Editing Germline

{{short description|Population of cells of a multicellular organism that pass on their genetic material to the progeny}}  
[[File:Watsonia meriana detail of cormlets on inflorescence IMG 6909.JPG|thumb|Cormlets of ''[[Watsonia meriana]]'', an example of [[apomixis]]]]
[[File:Clathria_tuberosa_(Sponge).jpg|thumb|''[[Clathria]] tuberosa'', an example of a sponge that can grow indefinitely from somatic tissue and reconstitute itself from [[Cell potency#Totipotency|totipotent]] separated somatic cells]]
In [[biology]] and [[genetics]], the '''germline''' is the population of a [[multicellular organism]]'s cells that develop into [[germ cell]]s. In other words, they are the cells that form [[gamete]]s ([[Egg cell|eggs]] and [[sperm]]), which can come together to form a [[zygote]]. They differentiate in the [[gonad]]s from [[Germ cell|primordial germ cells]] into [[Gametogonium|gametogonia]], which develop into [[gametocyte]]s, which develop into the final gametes.<ref>{{Cite journal |last1=Yao |first1=Chunmeng |last2=Yao |first2=Ruqiang |last3=Luo |first3=Haining |last4=Shuai |first4=Ling |date=2022 |title=Germline specification from pluripotent stem cells |journal=Stem Cell Research & Therapy |volume=13 |issue=1 |pages=74 |doi=10.1186/s13287-022-02750-1 |doi-access=free |pmc=8862564 |pmid=35189957}}</ref> This process is known as [[Gametogenesis#Stages|gametogenesis]].

Germ cells pass on genetic material through the process of sexual reproduction. This includes [[Fertilisation|fertilization]], [[Genetic recombination|recombination]] and [[meiosis]]. These processes help to increase genetic diversity in offspring.<ref>{{Cite journal |last1=Zickler |first1=Denise |last2=Kleckner |first2=Nancy |date=2015 |title=Recombination, Pairing, and Synapsis of Homologs during Meiosis |url=https://cshperspectives.cshlp.org/content/7/6/a016626 |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=7 |issue=6 |pages=a016626 |doi=10.1101/cshperspect.a016626 |pmc=4448610 |pmid=25986558}}</ref>

Certain organisms reproduce asexually via processes such as [[apomixis]], [[parthenogenesis]], [[autogamy]], and [[cloning]].<ref>{{Cite book |title=Fertilization in protozoa and metazoan animals: cellular and molecular aspects |date=2000 |publisher=Springer |isbn=978-3-540-67093-3 |editor-last=Tarín |editor-first=Juan J. |location=Berlin Heidelberg |editor-last2=Cano |editor-first2=Antonio}}</ref><ref>Lowe, Andrew; Harris, Stephen; Ashton, Paul (1 April 2000). ''Ecological Genetics: Design, Analysis, and Application''. John Wiley & Sons. {{ISBN|978-1-444-31121-1}}.</ref> Apomixis and Parthenogenesis both refer to the development of an embryo without fertilization. The former typically occurs in plants seeds, while the latter tends to be seen in nematodes, as well as certain species of reptiles, birds, and fish.<ref>{{Cite journal |last1=Niccolò |first1=Terzaroli |last2=Anderson |first2=Aaron W. |last3=Emidio |first3=Albertini |date=2023 |title=Apomixis: oh, what a tangled web we have! |journal=Planta |language=en |volume=257 |issue=5 |pages=92 |doi=10.1007/s00425-023-04124-0 |pmc=10066125 |pmid=37000270|bibcode=2023Plant.257...92N }}</ref><ref>{{Cite journal |last1=Dudgeon |first1=Christine L. |last2=Coulton |first2=Laura |last3=Bone |first3=Ren |last4=Ovenden |first4=Jennifer R. |last5=Thomas |first5=Severine |date=2017 |title=Switch from sexual to parthenogenetic reproduction in a zebra shark |journal=Scientific Reports |language=en |volume=7 |issue=1 |pages=40537 |doi=10.1038/srep40537 |pmc=5238396 |pmid=28091617|bibcode=2017NatSR...740537D }}</ref> Autogamy is a term used to describe self pollination in plants.<ref>{{Cite journal |last=Eckert |first=Christopher G. |date=February 2000 |title=Contributions of Autogamy and Geitonogamy to Self-Fertilization in a Mass-Flowering, Clonal Plant |url=http://doi.wiley.com/10.1890/0012-9658(2000)081[0532:COAAGT]2.0.CO;2 |journal=Ecology |language= |publisher=Ecological Society of America |volume=81 |issue=2 |pages=532–542 |doi=10.1890/0012-9658(2000)081[0532:COAAGT]2.0.CO;2 |issn=0012-9658 |via=John Wiley and Sons|url-access=subscription }}</ref> Cloning is a technique used to creation of genetically identical cells or organisms.<ref>{{Cite journal |last1=Bonetti |first1=G. |last2=Donato |first2=K. |last3=Medori |first3=M. C. |last4=Dhuli |first4=K. |last5=Henehan |first5=G. |last6=Brown |first6=R. |last7=Sieving |first7=P. |last8=Sykora |first8=P. |last9=Marks |first9=R. |last10=Falsini |first10=B. |last11=Capodicasa |first11=N. |last12=Miertus |first12=S. |last13=Lorusso |first13=L. |last14=Dondossola |first14=D. |last15=Tartaglia |first15=G. M. |date=2023 |title=Human Cloning: Biology, Ethics, and Social Implications |url=https://clinicaterapeutica.it/ojs/index.php/1/article/view/806/581 |journal=La Clinica Terapeutica |language=it |volume=174 |issue=6 |doi=10.7417/ct.2023.2492}}</ref>

