Paternal age effect

The genetic quality of sperm, as well as its volume and motility, may decrease with age,<ref>{{cite journal | vauthors = Kovac JR, Addai J, Smith RP, Coward RM, Lamb DJ, Lipshultz LI | title = The effects of advanced paternal age on fertility | journal = Asian Journal of Andrology | volume = 15 | issue = 6 | pages = 723–8 | date = November 2013 | pmid = 23912310 | pmc = 3854059 | doi = 10.1038/aja.2013.92 | doi-access = free }}</ref> leading the population geneticist [[James F. Crow]] to claim that the "greatest mutational health hazard to the human genome is fertile older males".<ref name="Crow 8380–8386">{{cite journal | vauthors = Crow JF | title = The high spontaneous mutation rate: is it a health risk? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 16 | pages = 8380–6 | date = August 1997 | pmid = 9237985 | pmc = 33757 | doi = 10.1073/pnas.94.16.8380 | doi-access = free | bibcode = 1997PNAS...94.8380C }}</ref>

The genetic quality of sperm, as well as its volume and motility, may decrease with age,<ref>{{cite journal | vauthors = Kovac JR, Addai J, Smith RP, Coward RM, Lamb DJ, Lipshultz LI | title = The effects of advanced paternal age on fertility | journal = Asian Journal of Andrology | volume = 15 | issue = 6 | pages = 723–8 | date = November 2013 | pmid = 23912310 | pmc = 3854059 | doi = 10.1038/aja.2013.92 | doi-access = free }}</ref> leading the population geneticist [[James F. Crow]] to claim that the "greatest mutational health hazard to the human genome is fertile older males".<ref name="Crow 8380–8386">{{cite journal | vauthors = Crow JF | title = The high spontaneous mutation rate: is it a health risk? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 16 | pages = 8380–6 | date = August 1997 | pmid = 9237985 | pmc = 33757 | doi = 10.1073/pnas.94.16.8380 | doi-access = free | bibcode = 1997PNAS...94.8380C }}</ref>

The paternal age effect was first proposed implicitly by physician [[Wilhelm Weinberg]] in 1912<ref name="Weinberg 1912">{{cite journal |last=Weinberg |first=W |title=Zur Vererbung des Zwergwuchses |trans-title=On the inheritance of dwarfism |language=de |date=1912 |volume=9 |pages=710–718 |journal=Arch Rassen-u Gesell Biol |id={{NAID|10017956735}} }}</ref> and explicitly by psychiatrist [[Lionel Penrose]] in 1955.<ref name="Penrose 1955">{{cite journal | vauthors = Penrose LS | title = Parental age and mutation | journal = Lancet | volume = 269 | issue = 6885 | pages = 312–3 | date = August 1955 | pmid = 13243724 | doi = 10.1016/s0140-6736(55)92305-9 }}</ref> DNA-based research started more recently, in 1998, in the context of paternity testing.

The paternal age effect was first proposed implicitly by physician [[Wilhelm Weinberg]] in 1912<ref name="Weinberg 1912">{{cite journal |last=Weinberg |first=W |title=Zur Vererbung des Zwergwuchses |trans-title=On the inheritance of dwarfism |language=de |date=1912 |volume=9 |pages=710–718 |journal=Arch Rassen-u Gesell Biol |id={{NAID|10017956735}} }}</ref> and explicitly by psychiatrist [[Lionel Penrose]] in 1955.<ref name="Penrose 1955">{{cite journal | vauthors = Penrose LS | title = Parental age and mutation | journal = Lancet | volume = 269 | issue = 6885 | pages = 312–3 | date = August 1955 | pmid = 13243724 | doi = 10.1016/s0140-6736(55)92305-9 }}</ref> DNA-based research started more recently, in 1998, in the context of [[paternity testing]].

==Health effects==

==Health effects==

Birth defects were acknowledged in the children of older men and women even in antiquity. In book six of [[Plato]]'s [[Republic (Plato)|Republic]], [[Socrates]] states that men and women should have children in the "prime of their life" which is stated to be twenty in a woman and thirty in a man. He states that in his proposed society men should be forbidden to father children in their fifties and that the offspring of such unions should be considered "the offspring of darkness and strange lust." He suggests appropriate punishments be administered to the offenders and their offspring.<ref>{{cite web | url=http://classics.mit.edu/Plato/republic.6.v.html | title=The Internet Classics Archive &#124; the Republic by Plato }}</ref><ref>{{cite journal | last=Galton | first=D J | title=Greek theories on eugenics. | journal=Journal of Medical Ethics| volume=24 | issue=4 | date=1 August 1998 | doi=10.1136/jme.24.4.263 | pages=263–267| pmid=9752630 | pmc=1377679 }}</ref>

