Editing Germline mutation (section)

== Causes ==

=== Endogenous factors ===
A germline mutation often arises due to [[Endogeny (biology)|endogenous]] factors, like errors in cellular replication and oxidative damage.<ref name=":1" /> This damage is rarely repaired imperfectly, but due to the high rate of germ cell division, can occur frequently.<ref name=":1">{{cite journal | vauthors = Crow JF | title = The origins, patterns and implications of human spontaneous mutation | journal = Nature Reviews Genetics | volume = 1 | issue = 1 | pages = 40–7 | date = October 2000 | pmid = 11262873 | doi = 10.1038/35049558 | s2cid = 22279735 }}</ref>

Endogenous mutations are more prominent in sperm than in ova.<ref name=":2">{{cite journal | vauthors = Wong WS, Solomon BD, Bodian DL, Kothiyal P, Eley G, Huddleston KC, Baker R, Thach DC, Iyer RK, Vockley JG, Niederhuber JE | title = New observations on maternal age effect on germline de novo mutations | journal = Nature Communications | volume = 7 | pages = 10486 | date = January 2016 | pmid = 26781218 | doi = 10.1038/ncomms10486 | pmc=4735694| bibcode = 2016NatCo...710486W }}</ref> This is because [[spermatocyte]]s go through a larger number of cell divisions throughout a male's life, resulting in more replication cycles that could result in a DNA mutation.<ref name=":1" /> Errors in maternal ovum also occur, but at a lower rate than in paternal sperm.<ref name=":1" /> The types of mutations that occur also tend to vary between the sexes.<ref name=":12" /> A mother's eggs, after production, remain in stasis until each is utilized in ovulation. This long stasis period has been shown to result in a higher number of chromosomal and large sequence deletions, duplications, insertions, and transversions.<ref name=":12">{{cite journal | vauthors = Hassold T, Hunt P | title = Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew | journal = Current Opinion in Pediatrics | volume = 21 | issue = 6 | pages = 703–8 | date = December 2009 | pmid = 19881348 | pmc = 2894811 | doi = 10.1097/MOP.0b013e328332c6ab }}</ref> The father's sperm, on the other hand, undergoes continuous replication throughout his lifetime, resulting in many small point mutations that result from errors in replication. These mutations commonly include single base pair substitutions, deletions, and insertions.<ref name=":2" />

Oxidative damage is another endogenous factor that can cause germline mutations. This type of damage is caused by [[reactive oxygen species]] that build up in the cell as a by-product of [[cellular respiration]].<ref name=":13" /> These reactive oxygen species are missing an electron, and because they are highly [[Electronegativity|electronegative]] (have a strong electron pull) they will rip an electron away from another molecule.<ref name=":13">{{cite journal | vauthors = Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ | title = Production of reactive oxygen species by mitochondria: central role of complex III | journal = The Journal of Biological Chemistry | volume = 278 | issue = 38 | pages = 36027–31 | date = September 2003 | pmid = 12840017 | doi = 10.1074/jbc.M304854200 | doi-access = free }}</ref> This can initiate DNA damage because it causes the nucleic acid guanine to shift to 8-oxoguanine (8-oxoG). This 8-oxoG molecule is then mistaken for a thymine by [[DNA polymerase]] during replication, causing a G>T [[transversion]] on one DNA strand, and a C>A transversion on the other.<ref>{{cite journal | vauthors = Ohno M, Sakumi K, Fukumura R, Furuichi M, Iwasaki Y, Hokama M, Ikemura T, Tsuzuki T, Gondo Y, Nakabeppu Y | title = 8-oxoguanine causes spontaneous de novo germline mutations in mice | journal = Scientific Reports | volume = 4 | pages = 4689 | date = April 2014 | pmid = 24732879 | pmc = 3986730 | doi = 10.1038/srep04689 | bibcode = 2014NatSR...4E4689O }}</ref>

===Male germline===

In mice and humans the spontaneous [[mutation rate]] in the male germ line is significantly lower than in [[somatic cell]]s.<ref name = Aitken2023>Aitken RJ, Lewis SEM. DNA damage in testicular germ cells and spermatozoa. When and how is it induced? How should we measure it? What does it mean? Andrology. 2023 Jan 5. doi: 10.1111/andr.13375. Epub ahead of print. PMID 36604857</ref>  Furthermore, although the spontaneous mutation rate in the male germ line increases with age, the rate of increase is lower than in somatic tissues.  Within the testicular [[spermatogonium|spermatogonial]] stem cell population the integrity of [[DNA]] appears to be maintained by highly effective [[DNA damage (naturally occurring)|DNA damage]] surveillance and protective [[DNA repair]] processes.<ref name = Aitken2023/>  The progressive increase in the mutation rate with age in the male germ line may be a result of a decline in the accuracy of the repair of DNA damages, or of an increase in [[DNA replication]] errors. Once [[spermatogenesis]] is complete, the differentiated spermatozoa that are formed no longer have the capability for DNA repair, and are thus vulnerable to attack by prevalent oxidative free radicals that cause oxidative DNA damage. Such damaged [[spermatozoon|spermatozoa]] may undergo programmed cell death ([[apoptosis]]).<ref name = Aitken2023/>

=== Exogenous factors ===
A germline mutation can also occur due to [[Exogeny|exogenous]] factors. Similar to somatic mutations, germline mutations can be caused by exposure to harmful substances, which damage the DNA of germ cells. This damage can then either be repaired perfectly, and no mutations will be present, or repaired imperfectly, resulting in a variety of mutations.<ref>{{cite web|url=https://evolution.berkeley.edu/evolibrary/article/evo_20|title=The causes of mutations|website=evolution.berkeley.edu|access-date=2017-11-30}}</ref> Exogenous [[mutagen]]s include harmful chemicals and [[ionizing radiation]]; the major difference between germline mutations and somatic mutations is that germ cells are not exposed to [[Ultraviolet|UV radiation]], and thus not often directly mutated in this manner.<ref>{{cite journal | vauthors = Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME | title = Timing, rates and spectra of human germline mutation | journal = Nature Genetics | volume = 48 | issue = 2 | pages = 126–133 | date = February 2016 | pmid = 26656846 | pmc = 4731925 | doi = 10.1038/ng.3469 }}</ref><ref>{{cite journal | vauthors = Cai L, Wang P | title = Induction of a cytogenetic adaptive response in germ cells of irradiated mice with very low-dose rate of chronic gamma-irradiation and its biological influence on radiation-induced DNA or chromosomal damage and cell killing in their male offspring | journal = Mutagenesis | volume = 10 | issue = 2 | pages = 95–100 | date = March 1995 | pmid = 7603336 | doi = 10.1093/mutage/10.2.95 }}</ref>