"It is very possible that PATERNAL AGE is the major predictor of(non-familial) autism." Harry Fisch, M.D., author "The Male Biological Clock". Sperm DNA mutates and autism, schizophrenia bipolar etc. results. What is the connection with autoimmune disorders? Having Type 1 diabetes, SLE,etc. in the family, also if mother had older father. NW Cryobank will not accept a sperm donor past 35th BD to minimize genetic abnormalities.VACCINATIONS also cause autism.

Thursday, August 30, 2007

Lisa Jo Rudy -- Does a Good Job, She Doesn't Know About All The Paternal Age Research

Do older parents run a higher risk of having a child with autism?
A. According to recent research, the answer is a qualified "yes." Several studies do seem to suggest that there is an association between parental age and autism. An association, though, is NOT the same thing as a causal connection. That means while older parents may be statistically more likely to have children with autism, no one knows why -- and the reasons may not relate to every couple.
Why would an older parent be more likely to have a child with autism? One possible answer lies in research that shows children with autism are far more likely than typical children to have new (not inherited) genetic mutations. New genetic mutations are often the result of damage to eggs and sperm...........

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By age 45 and up Red flags should go up about the dangers to many offspring because the odds of neurocognitive damage which become significant at paternal age 35 are far greater and increase with paternal age.

The assertion that researchers do not know the cause of spontaneous mutations which are also called sporadic or germ line or de novo or non-familial mutations is erroneous. By the paternal age of 45 offspring are 500 to 800% more likely to be autistic or schizophrenic or have other de novo genetic disorder too numerous to name. The autism/Asperger's/schizophrenia/type 1 diabetes epidemics are not like lightening strikes at all. Why do the researchers like Michael Wigler, Jonathan Sebat etc. play dumb about spontaneous mutations and paternal age?

James F. Crow: He concluded that many diseases caused by mutations in offspring were the result of fertile old men. His rationale was that the gametes of older men had gone through more cell divisions. More cell divisions mean more mutations since it increases the chance that there is a mistake whenever the genome divides. For women, it's different. By the time a female is born, all the eggs that she will ever produce during her lifetime are already present in the ovary.

"The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age." "I conclude that for a number of diseases the mutation rate increases with age at much faster rate than linear. This suggests that the greatest mutational hazard in the human population at present is fertile old males."

Warnings that autoimmune disorders and autism and schizophrenia are related beginning in the 1970s and since then from many researchers.

"All genetic illnesses have their origin in a distant or recent mutation. Paternal age is an important determinant of mutation frequency in new germ cell mutation, causing both autosomal dominant and X-linked recessive illnesses. The role of other mutagenic factors is not the subject of this study. The results of my own research are supported by other information which indicates that the leading cause of genetic illness present in human populations is the ageing process in the male. Conceiving children by men younger than 35 years of age would prevent many genetic illnesses in future generations."

"The optimal time for a man to father a healthy child is the same as for a woman — 25 or so," says Dolores Malaspina, a psychiatry professor at New York University and coauthor of the study.

More on spontaneous/germ line/sporadic/de novo/non-familial mutations and genetic disorders:

Another of her studies found that fathers of sporadic schizophrenia cases were 5 years older than familial case fathers
. If sporadic schizophrenia can originate from new mutations, then neurodevelopmental genes are reasonable candidates. Her study will examine if patients with sporadic schizophrenia, particularly those with fathers older than 35 at birth, show features found in other neurodevelopmental diseases that correlate with paternal age, such as craniofacial abnormalities, nonspecific cognitive deficits and delayed developmental milestones

Spain 1988

This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their
families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.

Public Health Advisory suggested because it has been shown in ten studies since 1958 older fathers and schizophrenia are related. An analysis of many studies has shown that paternal age 35 and above is related to significantly more

Most of our
donors are either currently involved with, or have finished
their higher education at the time of their participation in
our donor program. All donors are between 18 and 35
years of age in order to minimize genetic abnormalities

"Thus, it is good public health policy to recommend that both men and women complete their family a before age 40, if possible" ~
JM Friedman in an article called Genetic disease in the offspring of older fathers. Obstetrics & Gynecology 1981:57 745-749

Genetic disease in the offspring of older fathers
JM Friedman

Michael Craig Miller, M.D.

Mental Health Letter editor

"But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family."

"Although boys were more likely to develop autism than girls, the risk for girls also increased as fathers got older. When fathers were young, about 1 in 6 children with autism were girls. After fathers passed the 40 year-old mark, the proportion of girls with autism rose to about 1 in 3. This suggests that the genetic factors in play for offspring of older fathers are different from those for offspring of younger fathers."

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program

There is much, much more research to show that increasing paternal age in the last 25 or so years has lead to the vastly increased number of people with neurocognitive disorders now called autism and autoimmune disorders such as type 1 diabetes. This is apart from the role of the vaccination program in these and other disorders.

1: Hum Reprod. 1989 Oct;4(7):794-7. Links
Paternal age and mental functions of progeny in man.Auroux MR, Mayaux MJ, Guihard-Moscato ML, Fromantin M, Barthe J, Schwartz D.
Biologie de la Reproduction et du Développement, CHU Bicêtre, Le Kremlin-Bicêtre, France.

Study shows that genetic qualityof sperm deteriorates as men age

Understanding the effects of paternal age has become more important as increasing numbers of men are having children at older ages. Since 1980 there has been about a 40 percent increase in 35- to 49-year-old men fathering children, and a 20 percent decrease in fathers under 30.


Wednesday, August 29, 2007

On Saturday, January 25th, 1896

The Case Against Vaccination
Verbatim Report of
AN ADDRESS - By, WALTER HADWENJ.P., M.D., L.R.C.P., M.R.C.S., L.S.A., Etc(Gold Medalist in Medicine and in Surgery)
On Saturday, January 25th, 1896(During the Gloucester Smallpox Epidemic)
Foreward to Tenth Edition


End Fluoridation, Say 500 Physicians, Dentists, Scientists And Environmentalists

In a statement released recently, over 600 professionals are urging Congress to stop water fluoridation until Congressional hearings are conducted. They cite new scientific evidence that fluoridation, long promoted to fight tooth decay, is ineffective and has serious health risks. ( Signers include a Nobel Prize winner, three members of the prestigious 2006 National Research Council (NRC) panel that reported on fluoride's toxicology, two officers in the Union representing professionals at EPA headquarters, the President of the International Society of Doctors for the Environment, and hundreds of medical, dental, academic, scientific and environmental professionals, worldwide.


Video on Vaccinations-- A Must See For All

Vaccinations Good for children? Harmful?

Vaccines Are They Dangerous? Watch this Video!! What is the story?


An Introduction to the Contradictions Between Medical Science and Immunization Policy
by Rev. Alan Phillips, DirectorCitizens for Healthcare FreedomLast Revision: May 2001In Spanish


“Give no deadly medicine to anyone” - Hippocrates
If you raise the question of vaccinations with your doctor you are likely to be told that it is extremely important that you vaccinate your child. If you should be so naïve as to ask “why” you are likely to be told that vaccination is the most effective intervention of modern medicine which prevented more suffering and saved more lives than any other medical procedure.
If you decide to investigate independently, as lakhs of parents, doctors and scientists are now doing world wide, you will find, as I did, that nothing could perhaps, be further from the truth. Indeed, I urge you to investigate for yourselves. Dozens of Vaccine Research Books have been written - mostly by people from the medical profession itself. Some books are recommended at the end of this article.
There are many aspects of vaccinations that need to be addressed - however this report tries to deal with 2 basic questions only:
Do vaccinations prevent diseases?
Are vaccinations safe? Do they have side effects or contra-indications of which parents ought to be aware before they vaccinate?

