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{{Infobox_gene}}
{{Infobox_gene}}


'''PR domain<ref group="note">positive-regulatory domain</ref> zinc finger protein 9''' is a [[protein]] that in humans is encoded by the ''Prdm9'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PR domain containing 9| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=56979| accessdate = }}</ref> The protein has [[histone]] H3K4 trimethyltransferase activity, a [[Krüppel associated box|KRAB]] domain, and a [[DNA-binding domain]] consisting of multiple tandem [[zinc finger#Cys2His2|C2H2]] [[zinc finger]] (ZF) domains.<ref name="pmid20041164">{{cite journal |vauthors=Thomas JH, Emerson RO, Shendure J | title = Extraordinary molecular evolution in the PRDM9 fertility gene | journal = PLoS ONE | volume = 4 | issue = 12 | pages = e8505 | year = 2009 | pmid = 20041164 | pmc = 2794550 | doi = 10.1371/journal.pone.0008505 }} {{open access}}</ref> PRDM9 specifically trimethylates lysine 4 of histone H3 during meiotic prophase and is essential for proper meiotic progression, but does not have the ability to mono- and dimethylate lysine 4 of histone H3.
'''PR domain<ref group="note">positive-regulatory domain</ref> zinc finger protein 9''' is a [[protein]] that in humans is encoded by the ''Prdm9'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PR domain containing 9| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=56979| accessdate = }}</ref> PRDM9 is responsible for positioning [[recombination hotspot]]s during [[meiosis]] by binding a DNA sequence motif encoded in its zinc finger domain.<ref name=":0">{{cite journal | vauthors = Cheung VG, Sherman SL, Feingold E | title = Genetics. Genetic control of hotspots | journal = Science | volume = 327 | issue = 5967 | pages = 791–2 | date = February 2010 | pmid = 20150474 | doi = 10.1126/science.1187155 }}</ref> PRDM9 is the only [[Speciation#Genetics|speciation gene]] found so far in mammals, and is one of the fastest evolving genes in the genome.<ref>{{Cite web|url=https://royalsociety.org/science-events-and-lectures/2017/12/francis-crick-lecture/|title=There are millions of different species worldwide. But how do new species first appear, and then remain separate?|website=royalsociety.org-gb|access-date=2017-12-10}}</ref><ref>{{cite journal | vauthors = Ponting CP | title = What are the genomic drivers of the rapid evolution of PRDM9? | journal = Trends in Genetics | volume = 27 | issue = 5 | pages = 165–71 | date = May 2011 | pmid = 21388701 | doi = 10.1016/j.tig.2011.02.001 }}</ref>
H3K4 methylation represents a specific tag for epigenetic transcriptional activation which plays a central role in the transcriptional activation of genes during early meiotic prophase.


==Function==
==Domain Architecture==
PRDM9 is thought to mediate the process of [[Recombination hotspot|meiotic homologous recombination]].<ref name="pmid21460839">{{cite journal |vauthors=Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, Petukhova GV | title = Genome-wide analysis reveals novel molecular features of mouse recombination hotspots | journal = Nature | volume = 472 | issue = 7343 | pages = 375–8 |date=April 2011 | pmid = 21460839 | doi = 10.1038/nature09869 | pmc=3117304}}</ref>
[[File:PRDM9_Domain_Architechture.png|left|thumb|Schematic of the PRDM9 Domain Architecture in mice]]
PRDM9 has multiple domains including [[Krüppel associated box|KRAB]] domain, SSXRD, [[SET domain|PR/SET]] domain ([[Histone#Actively transcribed genes|H3K4 & H3K36 trimethyltransferase]]), and an array of C2H2 [[Zinc finger|Zinc Finger]] domains (DNA binding).<ref name="pmid20041164">{{cite journal | vauthors = Thomas JH, Emerson RO, Shendure J | title = Extraordinary molecular evolution in the PRDM9 fertility gene | journal = PLOS One | volume = 4 | issue = 12 | pages = e8505 | date = December 2009 | pmid = 20041164 | pmc = 2794550 | doi = 10.1371/journal.pone.0008505 }} {{open access}}</ref>