Birth defects were acknowledged in the children of older men and women even in antiquity. In book six of [[Plato]]'s [[Republic (Plato)|Republic]], [[Socrates]] states that men and women should have children in the "prime of their life" which is stated to be twenty in a woman and thirty in a man. He states that in his proposed society men should be forbidden to father children in their fifties and that the offspring of such unions should be considered "the offspring of darkness and strange lust." He suggests appropriate punishments be administered to the offenders and their offspring.<ref>{{cite web | url=http://classics.mit.edu/Plato/republic.6.v.html | title=The Internet Classics Archive &#124; the Republic by Plato }}</ref><ref>{{cite journal | last=Galton | first=D J | title=Greek theories on eugenics. | journal=Journal of Medical Ethics| volume=24 | issue=4 | date=1 August 1998 | doi=10.1136/jme.24.4.263 | pages=263–267| pmid=9752630 | pmc=1377679 }}</ref>

In 1912, [[Wilhelm Weinberg]], a German physician, was the first person to hypothesize that non-inherited cases of [[achondroplasia]] could be more common in last-born children than in children born earlier to the same set of parents.<ref name="Crow-2000">{{cite journal |last1=Crow |first1=James F. |title=The origins, patterns, and implications of human spontaneous mutation |journal=Nature Reviews Genetics |date=October 2000 |volume=1 |issue=1 |pages=40–47 |doi=10.1038/35049558 |pmid=11262873 |s2cid=22279735 }}</ref> Weinberg "made no distinction between paternal age, maternal age and [[birth order]]" in his hypothesis. In 1953, Krooth used the term "paternal age effect" in the context of achondroplasia, but mistakenly thought the condition represented a maternal age effect.<ref name="Crow-2000"/><ref name="Krooth-1953">{{cite journal | vauthors = Krooth RS | title = Comments on the estimation of the mutation rate for achondroplasia | journal = American Journal of Human Genetics | volume = 5 | issue = 4 | pages = 373–6 | date = December 1953 | pmid = 13104383 | pmc = 1716528 }}</ref>{{rp|375}} The paternal age effect for achondroplasia was described by [[Lionel Penrose]] in 1955. At a DNA level, the paternal age effect was first reported in 1998 in routine paternity tests.<ref name="Brinkmann-1998">{{cite journal | vauthors = Brinkmann B, Klintschar M, Neuhuber F, Hühne J, Rolf B | title = Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1408–15 | date = June 1998 | pmid = 9585597 | pmc = 1377148 | doi = 10.1086/301869 }}</ref>

In 1912, [[Wilhelm Weinberg]], a German physician, was the first person to hypothesize that non-inherited cases of [[achondroplasia]] could be more common in last-born children than in children born earlier to the same set of parents.<ref name="Crow-2000">{{cite journal |last1=Crow |first1=James F. |title=The origins, patterns, and implications of human spontaneous mutation |journal=Nature Reviews Genetics |date=October 2000 |volume=1 |issue=1 |pages=40–47 |doi=10.1038/35049558 |pmid=11262873 |s2cid=22279735 }}</ref> Weinberg "made no distinction between paternal age, maternal age and [[birth order]]" in his hypothesis. In 1953, Krooth used the term "paternal age effect" in the context of achondroplasia, but mistakenly thought the condition represented a maternal age effect.<ref name="Crow-2000"/><ref name="Krooth-1953">{{cite journal | vauthors = Krooth RS | title = Comments on the estimation of the mutation rate for achondroplasia | journal = American Journal of Human Genetics | volume = 5 | issue = 4 | pages = 373–6 | date = December 1953 | pmid = 13104383 | pmc = 1716528 }}</ref>{{rp|375}} The paternal age effect for achondroplasia was described by [[Lionel Penrose]] in 1955. At a DNA level, the paternal age effect was first reported in 1998 in routine [[paternity test]]s.<ref name="Brinkmann-1998">{{cite journal | vauthors = Brinkmann B, Klintschar M, Neuhuber F, Hühne J, Rolf B | title = Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1408–15 | date = June 1998 | pmid = 9585597 | pmc = 1377148 | doi = 10.1086/301869 }}</ref>

