Editing Mitochondrial DNA (section)

== Mitochondrial inheritance ==
In most [[metazoans|multicellular organisms]], mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains on average 200,000 mtDNA molecules, whereas a healthy human [[sperm]] has been reported to contain on average 5 molecules),<ref>{{Cite journal |vauthors=Wolff JN, Gemmell NJ |date=November 2008 |title=Lost in the zygote: the dilution of paternal mtDNA upon fertilization |journal=Heredity |volume=101 |issue=5 |pages=429–434 |doi=10.1038/hdy.2008.74 |pmid=18685570 |s2cid=5065133 |doi-access=free|bibcode=2008Hered.101..429W }}</ref><ref>{{Cite journal |vauthors=Gabriel MS, Chan SW, Alhathal N, Chen JZ, Zini A |date=August 2012 |title=Influence of microsurgical varicocelectomy on human sperm mitochondrial DNA copy number: a pilot study |journal=Journal of Assisted Reproduction and Genetics |volume=29 |issue=8 |pages=759–764 |doi=10.1007/s10815-012-9785-z |pmc=3430774 |pmid=22562241}}</ref> degradation of sperm mtDNA in the male genital tract and the fertilized egg; and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent ([[uniparental inheritance]]) pattern of mtDNA inheritance is found in most animals, most plants, and also in fungi.<ref>{{Cite journal |vauthors=Mendoza H, Perlin MH, Schirawski J |date=May 2020 |title=Mitochondrial Inheritance in Phytopathogenic Fungi-Everything Is Known, or Is It? |journal=Int J Mol Sci |volume=21 |issue=11 |page=3883 |doi=10.3390/ijms21113883 |pmc=7312866 |pmid=32485941 |doi-access=free}}</ref>

In a study published in 2018, human babies were reported to inherit mtDNA from both their fathers and their mothers resulting in mtDNA [[heteroplasmy]],<ref name="Biparental Inheritance of Mitochond">{{Cite journal |display-authors=6 |vauthors=Luo S, Valencia CA, Zhang J, Lee NC, Slone J, Gui B, Wang X, Li Z, Dell S, Brown J, Chen SM, Chien YH, Hwu WL, Fan PC, Wong LJ, Atwal PS, Huang T |date=December 2018 |title=Biparental Inheritance of Mitochondrial DNA in Humans |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=51 |pages=13039–13044 |bibcode=2018PNAS..11513039L |doi=10.1073/pnas.1810946115 |pmc=6304937 |pmid=30478036 |doi-access=free}}</ref> a finding that has been rejected by other scientists.<ref name="pmid34031572">{{Cite journal |vauthors=Pagnamenta AT, Wei W, Rahman S, Chinnery PF |date=August 2021 |title=Biparental inheritance of mitochondrial DNA revisited |url=https://discovery.ucl.ac.uk/id/eprint/10128999/ |journal=Nature Reviews. Genetics |volume=22 |issue=8 |pages=477–478 |doi=10.1038/s41576-021-00380-6 |pmid=34031572 |s2cid=235199218}}</ref><ref name="pmid32330850">{{Cite journal |vauthors=Salas A, Schönherr S, Bandelt HJ, Gómez-Carballa A, Weissensteiner H |date=July 2020 |title=Extraordinary claims require extraordinary evidence in asserted mtDNA biparental inheritance |journal=Forensic Science International. Genetics |volume=47 |page=102274 |doi=10.1016/j.fsigen.2020.102274 |pmid=32330850 |s2cid=216131636}}</ref><ref name="pmid32269217">{{Cite journal |vauthors=Wei W, Pagnamenta AT, Gleadall N, Sanchis-Juan A, Stephens J, Broxholme J, Tuna S, Odhams CA, Fratter C, Turro E, Caulfield MJ, Taylor JC, Rahman S, Chinnery PF |date=April 2020 |title=Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans |journal=Nature Communications |volume=11 |issue=1 |page=1740 |bibcode=2020NatCo..11.1740W |doi=10.1038/s41467-020-15336-3 |pmc=7142097 |pmid=32269217}}</ref>

