Where do spontaneous mutations come from?

Who is James F. Crow? 1997 The high spontaneous mutation rate: Is it a health risk?
James F. Crow

"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."

"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."


"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?

"The Harmful Mutation May Be Positively Selected Perhaps Because It Confers Some Benefit Within the Cellular Environment of the Testis"

Science 301 (5633): 606-607

Copyright © 2003 by the American Association for the Advancement of Science

DEVELOPMENT:
There's Something Curious About Paternal-Age Effects
James F. Crow
Gene mutation rates are higher in males than in females and increase with paternal age. In his Perspective, Crow explains unexpected results from a study of a congenital disease called Apert's syndrome in which the likelihood of a child developing the disease increases with the age of the father (Goriely et al.). The results of the new work imply that rather than sperm having a higher mutation rate, the harmful mutation may be positively selected perhaps because it confers some benefit within the cellular environment of the testis.

The author is in the Department of Genetics, University of Wisconsin, Madison, WI 53706, USA. E-mail: jfcrow@facstaff.wisc.edu



--------------------------------------------------------------------------------

The editors suggest the following Related Resources on Science sites:
In Science Magazine
REPORTS
Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line
Anne Goriely, Gilean A. T. McVean, Maria Röjmyr, Björn Ingemarsson, and Andrew O. M. Wilkie (1 August 2003)
Science 301 (5633), 643. [DOI: 10.1126/science.1085710]




--------------------------------------------------------------------------------

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Schizophrenia: a common disease caused by multiple rare alleles.
J. M. McClellan, E. Susser, and M.-C. King (2007)
Br. J. Psychiatry 190, 194-199

Fast, Triangular Voltage Clamp for Recording and Kinetic Analysis of an Ion Transporter Expressed in Xenopus Oocytes.
D. Gradmann and C. M. Boyd (2005)
Biophys. J. 89, 734-744

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia.
A. Goriely, G. A. T. McVean, A. M. M. van Pelt, A. W. O'Rourke, S. A. Wall, D. G. de Rooij, and A. O. M. Wilkie (2005)
PNAS 102, 6051-6056

Paternal age and schizophrenia: a population based cohort study.
A. Sipos, F. Rasmussen, G. Harrison, P. Tynelius, G. Lewis, D. A Leon, and D. Gunnell (2004)
BMJ 329, 1070

"New Point Mutations in Humans Are Introduced Through The Male Line" This Has Been Known Since the 1950s", "What is Intriguing is why society chooses

TO IGNORE THIS" said Malaspina.


But now it is becoming increasingly clear that the biological clock ticks
for men as well as women, as researchers turn up evidence that as would-be
fathers get older, they have an increased chance of passing on genetic
defects to their children.

"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."




CULTURAL RESISTANCE
There are many reason why paternal contribution to birth defects has a low
profile. James F. Crow, PhD, emeritus professor of genetics and medical
genetics at the University of Wisconsin in Madison, mentions that most of
these defects occur at low levels, on the order of 1 in tens of thousands.
In contrast, the odds of having a child with Down syndrome are about 1 in
350 when the mother is age 35 years and 1 in 100 at age 40 years. However,
some scientists hint that society may not be ready to hear that older men,
like older women, run the risk of passing on birth defects.

But the risk of having a child who later develops schizophrenia, Malaspina
notes, is about 1 in 110 when the father is age 40-similar to a 40-year-old
woman's risk of having a child with Down syndrome.

Malaspina says she believes her findings met resistance because of a
reluctance by men to accept that fathering children later in life poses
increased health risks to their children.

"Despite the fact that our paper received excellent reviews it was rejected
by two medical journals," she said, noting that the study results now have
been replicated five times with similar results. "And these biases really
hold us back from scientific advances."






from an article by Paul D. Thacker:

Biological Clock Ticks for Men, Too
Genetic Defects Linked to Sperm of Older Fathers
Paul D. Thacker

JAMA. 2004;291:1683-1685.



[mnchp-l] Genetic Defects Linked to Sperm of Older Fathers
McGillivray, Katrina katrina at beststart.org
Wed Apr 14 10:00:40 EDT 2004

Risk of Non-Familial Autism Is Often Related To the Age of the Father at a Child's Birth

Published on the EBD Blog

In order to access the links and the complete comment section please read this paper where it was originally published: THE EBD BLOG


cFathers’ Age as Contributor to Risk for Autism
Leslie FeldmanThe average age of fatherhood is increasing in the US and in Western Europe. Some research shows that offspring of older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. “The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent” (Malaspina et al., 2006). Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladóttir and colleagues (2007) reported increased diagnosese of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age. Crow said, the evidence suggested that the greatest mutational health hazard in the population is fertile old men.

A study by Reichenberg et al. (2006) found a strong connection between cases of autism and advancing paternal age. Reichenberg and colleagues, who found more autism as paternal age increased, also found that the ratio of girls to boys in this cohort was 1:1, suggesting that this was a special subset of autism, maybe de novo rather than familial autism.

What might be the mechanism that produces higher rates of disorders among children of older fathers? The DNA in a 20 year-old male has been copied approximately100 times but in a 50 year-old father it has been copied over 800 times. Singh and colleagues (2003) studied differences in the sperm of older and younger men. Men over age 35 have sperm with lower motility and more highly damaged DNA in the form of double-strand breaks. The older group also had fewer apoptotic cells, an important discovery. (Apoptosis is form of cell death that protects the parent organism from problems or that permits differentiation, as in resorption of a tadpole’s tail.) A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage, as most other cells do. As a result, the only way to avoid passing DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age. Singh is quoted in Science Blog (Sullivan, 2002) as explaining that, “In older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated.”

