Much Higher Rate of Spontaneous Mutation in Males , Why?

Maybe Dr. Wigler never read James F. Crow, or Dolores Malaspina, or Maurice Auroux, Isabelle Bray or Leslie B. Raschka, etc. maybe he doesn't know the origin of why mothers carry
the fragile X gene, the hemophilia gene, the Duchennes gene etc.


Examples of X-linked conditions associated with increased maternal grandfather's age include fragile X, hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), Duchenne muscular dystrophy, incontinentia pigmenti, Hunter syndrome, Bruton-type agammaglobulinemia, and retinitis pigmentosa.


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

There is enough research to advise men to complete their child bearing before age 35 to prevent neurocognitive genetic disorders in their offspring and in their grandchildren.


Now, in genetic research, it's known that for human genetic diseases, when a new case presents itself in a family, the mutation almost always arises during spermatogenesis. We have known for almost 100 years that the late born children in a family have more new genetic diseases. In the 1950s, a scientist named Penrose showed that only the age of the father predicts these genetic diseases.


Dr. Malaspina: When Penrose found that paternal age predicted new human genetic diseases, he proposed the Copy Error Theory. He said that each time the spermatozoa are copied there's an opportunity for a new mutation. Sperm cells divide every 16 days after puberty, so the DNA in the sperm of a 20-year-old father has been copied 100 times, but sperm DNA from a 50-year-old father has been copied more than 800 times. By comparison, egg cells from the mother only undergo a few dozen cell divisions all together. It is clear that there are many more opportunities for mutations to occur during spermatogenesis and that these increase with the age of the father. That is why new mutations are introduced in mammals in proportion to paternal age.

: Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4.LinksPaternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.INSERM U675, 16 rue Henri Huchard 75018 Paris, France.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) 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.PMID: 17142012 [PubMed - indexed for MEDLINE]1: Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4.Links

New Key to Autism
September 25, 2006
By Michael Craig Miller, M.D.Harvard Medical School
Convincing Evidence
What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older.
What Is Autism?
Autism is a profoundly disabling disorder that starts in early childhood. The key features are:
Abnormal social development – little or no eye contact, prefers to be alone
Difficulty communicating – impaired language ability, uses gestures or pointing rather than words
Unusual behavior – spins objects, doesn't like being cuddled
Evidence of strong abilities sometimes in non-verbal areas, such as math or music
Older people with autism may have some ability to interact with people, but about two-thirds are mentally retarded and most cannot live on their own
Unfortunately, the incidence of this illness appears to be on the rise. Some experts think autism is diagnosed more often simply because more people are aware of it. But that's probably not the whole explanation.
Genetic factors almost certainly play a big role. So autism researchers are eager to discover anything that might increase a person's genetic vulnerability, such as delaying parenthood until age 40 or beyond.
The risk was smallest for children of fathers younger than 20 and greatest for children of fathers older than 50. A man in his 40s, for example, was almost 6 times as likely to have an autistic child as a man age 20. This relationship held even after researchers adjusted the results for the year of the person's birth, their socioeconomic status, or the mother’s age.
This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.
Convincing Evidence
The Archives study took advantage of the extraordinarily complete health records of over 300,000 Israeli men and women who underwent a complete health assessment when they were 17-year olds — draft age. This gave researchers a good way to determine the incidence of autism in the population. The researchers had access to intellectual, medical and psychiatric evaluations of almost all Israeli boys and three-quarters of girls. (Their identities were kept secret, however.) For most individuals, the father’s age at birth was known.
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.
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What Causes These Genetic Errors?
All children inherit genetic material in equal amounts from both parents. In the case of autism, scientists think that the genetic material in the sperm of these older fathers has somehow become altered in harmful ways. These flaws make the child more vulnerable to developing the disease.
According to one theory, mutations (changes) are more likely to develop as men get older. Germ cells give rise to sperm throughout a man's life. These cells make copies of themselves and after several decades, the germ cells are copies of copies of copies. A second theory suggests that the offending genes passed down by older men are not properly marked or "imprinted." Accurate marking — which establishes whether a gene is from the father or the mother — determines if it will be active or not. If there is an error, the gene may function abnormally.
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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.
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

Paternal Age Effect James F. Crow



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
ABSTRACT
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).
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.