A Vital Video Paternal age autism, vaccination induced autism, mother's father's age autism, familial autism, combined age and vaccination induced autism.

More on vaccination dangers

Another view of vaccinations:

Critique of Government-Funded Epidemiology by Harris L. Coulter Ph.D.©
Since I have been occasionally criticized for adopting, as it were, too acerbic a tone in my contributions on vaccination questions, I will try to demonstrate why those of us who have opted to contest the position of the medical-industrial-governmental complex on this issue at times feel overcome with rage at the abominably poor quality of the pro-vaccination epidemiologic research which is foisted on the public in the hope and expectation that no one will ever take the trouble to check it out and criticize it.
One feels rage as well at the complicity of the "peer reviewed" journals which print these awful productions. It is abundantly clear, if further proof were needed, that "peer review" means simply preventing criticism of certain commercial interests and blocking the emergence of competing viewpoints.
Finally, one feels rage and exasperation at the total inability of journalists -- who are reputed to be professional sceptics -- to see through, and expose, this duplicity. They fearlessly cross-question generals and members of the cabinet, even the President himself, but are struck dumb by the self-promoting assertions of some character in a white coat ("Say Joe, how do you spell 'breakthrough'"?).
Let us not forget that it is small and defenceless babies who are being turned into mincemeat by these commercial products known as vaccines.
Once upon a time, long ago in the 1940s and 1950s, physicians who were interested in vaccine reactions actually (would you believe it?) went into hospitals, and even to people's homes, to examine babies who were thought to have suffered some sort of adverse reaction. They went so far as to speak with the parents and to ask their opinion. This was called by one British pioneer "shoe-leather epidemiology."
Today our epidemiologists have progressed way beyond those primitive techniques. Rarely do they actually observe a sick baby. Rarely do they actually discuss a case with the parents. Oh no! That would be accepting "anecdotal evidence" -- a cardinal sin. That would be mistaking the well-known "background incidence" of SIDS or epilepsy or asthma or diabetes, or you name it, for a vaccine reaction. Never mind that no research exists on any such "background incidence" in an unvaccinated U.S. population. Our epidemiologists are not fazed by this. They just keep repeating the mantra until everyone is convinced that a "background incidence" must have been demonstrated somehow, somewhere, by someone.
Fortified by these unproven assumptions and methodological limitations, epidemiologists funded by government agencies and the medical-industrial complex fill the pages of medical journals with trash epidemiology -- the articles discussed below are prime examples -- which, in a sort of scientific apotheosis of Gresham’s Law, drives good research out of circulation or prevents it from being published.

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Kenny Ye we estimate that majority of autism cases (about 2/3, or, conservatively 50%) are caused by new mutation (that is not in parents' genome but

happened in sperm and eggs).

Is autism really a genetic disorder created, in part, as a result of older parents? A large-scale research study conducted by a team based at Cold Spring Harbor Laboratory (CSHL) in Long Island, N.Y says, yes, perhaps.
According to the team's study, a combination of heredity and spontaneous genetic mutation is at the root of most cases of autism. Most interestingly (and, perhaps, disturbingly), those genetic mutations may be the outcome of a societal trend toward having children later in life. In addition, some mothers, say the researchers, may carry an autism gene which does not show its effects until it is passed down -- usually to a male child.
This is a complex set of findings, and hard to digest without further explanation. Kenny Ye, one of the primary researchers on the project, kindly agreed to provide a layperson's description of the team's finding:
To clarify.., we estimate that majority of autism cases (about 2/3, or, conservatively 50%) are caused by new mutation (that is not in parents' genome but happened in sperm and eggs).


Minding Your Mind

New Key to Autism
September 25, 2006
By Michael Craig Miller, M.D.Harvard Medical School

Should Older Men Stop Fathering Babies?
It's true that medical technology and general improvements in health have made life much more enjoyable for people in middle to late life. Maybe 50 is the new 30 when it comes to some aspects of aging. But a healthy and active lifestyle does not make 50-year-old sperm the new 30-year-old sperm.
The increased risk of passing on any genetic vulnerability to a child is significant when you are older. When it comes to autism, however, the numbers are sobering. A man younger than 30 has no more than a 1 in 1,000 chance of fathering a child with autism. But the risk bumps up to approximately 3 in 1,000 for a man in his 40s and 5 in 1,000 above age 50. If a father in his fifties has a son, the risk of autism may approach 1 in 100.


Tuesday, August 28, 2007

Any dose of ionizing radiation poses a risk and the body accomulates the damages and when enough damage is done, cancer will develop.