Scientific interest in paternal age effects is relevant because the average paternal age increased in countries such as the United Kingdom,<ref name="Bray-2006">{{cite journal | vauthors = Bray I, Gunnell D, Davey Smith G | title = Advanced paternal age: how old is too old? | journal = Journal of Epidemiology and Community Health | volume = 60 | issue = 10 | pages = 851–3 | date = October 2006 | pmid = 16973530 | pmc = 2566050 | doi = 10.1136/jech.2005.045179 }}</ref> Australia<ref>{{cite web |url=http://www.abs.gov.au/ausstats/[email protected]/Products/92A449676DCE3145CA25766A00120E3D?opendocument |title= 3301.0 - Births, Australia, 2008. Summary of findings. Births|author= Australian Bureau of Statistics|date=11 November 2009 |access-date=25 February 2010}}</ref> and Germany,<ref name="Kühnert-2004">{{cite journal | vauthors = Kühnert B, Nieschlag E | title = Reproductive functions of the ageing male | journal = Human Reproduction Update | volume = 10 | issue = 4 | pages = 327–39 | year = 2004 | pmid = 15192059 | doi = 10.1093/humupd/dmh030 | doi-access = free }}</ref> and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States.<ref>{{cite journal |title= Births: final data for 2006 |vauthors=Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Mathews TJ | journal = National Vital Statistics Reports | volume = 57 | issue = 7 | pages = 1–104 | year=2009 |url= https://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_07.pdf |access-date=25 February 2010}}</ref> Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage.<ref name="Kühnert-2004"/> Despite recent increases in average paternal age, however, the [[Ramjit Raghav|oldest father]] documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the ''[[Journal of the American Medical Association]]'' stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96.<ref name="Kühnert-2004"/><ref name="Seymour-1935">{{Cite journal |vauthors=Seymour FI, Duffy C, Koerner A | title = A case of authenticated fertility in a man, aged 94 | journal = J Am Med Assoc | volume = 105 | issue = 18 | pages = 1423–4| year = 1935 | doi=10.1001/jama.1935.92760440002009a}}</ref><ref>{{cite news |title=A father again at 96; North Carolinan's baby a sister to boy born two years ago |url=https://www.nytimes.com/1936/06/04/archives/a-father-again-at-96-north-carolinans-baby-a-sister-to-boy-born-two.html |url-access=subscription |agency=Associated Press |newspaper=The New York Times |date=4 June 1936 |page=10 |access-date=26 April 2019}}</ref>

Scientific interest in paternal age effects is relevant because the average paternal age increased in countries such as the United Kingdom,<ref name="Bray-2006">{{cite journal | vauthors = Bray I, Gunnell D, Davey Smith G | title = Advanced paternal age: how old is too old? | journal = Journal of Epidemiology and Community Health | volume = 60 | issue = 10 | pages = 851–3 | date = October 2006 | pmid = 16973530 | pmc = 2566050 | doi = 10.1136/jech.2005.045179 }}</ref> Australia<ref>{{cite web |url=http://www.abs.gov.au/ausstats/[email protected]/Products/92A449676DCE3145CA25766A00120E3D?opendocument |title= 3301.0 - Births, Australia, 2008. Summary of findings. Births|author= Australian Bureau of Statistics|date=11 November 2009 |access-date=25 February 2010}}</ref> and Germany,<ref name="Kühnert-2004">{{cite journal | vauthors = Kühnert B, Nieschlag E | title = Reproductive functions of the ageing male | journal = Human Reproduction Update | volume = 10 | issue = 4 | pages = 327–39 | year = 2004 | pmid = 15192059 | doi = 10.1093/humupd/dmh030 | doi-access = free }}</ref> and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States.<ref>{{cite journal |title= Births: final data for 2006 |vauthors=Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Mathews TJ | journal = National Vital Statistics Reports | volume = 57 | issue = 7 | pages = 1–104 | year=2009 |url= https://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_07.pdf |access-date=25 February 2010}}</ref> Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage.<ref name="Kühnert-2004"/> Despite recent increases in average paternal age, however, the [[Ramjit Raghav|oldest father]] documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the ''[[Journal of the American Medical Association]]'' stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96.<ref name="Kühnert-2004"/><ref name="Seymour-1935">{{Cite journal |vauthors=Seymour FI, Duffy C, Koerner A | title = A case of authenticated fertility in a man, aged 94 | journal = J Am Med Assoc | volume = 105 | issue = 18 | pages = 1423–4| year = 1935 | doi=10.1001/jama.1935.92760440002009a}}</ref><ref>{{cite news |title=A father again at 96; North Carolinan's baby a sister to boy born two years ago |url=https://www.nytimes.com/1936/06/04/archives/a-father-again-at-96-north-carolinans-baby-a-sister-to-boy-born-two.html |url-access=subscription |agency=Associated Press |newspaper=The New York Times |date=4 June 1936 |page=10 |access-date=26 April 2019}}</ref>