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Todd C. Wilson

Dr. Joan Herbers

EEOB 3310

14 Sep 14

Paternal age effect


 * Crow, James F. (August 5, 1997). Proc Natl Acad Sci U S A. 94 (16). pp. 8380–8386. doi:10.1073/pnas.94.16.8380. PMC 33757. . Retrieved 29 March 2013.


 * This lengthy study suggests that human males undergo higher mutation rates than females and this mutation increases correspondingly with the age of the father due to the large number of cell divisions in the male germ line. A comparison is made with Drosophila, in which presumably one new mutation occurs per zygote, a much higher rate occurs in humans due to a much larger number of genes and DNA. The article cites four classical conditions linked to a paternal age effect as Achondroplasia, Apert syndrome, Myositis ossicicans, and Marfan syndrome.


 * Reichenberg A, Gross R, Weiser M, et al. Advancing Paternal Age and Autism. Arch Gen Psychiatry. 2006;63(9):1026-1032. doi:10.1001/archpsyc.63.9.1026.


 * This study examined the paternal age at the birth of the offspring and the relationship with a risk for autism spectrum disorder (ASD). The results showed that men aged 40 years and older were nearly 6 times likely to have offspring with ASD than men 30 years and younger. The researchers listed the possible biological mechanisms with advanced paternal age as including de novo mutations or alterations with genetic imprinting.


 * Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, et al. (2009) Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med 6(3): e1000040. doi:10.1371/journal.pmed.1000040


 * This study states the known effects of offspring complications with older mothers and the often overlooked attention to the harmful effects caused by older fathers. It states that recent evidence has linked the paternal age effect with miscarriages, birth deformities, cancer, autism, and schizophrenia. Again, this study suggests that the mechanism is suspected to be the damage to sperm which is accumulated over a man's lifetime.


 * Rebecca G. Smith, Rachel L. Kember, Jonathan Mill, et al. Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model. PLoS One. 2009; 4(12): e8456. Published online 2009 December 30. doi: 10.1371/journal.pone.0008456 PMCID:PMC2794376


 * This study shows the results from a mouse model and the effects of an advanced paternal age with the behavior deficits on the offspring. The study compared results from offspring of young mice (2 months) and old mice (10 months) with 2 month mothers. The results showed strong evidence of deleterious effects in offspring from advanced paternal age on social and exploratory behavior.


 * Singh NP, Muller CH, Berger RE (2003). "Effects of age on DNA double-strand breaks and apoptosis in human sperm". Fertil Steril 80 (6): 1420–30. doi:10.1016/j.fertnstert.2003.04.002..


 * This study involved the test for a correlation between a man's age and the increased DNA damage and apoptosis in human sperm. The study recruited 66 men between the age of 20 and 57. The results clearly stated a direct relation between age and sperm double-stranded DNA breaks in addition to what the study reveals as a first time suggestion of the relation between age and the decrease of human sperm apoptosis. Again, this study mentions the lifelong cell replication of spermatozoa and the increased possibility of damage to DNA.


 * Kleinhaus K, et al. Paternal age and spontaneous abortion. Obstetrics and Gynecology. 2006;108:369.


 * This review discusses the advanced paternal age on reproductive outcome due to social and economical influences.

Identifying three ways the article can be improved:

Definition


 * MedicineNet.com lists two types of paternal age effects. The two types are autosomalmutations and an indirect paternal age effect from mutations on the X chromosome.

Clinical implications


 * MedicineNet.com also states that there is no universal definition of advanced paternal age, but does suggest that in the realm of genetic counseling, all men 40 yrs and older at the time of conception meet the criterion.

Pathophysiology


 * Commenting on the study of 78 Icelandic families, Harry Fisch, MD, clinical professor of urology and reproductive medicine at Weill Cornell Medical College of Cornell University, suggests that now men too have a reference point in decisions of advanced paternal age and risk for genetic defects. The article cites that for women the age of 35 is a benchmark in determining the age of increasing escalation of genetic defect risks and that now men can assume a doubling of the mutation rate every 16 years.

Main Page Addition:

The paternal age effect (PAE) is the study of the statistical relationship between an advanced paternal age to sperm and semen abnormalities, fertility, pregnancy outcomes, birth outcome (such as birthweight), probability that the offspring will have a health-related condition, or risk of mortality, or social and other psychological outcomes. The paternal age effect is of two different types. One effect is directly related to advanced paternal age and autosomalmutations in the offspring. The other (PAE) is an indirect effect in relation to mutations on the X chromosome which are passed to daughters at risk for having sons with X-linked diseases.

Paternal Age Effect

tw 4049

Thu 1830-1925

Paternal Age Effect
In the genetic counseling chapter of the most recent Genetic Disorders Sourcebook, a question is presented as to why a person might need a genetic consultation. The sourcebook cites the age of 35 for women at the time of pregnancy as one cause for consultation due to the higher frequencies of chromosomal disorders but makes no mention at all of the age of the father. Research suggests, however, that the age of the father at the time of conception plays a very important role in the risk of de novo mutations and possible birth defects in the offspring. This commentary aims to discuss the risks involved with current trends of delayed parenthood and genetic disorders from an advanced paternal age leading to population level consequences.