Paternal age and older maternal age also increases a child's risk of leukemia editor’s note: One of the biggest mistakes a consumer can make is to ask his doctor about the risk of ionizing radiations such as x-ray. The answer is standardized. He will be told that the risk is minimal, or the benefit overweighs the risk.
X-ray as an ionizing radiation is one of the most studied carcinogen and the U.S. government officially recognized it as a human carcinogen in 2005. Children who are exposed to a chest x-ray before 2 years have a 7 to 8 times higher risk of leukemia. Those who get exposed after two years of age will have 2 to 3 times higher risk of leukemia, according to the EPA data.
The risk is not just associated with radiotherapy used to treat cancer, which uses high doses of x-ray. Any dose of ionizing radiation poses a risk and the body accomulates the damages and when enough damage is done, cancer will develop.
X-ray does not only cause cancer, it also damage arteries causing heart disease which is less known to many ordinary consumers. According to John Gofman, PhD and MD, a nuclear physicist and a physician who retired now from The University fo California at Los Angeles, 75 percent breast cancer is related to the exposure to x-ray.
Ionizing Radiation and Childhood Leukemia
Environ Health Perspect 115:395-399 (2007). doi:10.1289/ehp.10080 available via [Online 24 June 2007]
Referencing: Risk Factors for Acute Leukemia in Children: A Review
I read with interest the recent review by Belson et al. (2007) on childhood leukemia, particularly the sections dealing with radiation exposure. Like the authors, I believe that ionizing radiation is strongly associated with childhood acute leukemia. I would like to point out that several critical pieces of information were overlooked; these support stronger and more meaningful conclusions.
Although atomic bomb survivors offer the clearest evidence of leukemia risk after childhood exposures to ionizing radiation, studies of children exposed to fallout in other contexts should not be downplayed. Belson et al. (2007) stated that "radiation exposure secondary to the Chernobyl accident has not been shown to increase the risk of leukemia in children who were exposed after birth . . . ," but they failed to mention the case–control study of Noshchenko et al. (2002), which found significant increases in childhood and acute leukemias in association with estimated childhood exposures. Children living downwind of the Nevada Test Site have also shown a significant increase in leukemia related to estimated fallout exposure (Stevens et al. 1990).
In utero exposure to ionizing radiation has been a known causal factor for childhood cancer for > 50 years. Although Belson et al. (2007) stated that the lack of evidence for a childhood leukemia risk among atomic bomb survivors constitutes the "most notable reason for doubt of a true association," they overlooked the reviews of Wakeford and Little (2002, 2003); these authors demonstrated that the highly uncertain atomic bomb survivor data are statistically compatible with the robust set of data found in the Oxford Survey of Childhood Cancers and related X-ray exposure cohorts. There is no valid reason to doubt this association at present.
The association between preconception paternal irradiation (PPI) and childhood leukemia has always been controversial. Two of the major objections to the "Gardner hypothesis," as Belson et al. (2007) pointed out, have been mixed evidence from studies of radiation-exposed fathers and a lack of positive evidence in the children of the atomic bomb survivors. Regarding the first objection, Belson et al. overlooked the two largest studies of the children of radiation workers. Draper et al. (1997) conducted a UK-wide case–control study of childhood cancers in relation to paternal radiation exposure. This study showed, based on > 13,000 cases not included in the study of Gardner et al. (1990), that children with leukemia or non-Hodgkin lymphoma were significantly more likely than controls to have fathers who were radiation workers. Dickinson and Parker (2002) conducted a cohort study of > 250,000 births in Cumbria, England, including the cases of Gardner et al. (1990), and found a significant 2-fold increase in the risk of leukemia and non-Hodgkin lymphoma among the children of radiation workers. These and other studies, taken together, give statistical support to the idea that paternal radiation work is a risk factor for childhood leukemia.
When interpreting the evidence for a PPI effect in atomic bomb survivors, it is important to consider what is known about potential mechanisms. As reviewed by Niwa (2003), Nomura (2003), and others, animal studies have consistently demonstrated that PPI can cause or increase the susceptibility to leukemia in offspring. In addition to fascinating evidence of postconception genomic instability after preconception exposure, many studies suggest that there may a window of sensitivity corresponding to postmeiotic stages of spermatogenesis; in humans, this would mean the few months leading up to conception (Adler 1996). Of the roughly 30,000 children of atomic bomb survivors, only about 2% were conceived in the 6 months after the bombings. Based on the spontaneous leukemia rate reported by Yoshimoto (1990), the expected number of spontaneous cases in this subcohort would be < 1, and an excess on the order suggested by the radiation worker studies would not be statistically apparent. For this and other reasons, the atomic bomb survivors may not be an appropriate comparison group.
To summarize, it is not unreasonable to observe that the weight of evidence generated to date supports the idea that preconception, prenatal, and postnatal exposures to ionizing radiation are all risk factors for childhood leukemia.
The author declares he has no competing financial interests.
Abel Russ
George Perkins Marsh Institute
Worcester, Massachusetts
Adler ID. 1996. Comparison of the duration of spermatogenesis between male rodents and humans. Mutat Res 352(1-2):169–172.
Belson M, Kingsley B, Holmes A. 2007. Risk factors for acute leukemia in children: a review. Environ Health Perspect 115:138–145.
Dickinson HO, Parker L. 2002. Leukemia and non-Hodgkin's lymphoma in children of male Sellafield radiation workers. Int J Cancer 99:437–444.
Draper GJ, Little MP, Sorahan T, Kinlen LJ, Bunch KJ, Conquest AJ, et al. 1997. Cancer in the offspring of radiation workers: a record linkage study. BMJ 315(7117): 1181–1188.
Gardner MJ, Snee MP, Hall AJ, Powell CA, Downes S, Terrell JD. 1990. Results of case-control study of leukemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ 300:423–429.
Niwa O. 2003. Induced genomic instability in irradiated germ cells and in the offspring: reconciling discrepancies among the human and animal studies. Oncogene 22: 7078–7086.
Nomura T. 2003. Transgenerational carcinogenesis: induction and transmission of genetic alterations and mechanisms of carcinogenesis. Mutat Res 544(2-3):425–432.
Noshchenko AG, Zamostyan PV, Bondar OY, Drozdova VD. 2002. Radiation-induced leukemia risk among those aged 0-20 at the time of the Chernobyl accident: a case-control study in the Ukraine. Int J Cancer 99(4):609–618.
Stevens W, Thomas DC, Lyon JL, Till JE, Kerber RA, Simon SL, et al. 1990. Leukemia in Utah and radioactive fallout from the Nevada test site. A case-control study. JAMA 264(5):585–591.
Wakeford R, Little MP. 2002. Childhood cancer after low-level intrauterine exposure to radiation. J Radiol Prot 22(3A):A123–A127.
Wakeford R, Little MP. 2003. Risk coefficients for childhood cancer after intrauterine irradiation: a review. Int J Radiat Biol 79(5):293–309.
Yoshimoto Y, Neel JV, Schull WJ, Kato H, Soda M, Eto R, et al. 1990. Malignant tumors during the first 2 decades of life in the offspring of atomic bomb survivors. Am J Hum Genet 46(6):1041–1052.
Editor's note: In accordance with journal policy, Belson et al. were asked whether they wanted to respond to this letter, but they chose not to do so.
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Monday, August 27, 2007

About the Strong Paternal Age Effect in Creating Spontaneous Mutations, Excess Coffee Drinking etc. also mutates sperm

It is unbelievable that Jonathan Sebat does not know that spontaneous mutations are known to increase with increasing paternal age past the age of 30. They are not mysterious, paternal age effect is well known.

"So far, says researcher Dr. J. Sebat, there is no indication of why these mutations occur - or whether they are on the rise." This statement is blatantly misleading.

Proc. Natl. Acad. Sci. USAVol. 94, pp. 8380-8386, August 1997
ReviewThe high spontaneous mutation rate: Is it a health risk?*
James F. Crow
Genetics Laboratory, University of Wisconsin, Madison, WI 53706