==Recombination hotspots==
== History ==
In humans and mice, recombination occurs at elevated rates at particular sites along the chromosomes called [[recombination hotspot]]s. Hotspots are regions of DNA about [[Base pair#Length measurements|1-2kb]] in length.<ref name=Myers>{{cite journal |vauthors=Myers S, Spencer CC, Auton A, Bottolo L, Freeman C, Donnelly P, McVean G |title=The distribution and causes of meiotic recombination in the human genome |journal=Biochem. Soc. Trans. |volume=34 |issue=Pt 4 |pages=526–30 |year=2006 |pmid=16856851 |doi=10.1042/BST0340526 |url=}}</ref>  There are approximately 30,000 to 50,000 hotspots within the human [[genome]] corresponding to one for every 50-100kb DNA on average.<ref name=Myers />  In humans, the average number of crossover recombination events per hotspot is one per 1,300 [[Meiosis|meioses]], and the most extreme hotspot has a crossover frequency of one per 110 meioses.<ref name=Myers />  These hotspots are predicted binding sites for PRDM9 protein.<ref name="pmid25395519">{{cite journal |vauthors=de Massy B |title=Human genetics. Hidden features of human hotspots |journal=Science |volume=346 |issue=6211 |pages=808–9 |year=2014 |pmid=25395519 |doi=10.1126/science.aaa0612 |url=}}</ref>
In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility.<ref name="pmid4452481">{{cite journal | vauthors = Forejt J, Iványi P | title = Genetic studies on male sterility of hybrids between laboratory and wild mice (Mus musculus L.) | journal = Genetical Research | volume = 24 | issue = 2 | pages = 189–206 | year = 1974 | pmid = 4452481 | doi = 10.1017/S0016672300015214 }}</ref>


PRDM9 is a [[meiosis]] specific [[histone methyltransferase]] and, upon binding to DNA, it catalyzes [[Histone#Trimethylation of H3 lysine 4 (H3K4Me3)|trimethylation of histone H3 at lysine 4]].<ref name="pmid25568937">{{cite journal |vauthors=Baker CL, Kajita S, Walker M, Saxl RL, Raghupathy N, Choi K, Petkov PM, Paigen K |title=PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination |journal=PLoS Genet. |volume=11 |issue=1 |pages=e1004916 |year=2015 |pmid=25568937 |pmc=4287450 |doi=10.1371/journal.pgen.1004916 |url=}}</ref>  As a result, local nucleosomes are reorganized.  This reorganization is apparently associated with increased probability of recombination.
In 1982 a haplotype was identified controlling recombination rate ''wm7'',<ref name="pmid6815537">{{cite journal | vauthors = Shiroishi T, Sagai T, Moriwaki K | title = A new wild-derived H-2 haplotype enhancing K-IA recombination | journal = Nature | volume = 300 | issue = 5890 | pages = 370–2 | year = 1982 | pmid = 6815537 | doi = 10.1038/300370a0 }}</ref> which would later be identified as PRDM9.<ref>{{cite journal | vauthors = Kono H, Tamura M, Osada N, Suzuki H, Abe K, Moriwaki K, Ohta K, Shiroishi T | title = Prdm9 polymorphism unveils mouse evolutionary tracks | journal = DNA Research | volume = 21 | issue = 3 | pages = 315–26 | date = June 2014 | pmid = 24449848 | doi = 10.1093/dnares/dst059 | pmc=4060951}}</ref>
 
In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3).<ref>{{cite journal | vauthors = Wahls WP, Swenson G, Moore PD | title = Two hypervariable minisatellite DNA binding proteins | journal = Nucleic Acids Research | volume = 19 | issue = 12 | pages = 3269–74 | date = June 1991 | pmid = 2062643 | pmc = 328321 | doi=10.1093/nar/19.12.3269}}</ref> This would later turn out to be the same PRDM9 protein independently identified later.<ref>{{cite journal | vauthors = Wahls WP, Davidson MK | title = DNA sequence-mediated, evolutionarily rapid redistribution of meiotic recombination hotspots | journal = Genetics | volume = 189 | issue = 3 | pages = 685–94 | date = November 2011 | pmid = 22084420 | doi = 10.1534/genetics.111.134130 | pmc=3213376}}</ref>
 
In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity.<ref>{{cite journal | vauthors = Hayashi K, Yoshida K, Matsui Y | title = A histone H3 methyltransferase controls epigenetic events required for meiotic prophase | journal = Nature | volume = 438 | issue = 7066 | pages = 374–8 | date = November 2005 | pmid = 16292313 | doi = 10.1038/nature04112 }}</ref>
 