=== Female inheritance ===
In [[sexual reproduction]], mitochondria are normally inherited exclusively from the mother; the mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, mitochondria are present solely in the midpiece, which is used for propelling the sperm cells, and sometimes the midpiece, along with the tail, is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with [[ubiquitin]] to select them for later destruction inside the [[embryo]].<ref>{{Cite journal |vauthors=Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G |date=November 1999 |title=Ubiquitin tag for sperm mitochondria |journal=Nature |volume=402 |issue=6760 |pages=371–372 |bibcode=1999Natur.402..371S |doi=10.1038/46466 |pmid=10586873 |s2cid=205054671}} Discussed in: {{cite journal |doi=10.2307/4012086 |jstor=4012086 |title=Mom's Eggs Execute Dad's Mitochondria |journal=Science News |volume=157 |issue=1 |page=5 |year=2000 | vauthors = Travis J |url=https://www.sciencenews.org/article/moms-eggs-execute-dads-mitochondria |archive-url=https://web.archive.org/web/20071219174548/http://www.sciencenews.org/articles/20000101/fob3.asp |archive-date=19 December 2007 |url-access=subscription }}</ref> Some ''[[in vitro]]'' fertilization techniques, particularly injecting a sperm into an [[oocyte]], may interfere with this.{{cn|date=November 2024}}

The fact that mitochondrial DNA is mostly maternally inherited enables [[Genetic genealogy|genealogical]] researchers to trace [[Matrilineality|maternal lineage]] far back in time. ([[Y chromosome|Y-chromosomal DNA]], paternally inherited, is used in an analogous way to determine the [[patrilineal]] history.) This is usually accomplished on [[human mitochondrial DNA]] by sequencing the [[hypervariable control region]]s (HVR1 or HVR2), and sometimes the complete molecule of the mitochondrial DNA, as a [[genealogical DNA test]].<ref>{{Cite web |date=2016 |title=Hiring a DNA Testing Company Genealogy |url=https://familysearch.org/wiki/en/Hiring_a_DNA_Testing_Company |url-status=live |archive-url=https://web.archive.org/web/20161003102034/https://familysearch.org/wiki/en/Hiring_a_DNA_Testing_Company |archive-date=3 October 2016 |access-date=2016-10-02 |website=Family Search |publisher=The Church of Jesus Christ of Latter-day Saints}}</ref> HVR1, for example, consists of about 440 base pairs. These 440 base pairs are compared to the same regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made with the revised [[Cambridge Reference Sequence]]. Vilà ''et al.'' have published studies tracing the matrilineal descent of domestic dogs from wolves.<ref name="Vila">{{Cite journal |display-authors=6 |vauthors=Vilà C, Savolainen P, Maldonado JE, Amorim IR, Rice JE, Honeycutt RL, Crandall KA, Lundeberg J, Wayne RK |date=June 1997 |title=Multiple and ancient origins of the domestic dog |url=https://www.consevol.org/pdf/Vila_1997_Science_1.pdf |url-status=live |journal=Science |volume=276 |issue=5319 |pages=1687–1689 |doi=10.1126/science.276.5319.1687 |pmid=9180076 |archive-url=https://ghostarchive.org/archive/20221009/https://www.consevol.org/pdf/Vila_1997_Science_1.pdf |archive-date=2022-10-09}}</ref>
The concept of the [[Mitochondrial Eve]] is based on the same type of analysis, attempting to discover the origin of [[human]]ity by tracking the lineage back in time.{{cn|date=November 2024}}