The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age. This effect is mainly, if not entirely, due to the large number of cell divisions in the male germ line. The mutation-rate increase is considerably greater than expected if the mutation rate were simply proportional to the number of cell divisions. In contrast, those mutations that are small deletions or rearrangements do not show the paternal age effect. The observed increase with the age of the father in the incidence of children with different dominant mutations is variable, presumably the result of different mixtures of base substitutions and deletions. In Drosophila, the rate of mutations causing minor deleterious effects is estimated to be about one new mutation per zygote. Because of a larger number of genes and a much larger amount of DNA, the human rate is presumably higher. Recently, the Drosophila data have been reanalyzed and the mutation-rate estimate questioned, but I believe that the totality of evidence supports the original conclusion. The most reasonable way in which a species can cope with a high mutation rate is by quasi-truncation selection, whereby a number of mutant genes are eliminated by one "genetic death."
My topic is mutation. Mutation is the ultimate source of variability on which natural selection acts; for neutral changes it is the driving force. Without mutation, evolution would be impossible. My concern, however, is not with mutation as a cause of evolution, but rather as a factor in current and future human welfare. Since most mutations, if they have any effect at all, are harmful, the overall impact of the mutation process must be deleterious. And it is this deleterious effect that I want to discuss.
The ideas that I am presenting are not new. Some go back to early in the century, but the evidence has been strengthened in recent times. In this review, I shall draw on the work of many who have contributed to this history.
This lecture is dedicated to three heroes. The first is Wilhelm Weinberg, a busy German physician and obstetrician42 years of practice and more than 3,500 birthswho somehow found time to invent all manner of clever tricks for studying heredity in that recalcitrant species, Homo sapiens. He was the first to suggest that the mutation rate might be a function of paternal age (1). The second hero is J. B. S. Haldane, an eccentric polymath with an enormous number and an incredible diversity of accomplishments. He was one of the first to measure a human mutation rate and was the first to notice a sex difference in the rate (2). The third is H. J. Muller, who made mutation an experimental subject by devising an objective way of measuring it and showing that ionizing radiation is mutagenic. In the later years of his life, Muller spent much of his energy, physical and emotional, in a crusade against unnecessary human exposure to radiation. Interestingly, he gave little attention to what is surely much more important, chemical mutagens. The main reason is that when he was still active there were no known mutagens that were not highly toxic; mustard gas is an example. Had he known of relatively harmless compounds that are highly mutagenic, he would surely have extended his crusade to environmental chemicals. Curiously, although Muller emphasized the high rate of spontaneous mutation, he did not include it in his crusade, mainly, I think, because he saw no feasible way to reduce it (3).
The Nature of Mutations
It is convenient to divide mutations into three main groups: (i) gain or loss of one or more chromosomes; (ii) rearrangement, gain, or loss of parts of chromosomes as a result of chromosome breakage; (iii) changes in individual genes or small regions of DNA. The first two are customarily called chromosome mutations, the third, gene mutations. Of course the categories overlap, and there are other kinds of changes that I have omitted. My concern today is with the third group, gene mutation. The mutational change can be, and often is, an individual nucleotide substitution. It may also be the gain, loss, or rearrangement of a group of nucleotides within or close to a gene. Classical genetics could not distinguish among these, but molecular techniques can, and, as I shall show later, the distinction is important.
The most important properties of gene mutations, for the purposes of this talk, are: First, to repeat, if they have an observable effect they are almost always harmful. Second, most of the changes are not in the genes, but in the great bulk of so-called "junk" DNA, most of which has no known function. Many of these changes are effectively neutral. Third, most mutations have very minor effects, if any. We usually think of a mutation as an eye color change, a conspicuous disease, or some other phenotypic change that is sharp and striking, and indeed these are the kinds of mutations that have been most useful for classical genetic analysis. But diverse experiments in various species, especially Drosophila, show that the typical mutation is very mild. It usually has no overt effect, but shows up as a small decrease in viability or fertility, usually detected only statistically. Fourth, that the effect may be minor does not mean that it is unimportant. A dominant mutation producing a very large effect, perhaps lethal, affects only a small number of individuals before it is eliminated from the population by death or failure to reproduce. If it has a mild effect, it persists longer and affects a correspondingly greater number. So, because they are more numerous, mild mutations in the long run can have as great an effect on fitness as drastic ones.
Mutation Rates in Males and Females
The first evidence for a sex difference in mutation rates came from Haldane, who studied the severe X-linked bleeding disease, hemophilia (2). A male with the disease gets the mutant gene from his mother. This can happen in two ways: (i) the mother carries the mutant gene on one of her X chromosomes, but because the gene is recessive she is normal, or (ii) the mutation occurs in a germ cell of the mother. Haldane showed that if the mutation rate is the same in both sexes, two-thirds of affected sons come from heterozygous (carrier) mothers. He discovered that almost all of the affected sons had carrier mothers, so the mutation must have occurred in an earlier generation. Thus, most mutations must occur in males, such as the maternal grandfather. Haldane's analysis was very clever, but not fully convincing, partly because of the elaborate calculations required and partly because identification of carrier women through an increased clotting time was sometimes ambiguous (4). Nevertheless, his conclusion was correct and subsequent work has supported it (5).
Another severe X-chromosomal disease, Lesch-Nyhan syndrome, is a severe defect in purine metabolism. It, like hemophilia, has a much higher male than female mutation rate (6). In contrast, another tragic X-linked disease, Duchenne-type muscular dystrophy, does not have a striking sex difference in mutation rate (5). I shall return to a discussion of why this gene should differ from the other two.
In classical genetics, there was no way to determine whether a mutation occurred in the mother or the father, except for X-linked genes. Molecular biology has changed this, and the results are dramatic. In a study of multiple endocrine neoplasia Type B (MEN2B), the investigators were able to determine the parent of origin in 25 de novo cases (7). All 25 of the mutations occurred in the father. A study of multiple endocrine neoplasia Type A (MEN2A) revealed 10 new cases, again all of paternal origin (8). A still more extreme example is Apert syndrome (achrocephalosyndactyly). Fifty-seven new mutations were identified, and again all were paternal (9). This is a total of 92 new mutations, all paternal. So it looks as if, for some classes of mutations, almost all occur in the male.
A much higher male than female mutation rate offers a ready explanation for the near-absence of affected males for severe (lethal or sterilizing) dominant X-linked disorders. This is precisely what is expected with a high male mutation rate (10). Since affected males would come almost entirely from heterozygous mothers, and such females do not reproduce, none or very few affected sons are expected. This seems a more attractive hypothesis than the ad hoc explanation usually invoked, prenatal lethality of all affected males, which seems unlikely for all 13 such diseases.
Classical hemophilia provides another example, but with a different mechanism (11). Almost one-half of the cases are caused by an X chromosome inversion. For some reason, the inversions happen entirely in males, or almost so. It is possible that, in the absence of a pairing partner in male meiosis, the X chromosome loops on itself to produce an inversion. Whether this is an isolated instance or an example of a more general mechanism remains to be seen.
There is additional evidence from a surprising source, molecular evolution. We know that the rate of evolution of a neutral allele is simply its mutation rate (12). The Y chromosome is found exclusively in males, whereas the autosomes occur equally in both sexes. Therefore, if almost all mutations occur in males the rate of evolution of a neutral locus on the Y chromosome should be about twice as high as that of an autosomal locus. A comparison in human ancestry of a pseudogene (argininosuccinate synthetase), with one copy on the Y chromosome and another on chromosome 7, showed that evolution in the Y chromosome was 2.2 times as fast (13). There are numerous uncertainties in such a study, but it adds support to the high male mutation rate hypothesis. A more extensive study of evolution in introns showed that in the higher primates, including humans, the estimated male/female ratio is 5.06, with 95% confidence limits 3.24 and 8.79 (14).
Paternal Age Effect
How can we account for a higher mutation rate in males than in females? The most obvious explanation lies in the much greater number of cell divisions in the male germ line than in the female germ line. In the female the germ cell divisions stop by the time of birth and meiosis is completed only when an egg matures. In the male, cell divisions are continuous and many divisions have occurred before a sperm is produced. If mutation is associated with cell division, as if mutations were replication errors, we should expect a much higher mutation rate in males than in females.
This makes the strong prediction that the mutation rate should increase with the age of the father, since the older the man, the more cell divisions have occurred. On the other hand, there should be no age effect in females.
Let me interject at this point that there is a well-known maternal age effect for traits that are caused by errors in chromosome transmission. The kind of accident that leads to a child with an extra chromosome is strongly associated with the mother's age (15). There may be a slight paternal age effect, but the far more striking effect is maternal. My concern, however, is with gene mutations which, when those with small effects are considered, are much more frequent.
I mentioned earlier Weinberg's suggestion that mutations should be associated with paternal age (1). He was unable to test the idea, and it lay dormant for many years. It is now, however, well established that a number of human inherited traits are associated with the father's age at the time of birth (or conception) of the affected child.
The procedure consisted of identifying children with dominantly inherited diseases whose parents were normal. Then, having ascertained such trios, the age of the parents was determined. In the classical literature (4), four conditions showed such an effect: achondroplasia, Apert syndrome, myositis ossificans, and Marfan syndrome. The average age of fathers at the time of birth of an affected child was 6.1 years greater than that of fathers of normal children in the same population. There was also a smaller maternal age increase, 3.8 years, mainly, if not entirely, because of the correlation of ages of husbands and wives. Maternal age and birth order showed no significant effect independent of paternal age (16).