In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.<ref>{{cite journal | vauthors = Mihola O, Trachtulec Z, Vlcek C, Schimenti JC, Forejt J | title = A mouse speciation gene encodes a meiotic histone H3 methyltransferase | journal = Science | volume = 323 | issue = 5912 | pages = 373–5 | date = January 2009 | pmid = 19074312 | doi = 10.1126/science.1163601 }}</ref>
 
Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome.<ref name="pmid20041164" /><ref>{{cite journal | vauthors = Oliver PL, Goodstadt L, Bayes JJ, Birtle Z, Roach KC, Phadnis N, Beatson SA, Lunter G, Malik HS, Ponting CP | title = Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa | journal = PLoS Genetics | volume = 5 | issue = 12 | pages = e1000753 | date = December 2009 | pmid = 19997497 | doi = 10.1371/journal.pgen.1000753 | pmc=2779102}}</ref>
 
In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice.<ref name=":0" /><ref>{{cite journal | vauthors = Neale MJ | title = PRDM9 points the zinc finger at meiotic recombination hotspots | journal = Genome Biology | volume = 11 | issue = 2 | pages = 104 | date = 2010-02-26 | pmid = 20210982 | doi = 10.1186/gb-2010-11-2-104 | pmc=2872867}}</ref><ref>{{cite journal | vauthors = Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P | title = Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination | journal = Science | volume = 327 | issue = 5967 | pages = 876–9 | date = February 2010 | pmid = 20044541 | doi = 10.1126/science.1182363 }}</ref><ref>{{cite journal | vauthors = Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, de Massy B | title = PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice | journal = Science | volume = 327 | issue = 5967 | pages = 836–40 | date = February 2010 | pmid = 20044539 | doi = 10.1126/science.1183439 }}</ref><ref>{{cite journal | vauthors = Parvanov ED, Petkov PM, Paigen K | title = Prdm9 controls activation of mammalian recombination hotspots | journal = Science | volume = 327 | issue = 5967 | pages = 835 | date = February 2010 | pmid = 20044538 | doi = 10.1126/science.1181495 | pmc=2821451}}</ref>
 
in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters.<ref>{{cite journal | vauthors = Brick K, Smagulova F, Khil P, Camerini-Otero RD, Petukhova GV | title = Genetic recombination is directed away from functional genomic elements in mice | journal = Nature | volume = 485 | issue = 7400 | pages = 642–5 | date = May 2012 | pmid = 22660327 | doi = 10.1038/nature11089 | pmc=3367396}}</ref>
 
In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro,<ref>{{cite journal | vauthors = Eram MS, Bustos SP, Lima-Fernandes E, Siarheyeva A, Senisterra G, Hajian T, Chau I, Duan S, Wu H, Dombrovski L, Schapira M, Arrowsmith CH, Vedadi M | title = Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein | journal = The Journal of Biological Chemistry | volume = 289 | issue = 17 | pages = 12177–88 | date = April 2014 | pmid = 24634223 | doi = 10.1074/jbc.M113.523183 | pmc=4002121}}</ref> which was confirmed in vivo in 2016.<ref>{{cite journal | vauthors = Powers NR, Parvanov ED, Baker CL, Walker M, Petkov PM, Paigen K | title = The Meiotic Recombination Activator PRDM9 Trimethylates Both H3K36 and H3K4 at Recombination Hotspots In Vivo | journal = PLoS Genetics | volume = 12 | issue = 6 | pages = e1006146 | date = June 2016 | pmid = 27362481 | doi = 10.1371/journal.pgen.1006146 | pmc=4928815}}</ref>
 
In 2016 it was shown that the hybrid sterility caused by PRDM9 can be reversed and that the sterility is caused by asymmetric double strand breaks.<ref>{{cite journal | vauthors = Davies B, Hatton E, Altemose N, Hussin JG, Pratto F, Zhang G, Hinch AG, Moralli D, Biggs D, Diaz R, Preece C, Li R, Bitoun E, Brick K, Green CM, Camerini-Otero RD, Myers SR, Donnelly P | title = Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice | journal = Nature | volume = 530 | issue = 7589 | pages = 171–176 | date = February 2016 | pmid = 26840484 | doi = 10.1038/nature16931 | pmc=4756437}}</ref><ref>{{cite journal | vauthors = Forejt J | title = Genetics: Asymmetric breaks in DNA cause sterility | journal = Nature | volume = 530 | issue = 7589 | pages = 167–8 | date = February 2016 | pmid = 26840487 | doi = 10.1038/nature16870 }}</ref>
 