Current Trends
Current trends indicate that women are delaying childbirth for several socioeconomic reasons. Balancing education, careers, and family has shown that in the decade 1991-2001, the number of first births per 1000 women 40 to 44 years of age increased 70 percent (Heffner 2004). These delayed parenthood statistics are occurring with a well-documented risk of genetic disorders, such as Down syndrome, to ageing mothers. What is not generally well known or documented is an increasing risk for genetic defects from an advanced paternal age. Since 1980, U.S. birth rates for men aged 35–49 have increased up to 40 percent (Wyrobek et al 2006). In 2003, as much as 40 percent of live births within marriage in England and Wales were to fathers aged 35–54 (Bray 2006). With increasing implications to a broad range of abnormal reproductive outcomes from ageing fathers, measures are being put in place to help minimize the risks. Both the American Society for Reproductive Medicine and the British Andrology Society have placed an upper age limit of 40 years for all sperm donors (de La Rochebrochard E, et al 2006). Although the recent edition of the Genetic Disorders Sourcebook fails to mention paternal risks, in the realm of genetic counseling the age of 40 or greater at the time of conception now meets the criterion for an advanced paternal age (medicinenet.com 2012).

Definition and History
The paternal age effect (PAE) is an epidemiological concept describing the fact that some spontaneous disorders tend to arise more frequently in the progeny of older men (Goriely and Wilkie 2012). The first person to suggest that paternal age was a factor in a genetic disorder was Wilhelm Weinberg in 1912 while studying the achondroplasia condition and the higher incidence of the disease in the last born children. It was in 1955 that Lionel Penrose suggested that the higher incident rates were due more to the advanced paternal age and not the birth order. While studying the X-chromosomal disease, hemophilia, J.B.S. Haldane was the first to notice a sex difference in mutation rates. Males with hemophilia receive the mutant gene from their mother. This occurs in one of two ways; the mother is a heterozygous carrier for the disorder, or the mutation has occurred in the female germ line. Instead of the expected rates of the disease, if the mutation rates were the same in both sexes, Haldane discovered that nearly all of the affected sons had heterozygous mothers suggesting that the mutation rate occurred in previous generations and were likely due to the maternal grandfather (Haldane 1947). Haldane’s analysis showed that most mutations occur in males. This example of an X-linked disorder was at one time the only way to determine whether the mutation occurred in the mother or the father. But it was as recent as 2012, with the use of molecular biology, that Kong et al conducted the first study of genome-wide mutation rates in parent-offspring trios that shown the importance in father’s age to the risk of diseases such as schizophrenia and autism. This study suggested that, not only was the mutation occurring in males, but the number of paternal de novo mutations increased at a rate that accelerated with the age of the father (Kong et al 2012).

Mutation Rates
Higher mutation rates are occurring in males than in females and the difference in germ cell development offers an explanation. As female germ cell divisions stop at the time of birth, male germ cell divisions are continuous and occur throughout the life of the man. In females, germ cells undergo 22 mitotic cell divisions in utero and oocyte maturation is complete when meiosis resumes just before ovulation. The mitotic divisions in males are much greater. Males undergo 30 mitotic divisions during embryogenesis and at puberty spermatogenesis divides adult stem cells once every 16 days to produce sperm. Approximately 150 cell divisions would have occurred in a 20 year old male and by the age of 50 the number is 840 (Goriely et al 2013). Since mutations are associated with cell division, the higher mutation rate is with the father. Mutations are conveniently divided into either chromosome mutations or gene mutations (Crow 1997). There are mutations that are meiotic in origin and involve chromosome transmission errors associated with an advanced maternal age such as Down syndrome (Hassold and Hunt 2009). However, gene mutations involving point mutations (nucleotide substitutions), small insertion-deletion errors, microsatellite repeats, and nonrecurrent copy number variations are mitotic in origin and are associated with an advanced paternal age (Goriely et al 2013). Whole-genome sequencing has discovered that about two point mutations occur every year which corresponds to a doubling of mutations paternal in origin every 16.5 years (Kong et al 2012).