=== The mitochondrial bottleneck ===
Entities subject to uniparental inheritance and with little to no recombination may be expected to be subject to [[Muller's ratchet]], the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this through a developmental process known as the [[Heteroplasmy#Mitochondrial bottleneck|mtDNA bottleneck]]. The bottleneck exploits [[cellular noise|random processes in the cell]] to increase the cell-to-cell variability in [[heteroplasmy|mutant load]] as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo in which different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated,<ref>{{Cite journal |vauthors=Wolff JN, White DJ, Woodhams M, White HE, Gemmell NJ |year=2011 |title=The strength and timing of the mitochondrial bottleneck in salmon suggests a conserved mechanism in vertebrates |journal=PLOS ONE |volume=6 |issue=5 |pages=e20522 |bibcode=2011PLoSO...620522W |doi=10.1371/journal.pone.0020522 |pmc=3105079 |pmid=21655224 |doi-access=free}}</ref><ref>{{Cite journal |display-authors=6 |vauthors=Cree LM, Samuels DC, de Sousa Lopes SC, Rajasimha HK, Wonnapinij P, Mann JR, Dahl HH, Chinnery PF |date=February 2008 |title=A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes |journal=Nature Genetics |volume=40 |issue=2 |pages=249–254 |doi=10.1038/ng.2007.63 |pmid=18223651 |s2cid=205344980}}</ref><ref>{{Cite journal |display-authors=6 |vauthors=Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H |date=March 2007 |title=The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells |journal=Nature Genetics |volume=39 |issue=3 |pages=386–390 |doi=10.1038/ng1970 |pmid=17293866 |s2cid=10686347}}</ref><ref>{{Cite journal |vauthors=Wai T, Teoli D, Shoubridge EA |date=December 2008 |title=The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes |journal=Nature Genetics |volume=40 |issue=12 |pages=1484–1488 |doi=10.1038/ng.258 |pmid=19029901 |s2cid=225349}}</ref> with a recent mathematical and experimental metastudy providing evidence for a combination of the random partitioning of mtDNAs at cell divisions and the random turnover of mtDNA molecules within the cell.<ref name="pmid26035426">{{Cite journal |display-authors=6 |vauthors=Johnston IG, Burgstaller JP, Havlicek V, Kolbe T, Rülicke T, Brem G, Poulton J, Jones NS |date=June 2015 |title=Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism |journal=eLife |volume=4 |pages=e07464 |arxiv=1512.02988 |doi=10.7554/eLife.07464 |pmc=4486817 |pmid=26035426 |doi-access=free}}</ref>

=== Male inheritance ===
{{Main|Paternal mtDNA transmission}}

Male mitochondrial DNA inheritance has been discovered in [[Plymouth Rock chicken]]s.<ref>{{Cite journal |display-authors=6 |vauthors=Alexander M, Ho SY, Molak M, Barnett R, Carlborg Ö, Dorshorst B, Honaker C, Besnier F, Wahlberg P, Dobney K, Siegel P, Andersson L, Larson G |date=October 2015 |title=Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance |journal=Biology Letters |volume=11 |issue=10 |page=20150561 |doi=10.1098/rsbl.2015.0561 |pmc=4650172 |pmid=26510672}}</ref> Evidence supports rare instances of male mitochondrial inheritance in some mammals as well.  Specifically, documented occurrences exist for mice,<ref>{{Cite journal |vauthors=Gyllensten U, Wharton D, Josefsson A, Wilson AC |date=July 1991 |title=Paternal inheritance of mitochondrial DNA in mice |journal=Nature |volume=352 |issue=6332 |pages=255–257 |bibcode=1991Natur.352..255G |doi=10.1038/352255a0 |pmid=1857422 |s2cid=4278149}}</ref><ref>{{Cite journal |vauthors=Shitara H, Hayashi JI, Takahama S, Kaneda H, Yonekawa H |date=February 1998 |title=Maternal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked paternal mtDNA followed by the prevention of subsequent paternal leakage |journal=Genetics |volume=148 |issue=2 |pages=851–857 |doi=10.1093/genetics/148.2.851 |pmc=1459812 |pmid=9504930}}</ref> where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep,<ref>{{Cite journal |display-authors=6 |vauthors=Zhao X, Li N, Guo W, Hu X, Liu Z, Gong G, Wang A, Feng J, Wu C |date=October 2004 |title=Further evidence for paternal inheritance of mitochondrial DNA in the sheep (Ovis aries) |journal=Heredity |volume=93 |issue=4 |pages=399–403 |doi=10.1038/sj.hdy.6800516 |pmid=15266295 |doi-access=free|bibcode=2004Hered..93..399Z }}</ref> and in cloned cattle.<ref>{{Cite journal |vauthors=Steinborn R, Zakhartchenko V, Jelyazkov J, Klein D, Wolf E, Müller M, Brem G |date=April 1998 |title=Composition of parental mitochondrial DNA in cloned bovine embryos |journal=FEBS Letters |volume=426 |issue=3 |pages=352–356 |bibcode=1998FEBSL.426..352S |doi=10.1016/S0014-5793(98)00350-0 |pmid=9600265 |doi-access=free}}</ref> Rare cases of male mitochondrial inheritance have been documented in humans.<ref>{{Cite journal |vauthors=Singh AN |date=April 2012 |title=A105 Family Decoded: Discovery of Genome-Wide Fingerprints for Personalized Genomic Medicine |journal=ScienceMED |volume=3 |issue=2 |pages=115–126}}</ref><ref>{{Cite journal |vauthors=Singh AN |date=May 2018 |title=Customized Biomedical Informatics |journal=Big Data Analytics |volume=3 |doi=10.1186/s41044-018-0030-3 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Schwartz M, Vissing J |date=August 2002 |title=Paternal inheritance of mitochondrial DNA |journal=The New England Journal of Medicine |volume=347 |issue=8 |pages=576–580 |doi=10.1056/NEJMoa020350 |pmid=12192017 |doi-access=free}}</ref><ref name="Biparental Inheritance of Mitochond" /> Although many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document ''[[in vivo]]'' inheritance and persistence under lab conditions.{{cn|date=November 2024}}