In sexually reproducing organisms, cells that are not in the germline are called [[somatic cell]]s. According to this definition, [[mutation]]s, recombinations and other genetic changes in the germline may be passed to offspring, but changes in a somatic cell will not be.<ref>C.Michael Hogan. 2010. [http://www.eoearth.org/article/Mutation?topic=49496 ''Mutation''. ed. E.Monosson and C.J.Cleveland. Encyclopedia of Earth. National Council for Science and the Environment. Washington DC] {{webarchive |url=https://web.archive.org/web/20110430051516/http://www.eoearth.org/article/Mutation?topic=49496 |date=April 30, 2011 }}</ref> This need not apply to somatically reproducing organisms, such as some [[Sponge|Porifera]]<ref name="Brusca">{{cite book |author1=Brusca, Richard C.  |author2=Brusca, Gary J. | title = Invertebrates |url=https://archive.org/details/invertebrates0000brus  |url-access=registration  | publisher = Sinauer Associates | location = Sunderland | year = 1990 | isbn = 978-0878930982 }}</ref> and many plants. For example, many varieties of [[citrus]],<ref>{{Cite journal |last=Wakana |first=Akira |last2=Uemoto |first2=Shunpei |date=1988 |title=Adventive Embryogenesis in Citrus (Rutaceae). II. Postfertilization Development |url=https://www.jstor.org/stable/2443771 |journal=American Journal of Botany |volume=75 |issue=7 |pages=1033–1047 |doi=10.2307/2443771 |issn=0002-9122|url-access=subscription }}</ref> plants in the [[Rosaceae]] and some in the [[Asteraceae]], such as ''[[Taraxacum]]'', produce seeds apomictically when somatic [[diploid]] cells displace the ovule or early embryo.<ref name="Peter2009">{{cite book|author=K V Ed Peter|title=Basics Of Horticulture|url=https://books.google.com/books?id=NWMa741kG_gC&pg=PA9|date=5 February 2009|publisher=New India Publishing|isbn=978-81-89422-55-4|pages=9–}}</ref>

In an earlier stage of genetic thinking, there was a clear distinction between germline and somatic cells. For example, [[August Weismann]] proposed and pointed out, a germline cell is immortal in the sense that it is part of a lineage that has reproduced indefinitely since the beginning of life and, barring accident, could continue doing so indefinitely.<ref name="Weismann1892">{{cite book|author=August Weismann|title=Essays upon heredity and kindred biological problems|url=https://archive.org/details/essaysuponhered02weisgoog|year=1892|publisher=Clarendon press}}</ref> However, it is now known in some detail that this distinction between somatic and germ cells is partly artificial and depends on particular circumstances and internal cellular mechanisms such as [[telomeres]] and controls such as the selective application of [[telomerase]] in germ cells, [[stem cells]] and the like.<ref>Watt, F. M. and B. L. M. Hogan.  2000 Out of Eden: Stem Cells and Their Niches ''Science 287:1427-1430''.</ref>

Not all multicellular organisms [[Cellular differentiation|differentiate]] into somatic and germ lines,<ref name=":0">{{Cite journal|last1=Radzvilavicius|first1=Arunas L.|last2=Hadjivasiliou|first2=Zena|last3=Pomiankowski|first3=Andrew|last4=Lane|first4=Nick|date=2016-12-20|title=Selection for Mitochondrial Quality Drives Evolution of the Germline|journal=PLOS Biology|volume=14|issue=12|pages=e2000410|doi=10.1371/journal.pbio.2000410|issn=1545-7885|pmc=5172535|pmid=27997535 |doi-access=free }}</ref> but in the absence of specialised technical human intervention practically all but the simplest multicellular structures do so. In such organisms somatic cells tend to be practically [[Cell potency#Totipotency|totipotent]], and for over a century sponge cells have been known to reassemble into new sponges after having been separated by forcing them through a sieve.<ref name= "Brusca"/>

''Germline'' can refer to a lineage of cells spanning many generations of individuals—for example, the germline that links any living individual to the hypothetical [[last universal common ancestor]], from which all plants and animals [[common descent|descend]].

