipolar disorder, two debilitating mental illnesses, the rate for their identical twins hovers near 50 and 75 percent.

Doctors have explained this twin paradox by saying something in the environment – a virus, say, or stress – triggers disease in one twin but not the other. But decades of searching hasn't turned up convincing triggers.

Enter epigenetics. What if, scientists are asking, chemical flags settle on one twin's DNA but not the other's? If these flags are sprinkled on or stripped from a gene that's critical for brain development, could autism or schizophrenia develop?

Epigenetically unique
The scientists scrutinized the epigenetic flags on a gene implicated in schizophrenia. In the pair who both had the disease, the scientists noted similar epigenetic patterns. In the other pair, the twin who had schizophrenia was epigenetically more similar to the first pair than to the sibling. It could be that the "sick" epigenetic pattern is contributing to schizophrenia, Petronis said. Even if that's not the case, he said, the study shows that two people who are genetically matched can be epigenetically unique.


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Thursday, August 23, 2007
NEW PAPER Older Paternal Age and Schizophrenia, CNVs, Point Mutations,Dysregulation of Epigenic Factors, Chromosome Breakage




Schizophr Bull. 2007 Aug 21; [Epub ahead of print]
Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia.
Perrin MC, Brown AS, Malaspina D.
2Department of Psychiatry, School of Medicine, New York University, New York, NY.
The causal mechanism underlying the well-established relation between advancing paternal age and schizophrenia is hypothesized to involve mutational errors during spermatogenesis that occur with increasing frequency as males age. Point mutations are well known to increase with advancing paternal age while other errors such as altered copy number in repeat DNA and chromosome breakage have in some cases also been associated with advancing paternal age. Dysregulation of epigenetic processes may also be an important mechanism underlying the association between paternal age and schizophrenia. Evidence suggests that advancing age as well as environmental exposures alter epigenetic regulation. Errors in epigenetic processes, such as parental imprinting can have serious effects on the offspring both pre- and postnatally and into adulthood. This article will discuss parental imprinting on the autosomal and X chromosomes and the alterations in epigenetic regulation that may lead to such errors.
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"Pediatricians will call me and say this is cool," said Rockefeller's David Allis. "One identical twin will be hugely normal and the other will be hugely autistic. What gives? The biology tells us that the kids are really genetically matched sets."

There's still no proof that epigenetics is behind identical twins' differences. But it's such a logical explanation, researchers argue, it's worth investigating.

A recent study by Petronis and colleagues, for example, shows that genetically identical twins can differ epigenetically. This year in Schizophrenia Bulletin, the scientists reported on a study of two pairs of identical twins. In one pair, both twins had schizophrenia. In the other pair, only one did.

high paternal age carries a risk not only for the fetus but also for surviving children, arising from mutations of paternal origin?

"Our results may, however, have wider implications. If advanced paternal age constitutes a risk for spontaneous abortion and stillbirth, then it is plausible that high paternal age carries a risk not only for the fetus but also for surviving children, arising from mutations of paternal origin."

"And contrary to the general case in humans, in chimps old females are preferred by males"

Chimps share many traits that we consider to be uniquely human, but now a new study suggests that the menopause really does set humans apart from other apes.

A detailed look at long-term fertility data from six populations of chimpanzees, compared with similar data from populations of hunter-gatherer humans, shows that both chimp and human birth rates have similar patterns of reproductive decline after the age of 40.

But where chimp survival drops along with fertility, humans stop reproducing and continue to live for a long time. Some chimps in their 40s are in fact better at reproducing than humans at that age. And contrary to the general case in humans, in chimps old females are preferred by males.

those between 45 and 49 years old were 64% more likely to have an infant with a 1-minute total Apgar score of between 1 and 3

Older Paternal Age Could Mean Sicker Babies

A recent study shows that new fathers in their 40s and 50s tend to have newborns with lower Apgar scores than fathers in their 20s. The Apgar score rates the infant on 5 aspects: respiratory effort, heart rate, reflex irritability, muscle tone, and skin color, with a value of 0 to 2 (worst to best) for each one. The score is calculated at 1 and 5 minutes after birth.

Researchers at the University of Aarhus in Denmark analyzed data from >70,000 couples who had their firstborn between 1980 and 1996. Compared with new fathers in their 20s, those between 45 and 49 years old were 64% more likely to have an infant with a 1-minute total Apgar score of between 1 and 3. Newborns with fathers over age 50 were 49% more likely to score in this range as well (a score of 10 is optimal). All fathers over age 45 were at an increased risk of having an infant with a 5-minute Apgar score of <7.