==Function in Recombination==
PRDM9 mediates the process of meiosis by directing the sites of homologous recombination.<ref name="pmid21460839">{{cite journal | vauthors = Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, Petukhova GV | title = Genome-wide analysis reveals novel molecular features of mouse recombination hotspots | journal = Nature | volume = 472 | issue = 7343 | pages = 375–8 | date = April 2011 | pmid = 21460839 | pmc = 3117304 | doi = 10.1038/nature09869 }}</ref> In humans and mice, recombination does not occur evenly throughout the genome but at particular sites along the chromosomes called [[recombination hotspot]]s.  Hotspots are regions of DNA about [[Base pair#Length measurements|1-2kb]] in length.<ref name="Myers">{{cite journal | vauthors = Myers S, Spencer CC, Auton A, Bottolo L, Freeman C, Donnelly P, McVean G | title = The distribution and causes of meiotic recombination in the human genome | journal = Biochemical Society Transactions | volume = 34 | issue = Pt 4 | pages = 526–30 | date = August 2006 | pmid = 16856851 | doi = 10.1042/BST0340526 }}</ref>  There are approximately 30,000 to 50,000 hotspots within the human [[genome]] corresponding to one for every 50-100kb DNA on average.<ref name="Myers" />  In humans, the average number of crossover recombination events per hotspot is one per 1,300 [[Meiosis|meioses]], and the most extreme hotspot has a crossover frequency of one per 110 meioses.<ref name="Myers" />  These hotspots are binding sites for the PRDM9 Zinc Finger array.<ref name="pmid25395519">{{cite journal | vauthors = de Massy B | title = Human genetics. Hidden features of human hotspots | journal = Science | volume = 346 | issue = 6211 | pages = 808–9 | date = November 2014 | pmid = 25395519 | doi = 10.1126/science.aaa0612 }}</ref> Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and Histone 4 at lysine 36.<ref name="pmid25568937">{{cite journal | vauthors = Baker CL, Kajita S, Walker M, Saxl RL, Raghupathy N, Choi K, Petkov PM, Paigen K | title = PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination | journal = PLoS Genetics | volume = 11 | issue = 1 | pages = e1004916 | date = January 2015 | pmid = 25568937 | pmc = 4287450 | doi = 10.1371/journal.pgen.1004916 }}</ref>  As a result, local nucleosomes are reorganized and through an unknown mechanism the recombination machinery is recruited to form double strand breaks.


