The greatest mutational hazard on earth Fertile old (34+) men not women

"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.)"





Alexander Kolevzon, MD; Raz Gross, MD, MPH; Abraham Reichenberg, PhD

Vol. 161 No. 4, April 2007



The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.



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Vol. 63 No. 9, September 2006 Archives










Advancing Paternal Age and Autism
Abraham Reichenberg, PhD; Raz Gross, MD, MPH; Mark Weiser, MD; Michealine Bresnahan, PhD; Jeremy Silverman, PhD; Susan Harlap, MBBS; Jonathan Rabinowitz, PhD; Cory Shulman, PhD; Dolores Malaspina, MD; Gad Lubin, MD; Haim Y. Knobler, MD; Michael Davidson, MD; Ezra Susser, MD, DrPH


Arch Gen Psychiatry. 2006;63:1026-1032.

Context Maternal and paternal ages are associated with neurodevelopmental disorders.

Objective To examine the relationship between advancing paternal age at birth of offspring and their risk of autism spectrum disorder (ASD).

Design Historical population-based cohort study.

Setting Identification of ASD cases from the Israeli draft board medical registry.

Participants We conducted a study of Jewish persons born in Israel during 6 consecutive years. Virtually all men and about three quarters of women in this cohort underwent draft board assessment at age 17 years. Paternal age at birth was obtained for most of the cohort; maternal age was obtained for a smaller subset. We used the smaller subset (n = 132 271) with data on both paternal and maternal age for the primary analysis and the larger subset (n = 318 506) with data on paternal but not maternal age for sensitivity analyses.

Main Outcome Measures Information on persons coded as having International Classification of Diseases, 10th Revision ASD was obtained from the registry. The registry identified 110 cases of ASD (incidence, 8.3 cases per 10 000 persons), mainly autism, in the smaller subset with complete parental age data.

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.


Author Affiliations: Department of Psychiatry (Drs Reichenberg, Silverman, and Davidson) and Seaver Center for Autism Research (Dr Silverman), Mount Sinai School of Medicine; Department of Epidemiology, Mailman School of Public Health, Columbia University (Drs Gross, Bresnahan, Harlap, Malaspina, and Susser); New York State Psychiatric Institute (Drs Gross, Bresnahan, Malaspina, and Susser), New York; Institute of Psychiatry, King's College, London, England (Dr Reichenberg); and Department of Psychiatry, Chaim Sheba Medical Center, Tel Hashomer (Drs Weiser and Davidson); School of Social Work, Bar Ilan University, Ramat-Gan (Dr Rabinowitz); School of Social Work, Hebrew University, Jerusalem (Dr Shulman); and Medical Corps, Israel Defense Forces, Tel Aviv (Drs Lubin and Knobler), Israel.


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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.Jim Crow said, the evidence from his research suggested that the greatest mutational health hazard in the population is fertile old men.




Average paternal age in the UK is increasing. The public
health implications of this trend have not been widely
anticipated or debated. This commentary aims to contribute
to such a debate. Accumulated chromosomal aberrations
and mutations occurring during the maturation of male germ
cells are thought to be responsible for the increased risk of
certain conditions with older fathers. Growing evidence
shows that the offspring of older fathers have reduced fertility
and an increased risk of birth defects, some cancers, and
schizophrenia. Adverse health outcomes should be weighed
up against advantages for children born to older parents,
mindful that these societal advantages are likely to change
over time.