Another test of the hypothesis is to examine the age of maternal grandfathers of males with severe X-chromosomal diseases. The fathers of five daughters heterozygous for Lesch-Nyhan disease, whose mothers were normal homozygotes, were about 7 years older than the population average; the standard error is of course very large (6).
Recently, a paternal age effect for heart defects has been reported (17). Pooling ventricular and atrial septal defects with patent ductus, the investigators found a small but significant increase in the fathers' ages. This was a case-controlled study, with smoking controlled and maternal age regressed out. About 5% of the incidence over age 35 is attributable to father's age. This suggests that a small fraction of these congenital defects is due to dominant mutations. It also suggests a strategy: examine families in which the fathers of affected children are unusually old. A linkage and molecular analysis might lead to the discovery of a gene predisposing to heart defects.
A study of birth and death records of European royal families suggests that daughters of old fathers have a slightly shortened life span (18). This is consistent with mutations on the X chromosome playing a small, but significant role in longevity. If confirmed, this will add to the evidence that mutation is one factor in aging.
Huntington disease is caused by an excess number of CAG repeats. The larger the number of repeats, the earlier the onset. Paternally derived cases have a larger increase over the parent value than maternally derived cases (19). The discrepancy may be the consequence of the greater number of cell divisions in the male germ line. Demonstrating a paternal age effect is complicated by the limitation of reproduction at older ages because of the severity of the disease.
Nonlinearity of the Paternal Age Effect
Let us now examine the number of cell divisions ancestral to a sperm produced by a father of a specified age. The necessary data are summarized by Vogel and Rathenberg (4). In the female, the number of divisions from zygote to egg is estimated to be 24. The male is more complicated. Until the age of puberty, Xp, taken to be 13 years (Xp = 13), there are 36 divisions (Np = 36). Afterward, there are 23 divisions per year (N = 23). Thus, the number of cell divisions prior to sperm production in a man of age X is
x=Np + &Dgr;N(X − Xp)=36 + 23(X − 13)." src="">
At age 20 the number of cell divisions is about 200, at age 30 it is 430, and at age 45, 770.
We can use these numbers to estimate the average increase in paternal age associated with an affected child, assuming that the number of mutations is proportional to the number of cell divisions. The calculations depend on the variance of fathers' ages, which is about 50, and lead to an expected increase of 2.7 years (20, 21). Although there are uncertainties, they are not sufficient to account for the great discrepancy between the expected paternal age increase, 2.7 years, and that observed, about 6 years. Clearly, the hypothesis that the number of mutations is proportional to the number of cell divisions is out.
The data are consistent with a power function of age; the best fit involves a cubic term. A somewhat different and more sophisticated analysis by Risch et al. (22) leads to a similar conclusion. The nonlinear effect is apparent for Apert syndrome and achondroplasia in Fig. 1.
Fig. 1. Relative frequency of affected children of normal parents (ordinate) as a function of paternal age (abscissa). (Left) Apert syndrome, n = 111. (Center) Achondroplasia, n = 152. (Right) Neurofibromatosis, n = 243. From ref. 22. [View Larger Version of this Image (9K GIF file)]
I don't find this nonlinear effect at all surprising. Everything gets worse with age, so I fully expect fidelity of replication, efficiency of editing, and error correction to deteriorate with age. For a man of age 20, the male mutation rate is about 8 times the female rate. With a linear increase, in a man at age 30, the ratio is 430/24 = 18, at age 45 it is 770/24 = 32. With nonlinearity, these ratios are much larger, some 30-fold at age 30 and as much as two orders of magnitude at age 40. Examples such as MEN2A, MEN2B, and Apert syndrome, in which a total of 92 new mutations were all paternal, are therefore not so surprising. Whatever selective forces reduced the mutation rate in our distant past, at a time when most reproduction must have been very early, were not effective for older males.
I conclude that for a number of diseases the mutation rate increases with age and at a rate much faster than linear. This suggests that the greatest mutational health hazard in the human population at present is fertile old males. If males reproduced shortly after puberty (or the equivalent result were attained by early collection of sperm and cold storage for later use) the mutation rate could be greatly reduced. (I am not advocating this. For one thing, until many more diseases are studied, the generality of the conclusion is not established. Furthermore, one does not lightly suggest such socially disruptive procedures, even if there were a well-established health benefit.)
Why Do Some Mutations Not Show a Paternal Age Effect?
Fig. 1 shows a much reduced paternal age effect for neurofibromatosis. Similarly, X-linked Duchenne muscular dystrophy shows no significant sex difference or grandparental age effect (5). Why should these two diseases be different?
Achondroplasia, which shows a striking paternal age effect (Fig. 1), is mainly, if not entirely, due to a base substitution. In 16 cases examined (23), all of the mutations were changes from glycine to arginine at a specific site; 15 were GGG AGG transitions, the other was GGG CGG. These all involve a CpG dinucleotide. Presumably, mutations occur elsewhere in the gene but do not produce the phenotype. Similarly, the 57 paternal mutations in Apert syndrome all involved C G transversions at two adjacent sites (9).
The genes for Duchenne muscular dystrophy and neurofibromatosis are both enormous, with many introns. One muscular dystrophy study reported that of 198 mutations, 62% were deletions or duplications (24). The 38% point mutations were almost entirely from sperm, whereas the deletions came from both parents; in fact, the data suggest a higher female rate, but the confidence limits are large. The data for neurofibromatosis are similar (25). About two-thirds are deletions and one-third are base substitutions. Again, base substitutions are largely paternal, whereas deletions are more often maternal.
The slight paternal age effect for neurofibromatosis (Fig. 1) is presumably due to a mixture of a minority of base substitutions with a strong paternal age effect and a majority of chromosome mishaps with no such effect.
This immediately suggests a hypothesis: point mutations are somehow associated with the replication process; they show a much higher mutation rate in males and a large increase with paternal age. Mutations due to small chromosomal changes are not specifically associated with replication, at least not correlated to the number of replications. Perhaps they happen at a particular time, such as meiosis; in any case, they do not seem to happen repeatedly during germ cell proliferation.
Of course, there are exceptions. S. S. Sommer (personal communication) has studied extensively the X-linked, hemophilia-like trait, factor IX. Transitions show the expected excess of paternal mutations, whereas deletions show a female excess. Curiously, GC AT transitions are more frequent in females and are usually associated with somatic mosaicism. The data suggest an increased maternal age for transversions. The numbers are small, and it will be interesting to see if the finding is confirmed. If so, are there other loci with similar effects or is this an isolated example?
In their extensive and detailed study, Risch et al. (22) classified the syndromes into two groups. The first, with a large paternal age effect, includes acrodysostosis, achondroplasia, Apert syndrome, basal cell nevus, cleidocranial dysostosis, Crouzon syndrome, fibrodysplasia ossificans progressiva, Marfan syndrome, oculodentodigital syndrome, Pfeiffer syndrome, Progeria, and Waardenburg syndrome. The second group, with little age effect, includes multiple exostoses, neurofibromatosis, retinoblastoma, Sotos syndrome, and Treacher-Collins syndrome. Thus, roughly two-thirds of these conditions appear to be strongly cell division dependent and the rest only slightly so. Presumably, these differences reflect different proportions of base substitutions and deletions.
Imprinting and Other Possibilities
Some workers (26, 27) have invoked imprinting to explain the higher male mutation rate. Imprinting is known to be sex dependent, so they suggest that faulty imprinting may be responsible for the high male mutation rate. Imprinting or methylation may "mark" the chromosome in some way, making it more mutable. The detailed mechanism is not clear.
This is a possible hypothesis, but I think there are strong arguments against it as the major explanation of the sex and paternal age effect. One is that the imprinting hypothesis, although it is consistent with a sex effect, does not predict an age effect, whereas the cell division hypothesis does. Furthermore, somatic mutations where imprinting is not involved show a mutation accumulation with age, and therefore with number of cell divisions. Somatic mutations of glycophorin A (the MN blood group locus) increase at a rate of about 3% per year (28). Finally, the imprinting hypothesis would predict a striking sex difference in the mouse, which has imprinting, but does not have the large number of cell divisions characteristic of the human male. Russell and Russell (29) give 7.7 × 106 and 3.2 × 106 for the spontaneous mutation rate per locus in males and females, respectively. These rates are uncertain, particularly the female rate, but it is clear that there is no such large sex difference as is found for most human genes.
For these reasons, I prefer the cell division hypothesis as the major explanation of a high ratio of male-to-female mutation rates and the paternal age effect. Yet this may not be the whole story. There are some unexplained minor discrepancies in the sex ratio, possible irregularities in X inactivation, and perhaps distortion of segregation ratios (26, 27). So we can't rule out at least some minor effects from causes other than the number of cell divisions.
There is much to be done. One job is to confirm or reject the hypothesis that base substitutions are cell division dependent, whereas small cytogenetic changes are not. Many more diseases should be studied to test the generalizations that I have made from a rather small number. Much of what I have discussed has depended on classical methods, but molecular studies of parent of origin and, presumably soon, direct analyses of spermatozoa should be very revealing. Also, are paternal inversions, such as are reported for some cases of hemophilia, and paternal expansion of repeated elements, as in Huntington disease, major causative factors or only minor players in the larger drama? Finally, what fraction of base substitutions occur at hot spots? Are these more or less related to paternal age than other mutations?
The Total Mutation Rate
The analysis so far has demonstrated the relative importance of sex and paternal age differences in mutation rates, but it says nothing about the absolute values. There is very little information about the human genomic mutation rate. Rates for some genes have been measured, but one cannot be sure as to how representative these are and uncertainty about the number of genes and the importance of extragenic mutations discourages simply multiplying the average rate by the gene number. Furthermore, the mutations of greatest frequency are those with very minor effects, which are difficult to study by any existing methods. So I shall turn to Drosophila for information about the genomic rate.
The Genomic Mutation Rate in Drosophila ...........................................