==Notes==
==Notes==
{{Reflist|group=note}}
{{Reflist|group=note}}


==References==
== References ==
{{Reflist}}
{{Reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal   |vauthors=Baudat F, Buard J, Grey C, etal |title=PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. |journal=Science |volume=327 |issue= 5967 |pages= 836–40 |year= 2010 |pmid= 20044539 |doi= 10.1126/science.1183439 }}
* {{cite journal | vauthors = Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, de Massy B | title = PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice | journal = Science | volume = 327 | issue = 5967 | pages = 836–40 | date = February 2010 | pmid = 20044539 | doi = 10.1126/science.1183439 }}
*{{cite journal   |vauthors=Berg IL, Neumann R, Lam KW, etal |title=PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. |journal=Nat. Genet. |volume=42 |issue= 10 |pages= 859–63 |year= 2010 |pmid= 20818382 |doi= 10.1038/ng.658 |pmc=3092422}}
* {{cite journal | vauthors = Berg IL, Neumann R, Lam KW, Sarbajna S, Odenthal-Hesse L, May CA, Jeffreys AJ | title = PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans | journal = Nature Genetics | volume = 42 | issue = 10 | pages = 859–63 | date = October 2010 | pmid = 20818382 | pmc = 3092422 | doi = 10.1038/ng.658 }}
*{{cite journal   |vauthors=Irie S, Tsujimura A, Miyagawa Y, etal |title=Single-nucleotide polymorphisms of the PRDM9 (MEISETZ) gene in patients with nonobstructive azoospermia. |journal=J. Androl. |volume=30 |issue= 4 |pages= 426–31 |year= 2009|pmid= 19168450 |doi= 10.2164/jandrol.108.006262 }}
* {{cite journal | vauthors = Irie S, Tsujimura A, Miyagawa Y, Ueda T, Matsuoka Y, Matsui Y, Okuyama A, Nishimune Y, Tanaka H | title = Single-nucleotide polymorphisms of the PRDM9 (MEISETZ) gene in patients with nonobstructive azoospermia | journal = Journal of Andrology | volume = 30 | issue = 4 | pages = 426–31 | year = 2009 | pmid = 19168450 | doi = 10.2164/jandrol.108.006262 }}
*{{cite journal   |vauthors=Sun XJ, Xu PF, Zhou T, etal |title=Genome-wide survey and developmental expression mapping of zebrafish SET domain-containing genes. |journal=PLoS ONE |volume=3 |issue= 1 |pages= e1499 |year= 2008 |pmid= 18231586 |doi= 10.1371/journal.pone.0001499 |pmc=2200798}} {{open access}}
* {{cite journal | vauthors = Sun XJ, Xu PF, Zhou T, Hu M, Fu CT, Zhang Y, Jin Y, Chen Y, Chen SJ, Huang QH, Liu TX, Chen Z | title = Genome-wide survey and developmental expression mapping of zebrafish SET domain-containing genes | journal = PLOS One | volume = 3 | issue = 1 | pages = e1499 | date = January 2008 | pmid = 18231586 | pmc = 2200798 | doi = 10.1371/journal.pone.0001499 }}
*{{cite journal |vauthors=Xiao B, Wilson JR, Gamblin SJ |title=SET domains and histone methylation. |journal=Curr. Opin. Struct. Biol. |volume=13 |issue= 6 |pages= 699–705 |year= 2003 |pmid= 14675547 |doi= 10.1016/j.sbi.2003.10.003 }}
* {{cite journal | vauthors = Xiao B, Wilson JR, Gamblin SJ | title = SET domains and histone methylation | journal = Current Opinion in Structural Biology | volume = 13 | issue = 6 | pages = 699–705 | date = December 2003 | pmid = 14675547 | doi = 10.1016/j.sbi.2003.10.003 }}
*{{cite journal |vauthors=Wahls WP, Swenson G, Moore PD |title=Two hypervariable minisatellite DNA binding proteins. |journal=Nucleic Acids Res. |volume=19 |issue= 12 |pages= 3269–74 |year= 1991 |pmid= 2062643 |PMC=328321|doi= 10.1093/nar/19.12.3269 }}
* {{cite journal | vauthors = Wahls WP, Swenson G, Moore PD | title = Two hypervariable minisatellite DNA binding proteins | journal = Nucleic Acids Research | volume = 19 | issue = 12 | pages = 3269–74 | date = June 1991 | pmid = 2062643 | doi = 10.1093/nar/19.12.3269 | PMC = 328321 }}
*{{cite journal |vauthors=Jiang GL, Huang S |title=The yin-yang of PR-domain family genes in tumorigenesis. |journal=Histol. Histopathol. |volume=15 |issue= 1 |pages= 109–17 |year= 2000 |pmid= 10668202 |doi=  }}
* {{cite journal | vauthors = Jiang GL, Huang S | title = The yin-yang of PR-domain family genes in tumorigenesis | journal = Histology and Histopathology | volume = 15 | issue = 1 | pages = 109–17 | date = January 2000 | pmid = 10668202 | doi =  }}
*{{cite journal |vauthors=Parvanov ED, Petkov PM, Paigen K |title=Prdm9 controls activation of mammalian recombination hotspots. |journal=Science |volume=327 |issue= 5967 |pages= 835 |year= 2010 |pmid= 20044538 |doi= 10.1126/science.1181495 |pmc=2821451}}
* {{cite journal | vauthors = Parvanov ED, Petkov PM, Paigen K | title = Prdm9 controls activation of mammalian recombination hotspots | journal = Science | volume = 327 | issue = 5967 | pages = 835 | date = February 2010 | pmid = 20044538 | pmc = 2821451 | doi = 10.1126/science.1181495 }}
*{{cite journal   |vauthors=Myers S, Bowden R, Tumian A, etal |title=Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. |journal=Science |volume=327 |issue= 5967 |pages= 876–9 |year= 2010 |pmid= 20044541 |doi= 10.1126/science.1182363 }}
* {{cite journal | vauthors = Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P | title = Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination | journal = Science | volume = 327 | issue = 5967 | pages = 876–9 | date = February 2010 | pmid = 20044541 | doi = 10.1126/science.1182363 }}
*{{cite journal   |vauthors=Miyamoto T, Koh E, Sakugawa N, etal |title=Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest. |journal=J. Assist. Reprod. Genet. |volume=25 |issue= 11–12 |pages= 553–7 |year= 2008|pmid= 18941885 |doi= 10.1007/s10815-008-9270-x |pmc=2593767}}
* {{cite journal | vauthors = Miyamoto T, Koh E, Sakugawa N, Sato H, Hayashi H, Namiki M, Sengoku K | title = Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest | journal = Journal of Assisted Reproduction and Genetics | volume = 25 | issue = 11–12 | pages = 553–7 | year = 2008 | pmid = 18941885 | pmc = 2593767 | doi = 10.1007/s10815-008-9270-x }}
*{{cite journal   |vauthors=Hussin J, Sinnett D, Casals F, etal |title=Rare allelic forms of PRDM9 associated with childhood leukemogenesis. |journal=Genome Res. |volume=23 |issue= 3 |pages= 419–30 |year= 2013 |pmid= 23222848 |doi= 10.1101/gr.144188.112 |pmc=3589531}}
* {{cite journal | vauthors = Hussin J, Sinnett D, Casals F, Idaghdour Y, Bruat V, Saillour V, Healy J, Grenier JC, de Malliard T, Busche S, Spinella JF, Larivière M, Gibson G, Andersson A, Holmfeldt L, Ma J, Wei L, Zhang J, Andelfinger G, Downing JR, Mullighan CG, Awadalla P | title = Rare allelic forms of PRDM9 associated with childhood leukemogenesis | journal = Genome Research | volume = 23 | issue = 3 | pages = 419–30 | date = March 2013 | pmid = 23222848 | pmc = 3589531 | doi = 10.1101/gr.144188.112 }}
{{refend}}
{{refend}}