== Evolution ==
Plants and basal metazoans such as sponges (Porifera) and corals (Anthozoa) do not sequester a distinct germline, generating gametes from multipotent stem cell lineages that also give rise to ordinary somatic tissues. It is therefore likely that germline sequestration first evolved in complex animals with sophisticated body plans, i.e. bilaterians. There are several theories on the origin of the strict germline-soma distinction. Setting aside an isolated germ cell population early in embryogenesis might promote cooperation between the somatic cells of a complex multicellular organism.<ref>{{Cite journal|last1=Buss|first1=L W|date=1983-03-01|title=Evolution, development, and the units of selection.|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=80|issue=5|pages=1387–1391|issn=0027-8424|pmc=393602|pmid=6572396|doi=10.1073/pnas.80.5.1387|bibcode=1983PNAS...80.1387B|doi-access=free}}</ref> Another recent theory suggests that early germline sequestration evolved to limit the accumulation of deleterious mutations in mitochondrial genes in complex organisms with high energy requirements and fast mitochondrial mutation rates.<ref name=":0" />

==DNA damage, mutation and repair==

[[Reactive oxygen species]] (ROS) are produced as byproducts of metabolism.  In germline cells, ROS are likely a significant cause of [[DNA damage (naturally occurring)|DNA damage]]s that, upon [[DNA replication]], lead to [[mutation]]s.  [[8-Oxoguanine]], an oxidized derivative of [[guanine]], is produced by spontaneous oxidation in the germline cells of mice, and during the cell's DNA replication cause GC to TA [[transversion]] mutations.<ref name="pmid24732879">{{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=Sci Rep |volume=4 |pages=4689 |year=2014 |pmid=24732879 |pmc=3986730 |doi=10.1038/srep04689 |bibcode=2014NatSR...4E4689O }}</ref>  Such mutations occur throughout the mouse [[chromosome]]s as well as during different stages of [[gametogenesis]].

The mutation frequencies for cells in different stages of gametogenesis are about 5 to 10-fold lower than in [[somatic cell]]s both for [[spermatogenesis]]<ref name="pmid9707592">{{cite journal |vauthors=Walter CA, Intano GW, McCarrey JR, McMahan CA, Walter RB |title=Mutation frequency declines during spermatogenesis in young mice but increases in old mice |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue=17 |pages=10015–9 |year=1998 |pmid=9707592 |pmc=21453 |doi= 10.1073/pnas.95.17.10015|bibcode=1998PNAS...9510015W |doi-access=free }}</ref> and [[oogenesis]].<ref name="pmid23153565">{{cite journal |vauthors=Murphey P, McLean DJ, McMahan CA, Walter CA, McCarrey JR |title=Enhanced genetic integrity in mouse germ cells |journal=Biol. Reprod. |volume=88 |issue=1 |pages=6 |year=2013 |pmid=23153565 |pmc=4434944 |doi=10.1095/biolreprod.112.103481 }}</ref>  The lower frequencies of mutation in germline cells compared to somatic cells appears to be due to more efficient [[DNA repair]] of DNA damages, particularly [[homologous recombination]]al repair, during germline [[meiosis]].<ref>Bernstein H, Byerly HC, Hopf FA, Michod RE. Genetic damage, mutation, and the evolution of sex. Science. 1985 Sep 20;229(4719):1277-81. doi: 10.1126/science.3898363. PMID 3898363</ref>  Among humans, about five percent of live-born offspring have a genetic disorder, and of these, about 20% are due to newly arisen [[germline mutation]]s.<ref name="pmid9707592" />

