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PRDM9

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PRDM9
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPRDM9, MEISETZ, MSBP3, PFM6, PRMD9, ZNF899, PR domain 9, PR/SET domain 9, KMT8B
External IDsOMIM: 609760; MGI: 2384854; HomoloGene: 104139; GeneCards: PRDM9; OMA:PRDM9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

56979

213389

Ensembl

ENSG00000164256

ENSMUSG00000051977

UniProt

Q9NQV7

E9Q4V2

RefSeq (mRNA)

NM_020227
NM_001310214
NM_001376900

NM_144809
NM_001361436

RefSeq (protein)

NP_001297143
NP_064612
NP_001363829

NP_659058
NP_001348365

Location (UCSC)Chr 5: 23.44 – 23.53 MbChr 17: 15.54 – 15.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PR domain[note 1] zinc finger protein 9 is a protein that in humans is encoded by the Prdm9 gene.[5] PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain.[6] PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.[7][8]

Domain Architechture

Schematic of the PRDM9 Domain Architechture 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).[9]

History

In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility.[10]

In 1982 a haplotype was identified controlling recombination rate wm7,[11] which would later be identified as PRDM9.[12]

In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3).[13] This would later turn out to be the same PRDM9 protein independently identified later.[14]

In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity.[15]

In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.[16]

Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome.[9][17]

In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice.[6][18][19][20][21]

in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters.[22]

In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro,[23] which was confirmed in vivo in 2016.[24]

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.[25][26]