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Sunday, August 26, 2007

Laws of Biology Find the Sperm Mutate Far More Than Eggs

Roni Rabin New York Times February 15, 2007
"Even grandchildren may be at greater risk for some conditions that are not expressed in the daughter of an older father, according to the American College of Medical Genetics. These include Duchenne muscular dystrophy, some types of hemophilia and fragile-X syndrome.

A recent study on autism attracted attention because of its striking findings about a perplexing disorder. Researchers analyzed a large Israeli military database to determine whether there was a correlation between paternal age and the incidence of autism and related disorders. It found that children of men who became a father at 40 or older were 5.75 times as likely to have an autism disorder as those whose fathers were younger than 30.
''Until now, the dominant view has been, 'Blame it on the mother,' '' said Dr. Avi Reichenberg, the lead author of the study, published in September in The Archives of General Psychiatry. ''But we found a dose-response relationship: the older the father, the higher the risk. We think there is a biological mechanism that is linked to aging fathers.''
The study controlled for the age of the mother, the child's year of birth and socioeconomic factors, but researchers did not have information about autistic traits in the parents.
A study on schizophrenia found that the risk of illness was doubled among children of fathers in their late 40s when compared with children of fathers under 25, and increased almost threefold in children born to fathers 50 and older. This study was also carried out in Israel, which maintains the kind of large centralized health databases required for such research. In this case, the researchers used a registry of 87,907 births in Jerusalem between 1964 and 1976, and linked the records with an Israeli psychiatric registry.
Researchers controlled for the age of the mother but did not have information on family psychiatric history."

This statement of Michael Wigler's is not true! Either he hasn't studied this subject or he is misleading the newsires. The opposite is true.

"Almost all cases [of spontaneous mutations] happen in the mother and are transmitted by the mother," he said, adding that the trait for Down is transmitted at the moment of conception. The trait is not hereditary in the same sense a "disease gene" is transmitted from one generation to the next. "


Saturday, August 25, 2007

Male Biological Clock Is Very Real

Tuesday, 15 October, 2002, 07:44 GMT 08:44 UK
Male biological clock is ticking

Sperm cells accumulate damage over time
The chances of a man having children dip past his 35th birthday, researchers have found.
The researchers, from the University of Washington in Seattle, found that damage to the genetic material containing sperm cells increases with age.
We found there is a significant change by the age of 35
Dr Narendra SinghUnlike most other cells in the body, sperm cells are unable to repair this damage.
In addition, the researchers found that as a man gets older he loses his natural ability to weed out unhealthy sperm cells through a process known as apoptosis.
This means that there is a greater chance that a damaged sperm cell will successfully fertilise the female egg.
This could mean that the risk of miscarriage is increased or, at the other end of the scale, that children have a greater chance of developing mild abnormalities such as uneven teeth, or asymmetrical limbs.
Lead researcher Dr Narendra Singh told the BBC: "We found there is a significant change by the age of 35."
Sperm quality
Dr Singh's team examined sperm quality in 60 men aged between 22 and 60. All had healthy sperm counts.
The researchers found that men aged 35 and older had higher concentrations of sperm with broken strands of DNA, and that the damage was greater.


Genetic Disorders Associated with Advanced Paternal Age - Tuberous Sclerosis One of Them

It is not parental germ line mutations it is paternal germ line mutations that cause autism. The mother's fathers age or the fathers age.

SYNDROMES WITH REPRODUCTIVE DYSFUNCTIONPaul J. Turek M.D.Associate Professor, Departments of Urology, Obstetrics, Gynecologyand Reproductive Sciences, University of California San FranciscoTable 1. Selected Genetic Disorders Associated with Advanced Paternal AgeAchondroplasias AniridiaApert syndrome Bilateral RetinoblastomaCrouzon syndrome Fibrodysplaisa OssificansHemophilia A Lesch Nyhan syndromeMarfan syndrome NeurofibromatosisOculodentodigital syndrome Polycystic kidney diseasePolyposis coli ProgeriaTreacher-Collins syndrome Tuberous sclerosisWardenburg syndromeFormal risk estimates for the contribution that advanced paternal age makes to autosomaldominant mutations have been calculated. Friedman estimated that in men <29>45 (22). The risk for a father over 40 years old tohave a child with an autosomal dominant mutation equals the risk of Down syndrome for a childwhose mother is 35-40 years old. These risk estimates were corroborated in a study by Lian et alin which all kinds of birth defects (anatomic and genetic) were assessed against paternal ageusing data over 12 years from Atlanta (23). They found no increase in chromosomal disorderswith advanced paternal age, but estimated that fathers over the age of 40 years had a 20% greaterincidence of having a baby born with a serious birth defect. More recently, an indictingrelationship between advanced paternal age and offspring with schizophrenia has becomeapparent (24).