==Epigenetic alterations==

[[File:5 methylcytosine methyl highlight.png|thumb|300px|5 methylcytosine methyl highlight.  The image shows a cytosine single ring base and a methyl group added on to the 5 carbon. In mammals, DNA methylation occurs almost exclusively at a cytosine that is followed by a [[guanine]].]]
[[Epigenetics|Epigenetic alterations]] of DNA include modifications that affect gene expression, but are not caused by changes in the sequence of bases in DNA.  A well-studied example of such an alteration is the [[methylation]] of DNA cytosine to form [[5-methylcytosine]].  This usually occurs in the DNA sequence [[CpG site|CpG]], changing the DNA at the [[CpG site]] from CpG to 5-mCpG.  Methylation of cytosines in CpG sites in [[Promoter (genetics)|promoter]] regions of genes can reduce or silence gene expression.<ref name="pmid11782440">{{cite journal |vauthors=Bird A |title=DNA methylation patterns and epigenetic memory |journal=Genes Dev |volume=16 |issue=1 |pages=6–21 |date=January 2002 |pmid=11782440 |doi=10.1101/gad.947102 |url=|doi-access=free }}</ref>  About 28 million CpG dinucleotides occur in the human genome,<ref name="pmid26932361">{{cite journal |vauthors=Lövkvist C, Dodd IB, Sneppen K, Haerter JO |title=DNA methylation in human epigenomes depends on local topology of CpG sites |journal=Nucleic Acids Res |volume=44 |issue=11 |pages=5123–32 |date=June 2016 |pmid=26932361 |pmc=4914085 |doi=10.1093/nar/gkw124 |url=}}</ref> and about 24 million CpG sites in the mouse genome (which is 86% as large as the human genome<ref name="pmid16339371">{{cite journal |vauthors=Guénet JL |title=The mouse genome |journal=Genome Res |volume=15 |issue=12 |pages=1729–40 |date=December 2005 |pmid=16339371 |doi=10.1101/gr.3728305 |url=|doi-access=free }}</ref>).  In most tissues of mammals, on average, 70% to 80% of CpG cytosines are methylated (forming 5-mCpG).<ref name="pmid15177689">{{cite journal |vauthors=Jabbari K, Bernardi G |title=Cytosine methylation and CpG, TpG (CpA) and TpA frequencies |journal=Gene |volume=333 |issue= |pages=143–9 |date=May 2004 |pmid=15177689 |doi=10.1016/j.gene.2004.02.043 |url=}}</ref>

In the mouse, by days 6.25 to 7.25 after fertilization of an egg by a sperm, cells in the embryo are set aside as primordial germ cells (PGCs).  These PGCs will later give rise to germline sperm cells or egg cells.  At this point the PGCs have high typical levels of methylation.  Then primordial germ cells of the mouse undergo genome-wide DNA [[demethylation]], followed by subsequent new methylation to reset the [[epigenome]] in order to form an egg or sperm.<ref name=Zeng>{{cite journal |vauthors=Zeng Y, Chen T |title=DNA Methylation Reprogramming during Mammalian Development |journal=Genes (Basel) |volume=10 |issue=4 |date=March 2019 |page=257 |pmid=30934924 |pmc=6523607 |doi=10.3390/genes10040257 |url=|doi-access=free }}</ref>

In the mouse, PGCs undergo DNA demethylation in two phases. The first phase, starting at about embryonic day 8.5, occurs during PGC proliferation and migration, and it results in genome-wide loss of methylation, involving '''almost''' all genomic sequences.  This loss of methylation occurs through passive demethylation due to repression of the major components of the methylation machinery.<ref name=Zeng />  The second phase occurs during embryonic days 9.5 to 13.5 and causes demethylation of most remaining specific loci, including germline-specific and meiosis-specific genes.  This second phase of demethylation is mediated by the [[TET enzymes]] TET1 and TET2, which carry out the first step in demethylation by converting 5-mC to [[5-hydroxymethylcytosine]] (5-hmC) during embryonic days 9.5 to 10.5.  This is likely followed by replication-dependent dilution during embryonic days 11.5 to 13.5.<ref name=Yamaguchi>{{cite journal |vauthors=Yamaguchi S, Hong K, Liu R, Inoue A, Shen L, Zhang K, Zhang Y |title=Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming |journal=Cell Res |volume=23 |issue=3 |pages=329–39 |date=March 2013 |pmid=23399596 |pmc=3587712 |doi=10.1038/cr.2013.22 |url=}}</ref>  At embryonic day 13.5, PGC genomes display the lowest level of global DNA methylation of all cells in the life cycle.<ref name=Zeng />

In the mouse, the great majority of differentially expressed genes in PGCs from embryonic day 9.5 to 13.5, when most genes are demethylated, are upregulated in both male and female PGCs.<ref name=Yamaguchi />

Following erasure of DNA methylation marks in mouse PGCs, male and female germ cells undergo new methylation at different time points during gametogenesis. While undergoing mitotic expansion in the developing gonad, the male germline starts the re-methylation process by embryonic day 14.5. The sperm-specific methylation pattern is maintained during mitotic expansion.  DNA methylation levels in primary oocytes before birth remain low, and re-methylation occurs after birth in the oocyte growth phase.<ref name=Zeng />

== See also ==
* [[Epigenetics]]
* [[Germ line development]]
* [[Germinal choice technology]]
* [[August Weismann]]
* [[Weismann barrier]]

==References==
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[[Category:Developmental biology]]
[[Category:Germ cells|*]]