Doubly uniparental inheritance of mtDNA is observed in bivalve mollusks. In those species, females have only one type of mtDNA (F), whereas males have F-type mtDNA in their somatic cells, but M-type mtDNA (which can be as much as 30% divergent) in [[germline]] cells.<ref>{{Cite journal |vauthors=Passamonti M, Ghiselli F |date=February 2009 |title=Doubly uniparental inheritance: two mitochondrial genomes, one precious model for organelle DNA inheritance and evolution |journal=DNA and Cell Biology |volume=28 |issue=2 |pages=79–89 |doi=10.1089/dna.2008.0807 |pmid=19196051}}</ref> Paternally inherited mitochondria have additionally been reported in some insects such as [[Drosophila|fruit flies]],<ref>{{Cite journal |vauthors=Kondo R, Matsuura ET, Chigusa SI |date=April 1992 |title=Further observation of paternal transmission of Drosophila mitochondrial DNA by PCR selective amplification method |journal=Genetical Research |volume=59 |issue=2 |pages=81–84 |doi=10.1017/S0016672300030287 |pmid=1628820 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Wolff JN, Nafisinia M, Sutovsky P, Ballard JW |date=January 2013 |title=Paternal transmission of mitochondrial DNA as an integral part of mitochondrial inheritance in metapopulations of Drosophila simulans |journal=Heredity |volume=110 |issue=1 |pages=57–62 |doi=10.1038/hdy.2012.60 |pmc=3522233 |pmid=23010820|bibcode=2013Hered.110...57W }}</ref> [[honeybee]]s,<ref>{{Cite journal |vauthors=Meusel MS, Moritz RF |date=December 1993 |title=Transfer of paternal mitochondrial DNA during fertilization of honeybee (Apis mellifera L.) eggs |journal=Current Genetics |volume=24 |issue=6 |pages=539–543 |doi=10.1007/BF00351719 |pmid=8299176 |s2cid=15621371}}</ref> and [[Magicicada|periodical cicadas]].<ref>{{Cite journal |vauthors=Fontaine KM, Cooley JR, Simon C |date=September 2007 |title=Evidence for paternal leakage in hybrid periodical cicadas (Hemiptera: Magicicada spp.) |journal=PLOS ONE |volume=2 |issue=9 |pages=e892 |bibcode=2007PLoSO...2..892F |doi=10.1371/journal.pone.0000892 |pmc=1963320 |pmid=17849021 |doi-access=free}}</ref>

=== Mitochondrial donation ===
{{Main|Mitochondrial donation}}
An IVF technique known as mitochondrial donation or mitochondrial replacement therapy (MRT) results in offspring containing mtDNA from a donor female, and nuclear DNA from the mother and father. In the spindle transfer procedure, the nucleus of an egg is inserted into the cytoplasm of an egg from a donor female which has had its nucleus removed but still contains the donor female's mtDNA. The composite egg is then fertilized with the male's sperm. The procedure is used when a woman with [[Mitochondrial disease|genetically defective mitochondria]] wishes to procreate and produce offspring with healthy mitochondria.<ref name="Frith">{{Cite news |date=14 October 2003 |title=Ban on scientists trying to create three-parent baby |url=https://www.independent.co.uk/news/science/ban-on-scientists-trying-to-create-threeparent-baby-583284.html |work=The Independent |vauthors=Frith M}}{{Dead link|date=September 2021 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The first known child to be born as a result of mitochondrial donation was a boy born to a Jordanian couple in Mexico on 6 April 2016.<ref>{{Cite news |date=2016-09-27 |title=First 'three person baby' born using new method |url=https://www.bbc.co.uk/news/health-37485263 |url-status=live |archive-url=https://web.archive.org/web/20190530025518/https://www.bbc.co.uk/news/health-37485263 |archive-date=30 May 2019 |access-date=2016-09-28 |work=BBC News |language=en-GB |vauthors=Roberts M}}</ref>