Friday, August 24, 2007

Type 1 diabetes risk rises with the age of the father and mother and yet there is no warning for the public

Type 1 diabetes risk rises with the age of the father and mother and yet there is no warning for the public To investigate perinatal risk factors for childhood Type 1 diabetes in a UK population cohort. METHODS: Perinatal data have been routinely recorded in Northern Ireland for all births in the period 1971-86 (n = 447 663). Diabetes status at the age of 15 years was ascertained in this cohort by identifying 991 children from 1079 registered with Type 1 diabetes diagnosed from 1971 to 2001 and date of birth in the period 1971-86. RESULTS: Increased Type 1 diabetes risk was associated with higher maternal age, paternal age, birth weight and birth weight for gestational and lower gestational age. After adjustment for maternal age, the association between Type 1 diabetes and paternal age remained significant [relative risk (RR) = 1.52 (1.10, 2.09) comparing father's age 35 years or more to less than 25 years] but not vice versa [RR = 1.11 (0.80, 1.54) comparing mother's age 35 years or more to less than 25 years]. Increased birth order was associated with a significant decrease in the risk of Type 1 diabetes [adjusted RR = 0.75 (0.62, 0.90) comparing birth order three or more with firstborn], but this only became apparent when adjustment was made for maternal age. Furthermore this association with birth order was significant only for diabetes diagnosed under the age of 5 years. CONCLUSIONS: Our analysis demonstrates, for the first time in a UK regional cohort setting, that maternal age and paternal age at delivery, birth order, birth weight and gestational age are significantly associated with Type 1 diabetes risk.PMID: 15660739 [PubMed - indexed for MEDLINE]

1: Eur J Pediatr. 1999 May;158(5):362-6. LinksRisk factors for type I diabetes mellitus in children in Austria.Rami B, Schneider U, Imhof A, Waldhör T, Schober E.University Children's Hospital Vienna, Austria.The aim of this study was to investigate environmental risk factors in the development of type 1 diabetes mellitus in a population-based case-control study. Parents of all patients with manifestation of type 1 diabetes between 1989 and 1994 in Vienna were asked to complete a questionnaire (n = 114). Control children (n = 495), matched for age and sex, were randomly recruited from all schools in Vienna. Fathers of diabetic children were significantly older at the time their children were born than fathers of control children (P = 0.015). Children with diabetes were more likely to be second- or third-born children (P<0.05) p =" 0.007)." p =" 0.038)." color="#cc0000">In our study, the development of type 1 diabetes mellitus was associated with higher paternal age and neonatal jaundice. No correlation could be found with dietary intake of cow's milk products in early infancy, vaccination and other environmental factors. Labels:
posted by concerned heart @ 8:32 AM 1 Comments

At 4:41 AM , Anonymous said...
The corporate filter at this point in time mandates that news sources only report what best serves conservative agendas (the "liberal media" accusation is no match for this filter). You'd think that this study would be important to republican propaganda, as reducing the financial tolls on society would be a big plus. The problem with that assumption is that the conservative agenda is inextricably laced with a patriarchally constructed value system. Guess which of the following studies were splashed across the news:1. Children in daycare do poorly later in life compared to children with stay-at-home moms.vs.2. Outcomes for children more positive as father's time spent at home increases.One was hyped and the other not even reported by mainstream news outlets. Why do you think that is?The problem with studies about advanced paternal age is that it knocks men off their self-made pedestal of privilege in regard to mate choice and the myths they propagate about biology being conflated with women necessarily lacking certain political/economic/personal rights and privileges. The power automatically afforded to men in virtually every sphere--personal, economic, political, social--doubles under a patriarchal system. Of course they don't want to give that up! Advanced paternal age studies have been around since the 1800s--long before maternal risk of Down Syndrome after age 35 was established, I'm sure. The problem with the paternal age information is that it empowers women in a way that is notsogewd for most men already in the throes of adulthood. And that's not just because many will lose value in the mate market, but mainly because it disrupts their entire artificially fabricated world view that supports their privilege in every other facet of life.-K.A.


Mother's Age Not Responsible for the Increase in Autism, No Matter What Dr. Wigler Says to the Press

By paternal age 35 there is a statistically significant greater risk of all genetic disease in offspring. Even after paternal age age 33 all kinds of problems show up including the ageing disease progeria.

Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.
[My paper] M Wohl , P Gorwood
BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win((R))) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.

RESULTS: There was a significant monotonic association between advancing paternal age and risk of ASD. Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46; P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on maternal age. CONCLUSIONS: Advanced paternal age was associated with increased risk of ASD. Possible biological mechanisms include de novo mutations associated with advancing age or alterations in genetic imprinting.
PMID: 16953005 [PubMed - indexed for MEDLINE]

The average paternal age in the Western Countries is increasing, and the public health implications of this trend have not been widely anticipated or debated.

Accumultion of chromosomal abberrations and mutations of genes during the maturation of sperm/ male germ cells are associated with conditions such as birth defects, cancers, schizophrenia, autoimmune disorders, autism, Alzheimer's. Breast, prostate, nervous system cancers all increase with rising paternal age as does MS, and type 1 diabetes.

There is a growing literature on the effects for offspring of advancing Paternal Age.

"New point mutations in humans are introduced through the male line," says Dolores Malaspina, MD, professor of clinical psychiatry at Columbia University and the New York State Psychiatric Institute. Furthermore, she adds, the number of mutations in sperm increases as men age. "This has been known since the 50s," said Malaspina. "What is intriguing is why society chooses to ignore this."

"it is well established that paternal age is the major source of de novo mutations in the human population" Dolores Malaspina

Somehow Dr. Wigler comes up with this statement which is not true at all. It is not true that almost all cases of (spontaneous mutations) happen in the mother and are tra.nsmitted by the mother. This is blatantly not true and quite bizarre.

Dr. Wigler's statement.

"Almost all cases [of spontaneous mutations] happen in the mother and are transmitted by the mother," he said, adding that the trait for Down is transmitted at the moment of conception. The trait is not hereditary in the same sense a "disease gene" is transmitted from one generation to the next.
As people age, their genes increasingly acquire mutations that are not fixed through DNA repair mechanisms. That's why a spontaneous strike can lead to Down syndrome. And that is also why autism can similarly occur through CNVs, Dr. Wigler said.
"The older the mother, the more likely she has acquired spontaneous mutations" in her chromosomes, and will transmit them at conception, Dr. Wigler said. Less frequently, but just as likely, Dr. Wigler said, fathers can transmit autism traits as well"

The science however says that mutations in the male germ line are vastly predominant in causing problems for offspring. Even Down syndrome has been found to be 50% caused by the age of the father. In schizophrenia which is related closely to autism because childhood schizophrenia is now called autism. There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study.


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.
PMID: 17712030 [PubMed - as supplied by publisher]

Study: Autism linked to genetic mutations, mother's age
Scientists say variants in DNA are key, call for federal research

Would Dr. Malaspina think that Dr. Wigler has a valid basis for this statement? Would she, as a pre-eminent researcher find the comparison between Down syndrome which is only 50% based on the age of the mother and autism misleading?

"Almost all cases [of spontaneous mutations] happen in the mother and are transmitted by the mother," he said, adding that the trait for Down is transmitted at the moment of conception. The trait is not hereditary in the same sense a "disease gene" is transmitted from one generation to the next.

"As people age, their genes increasingly acquire mutations that are not fixed through DNA repair mechanisms. That's why a spontaneous strike can lead to Down syndrome. And that is also why autism can similarly occur through CNVs, Dr. Wigler said.
"The older the mother, the more likely she has acquired spontaneous mutations" in her chromosomes, and will transmit them at conception, Dr. Wigler said. Less frequently, but just as likely, Dr. Wigler said, fathers can transmit autism traits as well."