(PAE) Disorders and Mechanism
Studies reveal that the following list of congenital disorders, collectively known as paternal age effect (PAE) disorders, are all caused by a small number of dominantly-acting point mutations and almost exclusively originate from unaffected fathers, suggesting that the mutations are taking place during spermatogenesis. Mutations in the fibroblast growth factor receptor genes (FGFR2) cause Apert, Crouzon, and Pfeiffer syndromes (Goriely and Wilkie 2012). Mutations in the FGFR3 gene lead to the formation of achondroplasia, thanatophoric dysplasia, hypochondroplasia, and Muenke syndromes (Goriely and Wilkie 2012). These disorders occur spontaneously as a result of advanced paternal age and at the rate of 1 in 30,000 for achondroplasia births (Orioli et al 1986; Waller et al 2008). Other conditions involving the mutations in the RET gene lead to multiple endocrine neoplasia types 2A and 2B, the PTPN11 gene which leads to Noonan syndrome, and the HRAS mutations which cause Costello syndrome (Schuffenecker et al 1997; Carlson et al 1994; Tartaglia et al 2004; Sol-Church et al 2006). In recent studies of multiple endocrine neoplasia Type 2A and 2B and Apert syndrome, a total of 92 new mutations were discovered and all were found to be paternal in origin (Carlson et al 1994; Schuffenecker et al 1997; Moloney et al 1996). These studies which show an extreme paternal bias for PAE mutations is argued to be caused by the distinct phenomenon of clonal expansion of spermatogonial cells with gain-of-function protein properties. This mechanism known as “selfish selection”, results in an enrichment of mutant sperm over time and may preferentially carry alterations in genes that could have far-reaching consequences for the health of future generations (Goriely and Wilkie 2007).

Conclusion
Delayed parenthood is becoming socially accepted. Socioeconomic factors that include higher education levels and occupation have been found to be associated with positive health outcomes from prenatal care services (D’Ascoli et al 1997). However, as advanced reproductive technologies and governmental efforts to prevent teenage pregnancy, for example, continue to delay maternal ages, there are risks involved (Blickstein 2003). For many years now it has been well-known that ageing mothers are susceptible to genetic aneuploidy disorders. And, considering that on average males are three years older than mothers at childbirth, a new emphasis is being placed on the role of paternal age with deleterious birth defects (London: Stationary Office 2002). It has been found that much higher mutation rates in males than females are due to the continuous cell divisions of the male germ line. With increasing age, among many other things, it is believed that the fidelity of replication, efficiency of editing, and error correction can all deteriorate over time (Crow 1997). In addition, these mutations have been found to be non-linear with regard to the proportion of cell divisions. This suggests that the data are consistent with a power function of age resulting in a mutation rate much higher than females at an advanced age (Crow 1997). Mutations are what make evolution possible. Selective forces that eliminate harmful mutations in the past are not as efficient today due to rapid environmental improvements. If harmful mutations are indeed accumulating, this suggests that the greatest mutational health hazard in the human population is fertile old males (Crow 1997).

(PAE) Disorders, mechanism, and other conditions
Studies reveal that the following list of congenital disorders, collectively known as paternal age effect (PAE) disorders, are all caused by a small number of dominantly-acting point mutations and almost exclusively originate from unaffected fathers, suggesting that the mutations are taking place during spermatogenesis. Mutations in the fibroblast growth factor receptor genes FGFR2, cause Apert syndrome,  Crouzon syndrome,   and Pfeiffer syndrome. Mutations in the FGFR3 gene lead to the formation of achondroplasia, thanatophoric dysplasia, hypochondroplasia, and Muenke syndrome. These disorders occur spontaneously as a result of advanced paternal age and at the rate of 1 in 30,000 for achondroplasia births. Other conditions involving the mutations in the RET gene lead to multiple endocrine neoplasia type 2A and 2B, the PTPN11 gene which leads to Noonan syndrome, and the HRAS mutations which cause Costello syndrome. In recent studies of multiple endocrine neoplasia Type 2A and 2B and Apert syndrome, a total of 92 new mutations were discovered and all were found to be paternal in origin. These studies which show an extreme paternal bias for PAE mutations is argued to be caused by the distinct phenomenon of clonal expansion of spermatogonial cells with gain-of-function protein properties. This mechanism known as “selfish selection”, results in an enrichment of mutant sperm over time and may preferentially carry alterations in genes that could have far-reaching consequences for the health of future generations.

Other conditions and diseases which have been suggested as having a possible correlation with paternal age include: Chondrodystrophy, Acrodysostosis, Aniridia, Basal cell nevus syndrome,  Cataracts, Cerebral palsy, athetoid/dystonic, CHARGE syndrome, Cleft palate,  Cleidocranial dysostosis,  Craniosynostosis, Diaphragmatic hernia, Duchenne muscular dystrophy, Exostoses, multiple,  congenital malformations in extremities, Fibrodysplasia ossificans progressiva,  Heart defects,   Hemangioma, Hemiplegia, Hemophilia A, Hydrocephalus, Klinefelter's syndrome, Lesch-Nyhan syndrome, Marfan syndrome, Nasal aplasia,  Neural tube defects, Oculodentodigital syndrome,  Osteogenesis imperfecta type IIA, Polycystic kidney disease, Polyposis coli, Preauricular cyst,  Progeria,  Psychotic disorders, von Recklinghausen neurofibromatosis,  Retinitis pigmentosa, Retinoblastoma, bilateral, Situs inversus, Soto's basal cell nevus,  Treacher-Collins Syndrome,  Tuberous sclerosis, Urethral stenosis,  Waardenburg syndrome,  and Wilms' tumor