The researchers stated, "The biologic link between advanced paternal age and low Apgar scores is unknown." Some studies have shown, however, that "expression of specific paternal genes is crucial for the placental development, and that chromosomal aberrations tend to increase with paternal age." The findings were published in the July 2006 issue of Epidemiology.

Reduce Germ Line Mutations- Have Healthier Kids- Father's Age Matters

Journal of Anti-Aging Medicine
The Role of Somatic and Germline Mutations in Aging and a Mutation Interaction Model of Aging

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Interventions that reduce somatic and germ cell mutations should, therefore, reduce the aging process in present and future generations

Recent literature demonstrates that the male contributes to recurrent pregnancy loss due to genetic factors, and age etc

The impact of male factor on recurrent pregnancy loss.




The impact of male factor on recurrent pregnancy loss.
Fertility Current Opinion in Obstetrics & Gynecology. 19(3):222-228, June 2007.Puscheck, Elizabeth E a; Jeyendran, Rajasingam S b
Abstract: Purpose of review: The present paper reviews the current literature on the impact of male factor on recurrent pregnancy loss.
Recent findings: Most clinicians focus their evaluation of recurrent pregnancy loss on the female, without much, if any, consideration of the other half of the couple - the male. Yet, the male contributes one-half of the genes for the embryo. Recent literature demonstrates that the male contributes to recurrent pregnancy loss due to genetic factors, semen factors or due to other factors such as age.
Summary: Recurrent pregnancy loss results as a factor of a couple. This paper emphasizes the contribution of the male to implantation failure, miscarriage, and congenital anomalies suggested by recent literature. The current data are preliminary. With further investigation, evaluation of the male may be considered a routine part of the evaluation in the near future.
(C) 2007 Lippincott Williams & Wilkins, Inc.

Mayo Clinic On Autism and Older Fathers One Fact Not Stated is Sperm Cannot Repair Itself

"A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage," he said. "Most other cells do."


On a related note, advancing maternal age appears to have little effect on autism risk.



Older fathers and autism risk: Is there a connection?Date updated: May 31, 2007 Content provided by MayoClinic.com
Is it true that children born to older fathers are at increased risk of autism?
Kristin, Utah
A growing body of evidence suggests that a father's age (paternal age) may play a role in autism risk.
A large study published in the Archives of General Psychiatry in 2006 examined the relationship between advancing paternal age and autism risk. Researchers reported that children born to men 40 years or older were almost six times more likely to have autism spectrum disorder than were children born to men younger than 30 years.
The reason for this increased risk of autism isn't clear. One theory is that as men age, their genetic material loses some ability to repair itself. As a result, spontaneous mutations in genes may be passed on rather than corrected - potentially leading to an increased risk of brain abnormalities in their children. Researchers have identified a number of gene mutations associated with autism.

Research Reveals A Cellular Basis For A Male Biological Clock
ScienceDaily (Nov. 27, 2002) — Researchers at the University of Washington have discovered a cellular basis for what many have long suspected: Men, as well as women, have a reproductive

http://www.sciencedaily.com/releases/2002/11/021126201311.htm

The researchers found that men over age 35 had sperm with lower motility and more highly damaged DNA in the form of DNA double-strand breaks. The older group also had fewer apoptotic cells – an important discovery, Singh said.
"A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage," he said. "Most other cells do."
As a result, the only way to avoid passing sperm DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age.
"So in older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated," Singh said. "That means some of that damage could be transmitted to the baby." More research is needed to determine just what the risks are. Other reseachers in the study included Richard E. Berger, UW professor of urology. The work was supported by the Paul G. Allen Foundation for Medical Research.
On a related note, advancing maternal age appears to have little effect on autism risk.

Please Read And Let Your Friends and Family Know

Excerpts from an article that everyone should read and take to heart:Male Health: The Long ShotFrom puberty on, reproductive health and the viability of sperm continue to evolve.By:Mark Teich


TeensUntil age 13 or 14, sperm is not fully formed, increasing the risk of infertility or birth defects.


Sperm may be extremely healthy in older teens, who are famous for their potency. But risky teen behavior may put sperm at risk.20sThese are prime years for male reproduction. Men have the maximum amount of mature sperm cells and the least DNA damage. The risk of producing birth defects or causing other problems in offspring is as low as it ever will be.