Sources

The following list of sources is for works cited in this document or for other studies finding a connection between age of fathers at conception and various disorders. Access to some of the Web-based resources may be limited because of the policies of the publishers.

Atladóttir, H. O., Parner, E. T., Schendel, D., Dalsgaard, S., Thomsen, P. H., & Thorsen, P. (2007). Time trends in reported diagnoses of childhood neuropsychiatric disorders. Arch Pediatr Adolesc Med., 161, 193-198. Link

Brown et al. (2002): Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry, 159, 1528-1533. Link

Bray, I., Gunnell, D., & Smith, G. D. (2006). Advanced paternal age: How old is too old? Journal of Epidemiology and Community Health, 60, 851-853. Link

Burd et al., (1999). Prenatal and perinatal risk factors for autism. J. Perinatal. Med., 27, 441-450. Link

Byrne, M., Agerbo, E., Ewald, H., Easton, W. W., & Mortensen, P. D. (2003). Parental age and risk of schizophrenia, A case control study. Arch Gen Psychiatry, 60, 673-678. Link

Centers for Disease Control, (2006). How common are Autism Spectrum Disorders (ASD)? Link

Centers for Disease Control. (2002). Prevalence of the Autism Spectrum Disorders (ASDs) in multiple areas of the United States, 2000 and 2002. Atlanta, GA: Author. Link

Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. USA, 94, 8380-8386. Link

Dalman, C., & Allebeck, D. (2002). Paternal age and schizophrenia: Further support for an association. Am J Psychiatry, 159, 1591-1592. Link

Gillberg, C. (1980). Maternal age and infantile autism. J. Autism and Developmental Disorders, 10, 293-297. Link

Lauritsen M. B., Pedersen, C. B., & Mortensen, P. B. (2005) Effect of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychology and Psychiatry, 46, 963-971. Link

Miller, M. C. (2006) A new key to Autism. Aetna IntelliHealth, September 25. Link

Malaspina, D., et al. (2001): Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry, 58, 361-367. Link

Malaspina, D. (2006). In session with Dolores Malaspina, MD, MSPH: Impact of childhood trauma on psychiatric illness (interview by N. Sussman). Primary Psychiatry, 13(7), 33-36. Link

Malaspina, D. (2006). Schizophrenia risk and the paternal germ line. Schizophrenia Research Forum. Link

Rasmussen, F. (2006) Paternal age, size at birth, size in young adulthood&mdashrisk factors for schizophrenia. Eur Journal of Endocrinology, 155 Suppl 1:S65-69. Link

Reichenburg, A., Gross, R., Weiser, M. Bresnahan, M., Silverman, J. Harlap, S., et al. (2006). Advancing paternal age and autism. Arch Gen Psychiatry, 63, 1026-1032. Link

Singh, N. P., Muller, C. H., & Burger, R. E. (2003). Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertility and Sterility, 80, 1420-1430. Link

Sipos, A., Rasmussen, R., Harrison, G., Tynelius, P., Lews, G., Leon, D. A., et al. (2004). Paternal age and schizophrenia: A population based cohort study. BMJ, 329, 1070. Link

Sullivan, B. J. (2002). Research reveals a cellular basis for a male biological clock. Science Blog, 2002-11-25 22:31. Link

Tarin, J. J., Brines, J., & Cano, A. (1998). Long-term effects of delayed parenthood. Human Reproduction, 13, 2371-2376. Link

Tsuchiya, K. J., Takagai, S., Kawai, M., Matsumoto, H., Nakamura, K., Minabe, Y., et al. (2005). Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophrenia Research, 76, 337-342. Link

Wohl, M. & Gorwood, P. (2006). Paternal ages below or above 35 are associated with a different risk for schizophrenia in offspring. Eur. Psychiatry, Dec 1 [Epub ahead of print]. Link

Zammit, S., Allebeck, P., Dalman, C., Lundgerg, I., Hemming, T., Owen, M. J., et al. (2003). Paternal age and risk for schizophrenia. Br. J. Psychiatry, 183, 405-408. Link

3 Comments »
[…] may view the document, including references and links to many resources on this topic, by following this link or by clicking on the page in the side rail (look under the heading […]

Pingback by EBDblog » Paternal age–more — 21 February 2007 @ 3:08 pm

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5601a1.htm

February 9, 2007 / 56(SS01);1-11

Prevalence of Autism Spectrum Disorders — Autism and Developmental Disabilities Monitoring Network, Six Sites, United States, 2000

Corresponding author: Catherine Rice, PhD, Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDC, 1600 Clifton Road, N.E., MS E-86, Atlanta, GA 30333. Telephone: 404-498-3860; Fax: 404-498-3550; E-mail: crice@cdc.gov.

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5601a1.htm

Comment by Leslie Feldman — 21 February 2007 @ 7:36 pm

Dr. Narendra P.Singh suggested that I elaborate about what happens when the DNA in the primitive sperm making cells divides hundreds and hundreds of times as men age.

I will try.

Mutations arise with each cell division and the mutation rate increases with age. There are base substitutions and deletions and other copying errors. In a man of 45 there have been 770 cell divisions ancestral to a sperm. See James F. Crow’s paper, “The high spontaneous mutation rate: Is it a health risk? in the sources section of the paper.

Comment by Leslie Feldman — 22 February 2007 @ 7:38 pm








551