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Latest revision as of 07:49, 20 October 2018

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PR domain[note 1] zinc finger protein 9 is a protein that in humans is encoded by the Prdm9 gene.[1] PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain.[2] PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.[3][4]

Domain Architecture

File:PRDM9 Domain Architechture.png
Schematic of the PRDM9 Domain Architecture in mice

PRDM9 has multiple domains including KRAB domain, SSXRD, PR/SET domain (H3K4 & H3K36 trimethyltransferase), and an array of C2H2 Zinc Finger domains (DNA binding).[5]

History

In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility.[6]

In 1982 a haplotype was identified controlling recombination rate wm7,[7] which would later be identified as PRDM9.[8]

In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3).[9] This would later turn out to be the same PRDM9 protein independently identified later.[10]

In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity.[11]

In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.[12]

Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome.[5][13]

In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice.[2][14][15][16][17]

in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters.[18]

In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro,[19] which was confirmed in vivo in 2016.[20]

In 2016 it was shown that the hybrid sterility caused by PRDM9 can be reversed and that the sterility is caused by asymmetric double strand breaks.[21][22]

Function in Recombination

PRDM9 mediates the process of meiosis by directing the sites of homologous recombination.[23] In humans and mice, recombination does not occur evenly throughout the genome but at particular sites along the chromosomes called recombination hotspots. Hotspots are regions of DNA about 1-2kb in length.[24] There are approximately 30,000 to 50,000 hotspots within the human genome corresponding to one for every 50-100kb DNA on average.[24] In humans, the average number of crossover recombination events per hotspot is one per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses.[24] These hotspots are binding sites for the PRDM9 Zinc Finger array.[25] Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and Histone 4 at lysine 36.[26] As a result, local nucleosomes are reorganized and through an unknown mechanism the recombination machinery is recruited to form double strand breaks.

Notes

  1. ↑ positive-regulatory domain

References

  1. ↑ "Entrez Gene: PR domain containing 9".
  2. ↑ 2.0 2.1 Cheung VG, Sherman SL, Feingold E (February 2010). "Genetics. Genetic control of hotspots". Science. 327 (5967): 791–2. doi:10.1126/science.1187155. PMID 20150474.
  3. ↑ "There are millions of different species worldwide. But how do new species first appear, and then remain separate?". royalsociety.org-gb. Retrieved 2017-12-10.
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