30sTestosterone levels start to decline at age 30, bringing a decrease in potency. By 32-34, fertility begins to fall. Men who are 35 or older are twice as likely to be infertile as men under age 25. The mid-thirties also bring a significant increase in sperm DNA damage and thus an increased risk of producing birth defects. One in 99 fathers ages 30-35 sire children with schizophrenia versus one in 141 for fathers under age 25.



40sThe risk of schizophrenia doubles in children of fathers in their late forties compared with children of fathers under age 25. Men 40 and older are nearly six times more likely to have offspring with autism than men younger than 30.50sBy age



50, the DNA cells that create sperm have gone through more than 800 rounds of division and replication, vastly decreasing the quality of sperm and increasing the chances of mutation and birth defects. The risk of schizophrenia almost triples for children of fathers 50 and older; one in 47 fathers sires a child with the condition..............

Zabeth Basic knowledge of age related changes in men’s sperm goes back nearly 60 years,

Does A Male Biological Clock Exist?
The answer would appear to be yes! Men often take for granted the fact that they can create sperm for their entire lives. There is no timeframe after which men are unable produce sperm in the same way that women go through menopause. Many men assume that because they make sperm all of their lives that they have the same ability to conceive healthy children at 50+ as they were able to do in their 20s and 30s. Science is mounting that that is in fact NOT the case.
Much has been made of the female biological clock; however, the male biological clock often goes ignored. Basic knowledge of age related changes in men’s sperm goes back nearly 60 years, HOWEVER SOCIETY CHOOSES TO IGNORE (OR FLAT OUT DENY) THIS INFORMATION. Here are some things to consider:
Age can make it harder for men to produce quality sperm that's able to conceive a child. The risk of birth defects also increases with the age of the father. For example, men over 40 are nearly six times more likely to father an autistic child than men under 30. Schizophrenia may also be more prevalent in children fathered by older men.
The cells that create a man's sperm divide roughly once every 16 days. By the time a man is 50, that division has occurred more than 800 times. Those cells determine the genetic code that will be in the sperm- and every time they divide, there's a chance that the genetic code will be altered. With every alteration comes a greater chance of genetic deterioration that could open the door to birth defects.
It takes only 24 cell divisions in a woman's body to produce her lifetime supply of eggs, and those divisions occur before the woman is even born. That may provide more genetic stability for eggs than for sperm.
With age a man's body can produce less testosterone. And that in turn can reduce sperm count and the quality of sperm available- including its ability to trigger a pregnancy.
Sexual performance can also decline with age.
Bottom line: Fertility rules! Nature doesn’t make mistakes. Men and women both can’t delay child rearing forever or until it’s the “perfect” time. There’s no such thing as the “perfect time,” by the way. If you want to have a family, you don’t have your whole life to wait things out.

Zabeth-- Basic knowledge of age related changes in men’s sperm goes back nearly 60 years,

Does A Male Biological Clock Exist?
The answer would appear to be yes! Men often take for granted the fact that they can create sperm for their entire lives. There is no timeframe after which men are unable produce sperm in the same way that women go through menopause. Many men assume that because they make sperm all of their lives that they have the same ability to conceive healthy children at 50+ as they were able to do in their 20s and 30s. Science is mounting that that is in fact NOT the case.
Much has been made of the female biological clock; however, the male biological clock often goes ignored. Basic knowledge of age related changes in men’s sperm goes back nearly 60 years, HOWEVER SOCIETY CHOOSES TO IGNORE (OR FLAT OUT DENY) THIS INFORMATION. Here are some things to consider:
Age can make it harder for men to produce quality sperm that's able to conceive a child. The risk of birth defects also increases with the age of the father. For example, men over 40 are nearly six times more likely to father an autistic child than men under 30. Schizophrenia may also be more prevalent in children fathered by older men.
The cells that create a man's sperm divide roughly once every 16 days. By the time a man is 50, that division has occurred more than 800 times. Those cells determine the genetic code that will be in the sperm- and every time they divide, there's a chance that the genetic code will be altered. With every alteration comes a greater chance of genetic deterioration that could open the door to birth defects.
It takes only 24 cell divisions in a woman's body to produce her lifetime supply of eggs, and those divisions occur before the woman is even born. That may provide more genetic stability for eggs than for sperm.
With age a man's body can produce less testosterone. And that in turn can reduce sperm count and the quality of sperm available- including its ability to trigger a pregnancy.
Sexual performance can also decline with age.
Bottom line: Fertility rules! Nature doesn’t make mistakes. Men and women both can’t delay child rearing forever or until it’s the “perfect” time. There’s no such thing as the “perfect time,” by the way. If you want to have a family, you don’t have your whole life to wait things out.