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Risk of Having A Baby With A Major Handicap 11% After Assisted Reproduction Compared to 5% after Natural Conception

European Journal Pediatr... 2003 162-64 Springer-Verlag 2002

In Sweden a study of 5680 infants born to mother between 1982 and 1995 after IVF compared to 11360 controls. "All data considered, it appears that the risk of having a baby with a major handicap is about 11% (9% morphological, 2% neurological) after assisted reproduction, compared to 5% (4% morphological, 1% neurological) after natural conception.

This study is only about handicaps seen at or near birth and not about IVF and autism etc.

1. Stromberg B, Dahlquist G, Ericson A, et al (2002) Neurological sequlae in children born after in-vitro fertilisation a population based study, Lancet 359: 461-465

2. Hansen M, Kurinczuk JJ, Bower C, Webb S (2002) The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization, New Eng J Med 346: 725-730.

3. Schieve LA, Meikle SF, Ferre C, et al (2002) Low and very low birth weight in infants conceived with use of assisted reproductive technology. New England J Med 246: 731-737


The results show that more deleterious induced mutations are transmitted to the progeny by a sperm than by an egg.

Plants, animals, people all have more sperm induced mutations! There certainly is a good time for conceiving babies for both men and women for different reasons for the health and well-being of the offspring.

It is misleading to be told by a nameless prominent scientist that autism is more frequently caused by mutations from an older egg than an older sperm. All the prior science points to sperm as the much more likely causes of CNVs or de novo autism in general. Until CNVs in eggs and testis are fully and fairly studied it would be prudent to look to the epidemiological research which points to the father's age over 32 or so and dangers of spontaneous mutation generated genetic illness in the offspring. The science on sperm mutations, the epidemiology, all point to sperm and not eggs. Whatever, the male biological clock is an area of concern for potential parents and there has been years of suppression of information the general public on this subject.

EvolutionMale-biased transmission of deleterious mutations to the progeny in Arabidopsis thaliana Carrie-Ann Whittle* and Mark O. Johnston
Department of Biology, Dalhousie University, 1355 Oxford Street, Halifax, NS, Canada B3H 4J1
Edited by Ronald R. Sederoff, North Carolina State University, Raleigh, NC, and approved February 3, 2003 (received for review January 29, 2003

The extent and cause of male-biased mutation rates, the higher number of mutations in sperm than in eggs, is currently an active and controversial subject. Recent evidence indicates that this male (sperm) bias not only occurs in animals but also in plants. The higher mutation rate in plant sperm was inferred from rates of evolution of neutral DNA regions, and the results were confined to the mitochondria and chloroplasts of gymnosperms. However, the relative transmission rates of deleterious mutations, which have substantial evolutionary consequences, have rarely been studied. Here, an investigation is described by using the hermaphroditic self-compatible flowering plant Arabidopsis thaliana, in which we artificially increased the rate of mutation in pollen (i.e., sperm donor) and maternal (i.e., egg donor) parents, by using two kinds of UV irradiation in parallel and separate experiments, and assessed the deleterious effects on fitness of the F2 generation. The results show that more deleterious induced mutations are transmitted to the progeny by a sperm than by an egg. These findings provide the first experimental evidence that more deleterious mutations are inherited from sperm than from an egg in any organism. Possible causes underlying this male bias are discussed.

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Wednesday, August 22, 2007

Give (or have your vet give) your stallion only one or two injections per day; wait at least a week before giving any more.

....10. You shouldn't vaccinate your stallion during breeding season--the vaccine may adversely affect sperm. Busted! Although old-time vaccines used to make a horse sick and feverish for a day or 2 (which we already know can adversely affect sperm), equine vaccines available today generally don't cause these problems.
However, stress definitely has a negative effect on all bodily functions, including reproductive processes-and giving your stallion multiple vaccines on the same day could be stressful for him. And, even when the injection is given properly, once in a while the injection site will get swollen, hot, sore, and stiff for a day or 2 afterward. The resultant discomfort can interfere with your stallion's libido, as well as his ability to tease, mount, and ejaculate.
To reduce the risk of vaccination-related stress, follow these tips:
Choose your stallion's vaccines wisely, in conjunction with your vet's advice. That is, don't just vaccinate your stallion willy-nilly for every disease ever discovered.
Acquire vaccines from a reputable source, so you know they've been properly stored. If stored improperly, they can become spoiled or contaminated, or otherwise rendered ineffective.
If possible, have your vet give all injections to ensure they're done properly and given in the right location.
Use (or have your vet use) only preloaded, single-dose syringes, rather than vaccine drawn from a multiple-dose vial, as they're less likely to be contaminated.

Give (or have your vet give) your stallion only one or two injections per day; wait at least a week before giving any more.


Tuesday, August 21, 2007

Testis Biopsies Would Probably Yield Mutations For Autism

Someone could do testis biopsies and look for CNVs with the Affymetrix array technology in fathers with children who have autism and copy number variations that the parents somatic cells do not have. By the age of 34 men have accumulated germ line mutations that cause all kinds of genetic disorders. To add the assault of a barrage of innoculations to any inborn genetic variation that comes with increasing paternal age is key to increased non-familial autism, diabetes, schizophrenia, MS, cancers, lupus, obesity, fibromyalgia, Alzheimer's in the offspring of older fathers. If scientists do not want to publicize the paternal age effect in autism, cancers, diabetes, other autoimmune disorders they will not do this research.

1: Fertil Steril. 2007 Aug 11; [Epub ahead of print]
Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies.
Dakouane Giudicelli M, Serazin V, Le Sciellour CR, Albert M, Selva J, Giudicelli Y.
Unité de Pathologie Cellulaire et Génétique, Université Versailles Saint-Quentin, Faculté de Médecine Paris-Ile-de-France-Ouest and Centre Hospitalier de Poissy-Saint Germain, Poissy, France.

1: Hum Genet. 2004 Aug;115(3):200-7. Epub 2004 Jul 7.
Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis.
Rannan-Eliya SV, Taylor IB, De Heer IM, Van Den Ouweland AM, Wall SA, Wilkie AO.
NDCLS, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe, Headington, Oxford, UK.
Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome. To understand the biology of this mutation, we have investigated its parental origin, and the ages of the parents, in 19 families with de novo c.749C>G mutations. All ten informative cases originated from the paternal allele (95% confidence interval 74-100% paternal); the average paternal age at birth overall was 34.7 years. An exclusive paternal origin of mutations, and increased paternal age, were previously described for a different mutation (c.1138G>A) of the FGFR3 gene causing achondroplasia, as well as for mutations of the related FGFR2 gene causing Apert, Crouzon and Pfeiffer syndromes. We conclude that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2. Copyright 2004 Springer-Verlag
PMID: 15241680 [PubMed - indexed for MEDLINE]

From Wikipedia on Achondroplasia
However, in 3 out of 4 cases, people with achondroplasia are born to parents who don't have the condition. This is the result of a new mutation.
New gene mutations are associated with increasing paternal age (over 35 years). Studies have demonstrated that new gene mutations are exclusively inherited from the father and occur during spermatogenesis (as opposed to resulting from a gonadal mosaicism). More than 99% of achondroplasia is caused by two different mutations in the fibroblast growth factor receptor 3 (FGFR3). In about 98% of cases, a G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine substitution (Bellus et al 1995, Shiang et al 1994, Rousseau et al 1996). About 1% of cases are caused by a G to C point mutation at nucleotide 1138.
There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia. Both of these disorders are also caused by a genetic mutation in the FGFR3 gene

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