Function in Recombination

PRDM9 mediates the process of meiosis by directing the sites of homologous recombination.[27] 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.[28] There are approximately 30,000 to 50,000 hotspots within the human genome corresponding to one for every 50-100kb DNA on average.[28] 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.[28] These hotspots are binding sites for the PRDM9 Zinc Finger array.[29] Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and Histone 4 at lysine 36.[30] 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. ^ a b c GRCh38: Ensembl release 89: ENSG00000164256 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051977 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: PR domain containing 9".
  6. ^ a b 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.
  7. ^ "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.
  8. ^ Ponting CP (May 2011). "What are the genomic drivers of the rapid evolution of PRDM9?". Trends in Genetics. 27 (5): 165–71. doi:10.1016/j.tig.2011.02.001. PMID 21388701.
  9. ^ a b Thomas JH, Emerson RO, Shendure J (December 2009). "Extraordinary molecular evolution in the PRDM9 fertility gene". PLOS One. 4 (12): e8505. doi:10.1371/journal.pone.0008505. PMC 2794550. PMID 20041164.{{cite journal}}: CS1 maint: unflagged free DOI (link) Open access icon
  10. ^ Forejt J, Iványi P (1974). "Genetic studies on male sterility of hybrids between laboratory and wild mice (Mus musculus L.)". Genetical Research. 24 (2): 189–206. doi:10.1017/S0016672300015214. PMID 4452481.
  11. ^ Shiroishi T, Sagai T, Moriwaki K (1982). "A new wild-derived H-2 haplotype enhancing K-IA recombination". Nature. 300 (5890): 370–2. doi:10.1038/300370a0. PMID 6815537.
  12. ^ Kono H, Tamura M, Osada N, Suzuki H, Abe K, Moriwaki K, Ohta K, Shiroishi T (June 2014). "Prdm9 polymorphism unveils mouse evolutionary tracks". DNA Research. 21 (3): 315–26. doi:10.1093/dnares/dst059. PMC 4060951. PMID 24449848.
  13. ^ Wahls WP, Swenson G, Moore PD (June 1991). "Two hypervariable minisatellite DNA binding proteins". Nucleic Acids Research. 19 (12): 3269–74. doi:10.1093/nar/19.12.3269. PMC 328321. PMID 2062643.
  14. ^ Wahls WP, Davidson MK (November 2011). "DNA sequence-mediated, evolutionarily rapid redistribution of meiotic recombination hotspots". Genetics. 189 (3): 685–94. doi:10.1534/genetics.111.134130. PMC 3213376. PMID 22084420.
  15. ^ Hayashi K, Yoshida K, Matsui Y (November 2005). "A histone H3 methyltransferase controls epigenetic events required for meiotic prophase". Nature. 438 (7066): 374–8. doi:10.1038/nature04112. PMID 16292313.
  16. ^ Mihola O, Trachtulec Z, Vlcek C, Schimenti JC, Forejt J (January 2009). "A mouse speciation gene encodes a meiotic histone H3 methyltransferase". Science. 323 (5912): 373–5. doi:10.1126/science.1163601. PMID 19074312.
  17. ^ Oliver PL, Goodstadt L, Bayes JJ, Birtle Z, Roach KC, Phadnis N, Beatson SA, Lunter G, Malik HS, Ponting CP (December 2009). "Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa". PLoS Genetics. 5 (12): e1000753. doi:10.1371/journal.pgen.1000753. PMC 2779102. PMID 19997497.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Neale MJ (2010-02-26). "PRDM9 points the zinc finger at meiotic recombination hotspots". Genome Biology. 11 (2): 104. doi:10.1186/gb-2010-11-2-104. PMC 2872867. PMID 20210982.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P (February 2010). "Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination". Science. 327 (5967): 876–9. doi:10.1126/science.1182363. PMID 20044541.
  20. ^ Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, de Massy B (February 2010). "PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice". Science. 327 (5967): 836–40. doi:10.1126/science.1183439. PMID 20044539.
  21. ^ Parvanov ED, Petkov PM, Paigen K (February 2010). "Prdm9 controls activation of mammalian recombination hotspots". Science. 327 (5967): 835. doi:10.1126/science.1181495. PMC 2821451. PMID 20044538.
  22. ^ Brick K, Smagulova F, Khil P, Camerini-Otero RD, Petukhova GV (May 2012). "Genetic recombination is directed away from functional genomic elements in mice". Nature. 485 (7400): 642–5. doi:10.1038/nature11089. PMC 3367396. PMID 22660327.
  23. ^ 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 (April 2014). "Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein". The Journal of Biological Chemistry. 289 (17): 12177–88. doi:10.1074/jbc.M113.523183. PMC 4002121. PMID 24634223.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Powers NR, Parvanov ED, Baker CL, Walker M, Petkov PM, Paigen K (June 2016). "The Meiotic Recombination Activator PRDM9 Trimethylates Both H3K36 and H3K4 at Recombination Hotspots In Vivo". PLoS Genetics. 12 (6): e1006146. doi:10.1371/journal.pgen.1006146. PMC 4928815. PMID 27362481.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ 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 (February 2016). "Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice". Nature. 530 (7589): 171–176. doi:10.1038/nature16931. PMC 4756437. PMID 26840484.
  26. ^ Forejt J (February 2016). "Genetics: Asymmetric breaks in DNA cause sterility". Nature. 530 (7589): 167–8. doi:10.1038/nature16870. PMID 26840487.
  27. ^ Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, Petukhova GV (April 2011). "Genome-wide analysis reveals novel molecular features of mouse recombination hotspots". Nature. 472 (7343): 375–8. doi:10.1038/nature09869. PMC 3117304. PMID 21460839.
  28. ^ a b c Myers S, Spencer CC, Auton A, Bottolo L, Freeman C, Donnelly P, McVean G (August 2006). "The distribution and causes of meiotic recombination in the human genome". Biochemical Society Transactions. 34 (Pt 4): 526–30. doi:10.1042/BST0340526. PMID 16856851.
  29. ^ de Massy B (November 2014). "Human genetics. Hidden features of human hotspots". Science. 346 (6211): 808–9. doi:10.1126/science.aaa0612. PMID 25395519.
  30. ^ Baker CL, Kajita S, Walker M, Saxl RL, Raghupathy N, Choi K, Petkov PM, Paigen K (January 2015). "PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination". PLoS Genetics. 11 (1): e1004916. doi:10.1371/journal.pgen.1004916. PMC 4287450. PMID 25568937.{{cite journal}}: CS1 maint: unflagged free DOI (link)

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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