Biology:PRDM9

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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

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 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". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=56979. 
  2. ↑ 2.0 2.1 "Genetics. Genetic control of hotspots". Science 327 (5967): 791–2. February 2010. 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?". https://royalsociety.org/science-events-and-lectures/2017/12/francis-crick-lecture/. 
  4. ↑ "What are the genomic drivers of the rapid evolution of PRDM9?". Trends in Genetics 27 (5): 165–71. May 2011. doi:10.1016/j.tig.2011.02.001. PMID 21388701. 
  5. ↑ 5.0 5.1 "Extraordinary molecular evolution in the PRDM9 fertility gene". PLOS ONE 4 (12): e8505. December 2009. doi:10.1371/journal.pone.0008505. PMID 20041164. Bibcode: 2009PLoSO...4.8505T.  open access
  6. ↑ "Genetic studies on male sterility of hybrids between laboratory and wild mice (Mus musculus L.)". Genetical Research 24 (2): 189–206. 1974. doi:10.1017/S0016672300015214. PMID 4452481. 
  7. ↑ "A new wild-derived H-2 haplotype enhancing K-IA recombination". Nature 300 (5890): 370–2. 1982. doi:10.1038/300370a0. PMID 6815537. Bibcode: 1982Natur.300..370S. 
  8. ↑ "Prdm9 polymorphism unveils mouse evolutionary tracks". DNA Research 21 (3): 315–26. June 2014. doi:10.1093/dnares/dst059. PMID 24449848. 
  9. ↑ "Two hypervariable minisatellite DNA binding proteins". Nucleic Acids Research 19 (12): 3269–74. June 1991. doi:10.1093/nar/19.12.3269. PMID 2062643. 
  10. ↑ "DNA sequence-mediated, evolutionarily rapid redistribution of meiotic recombination hotspots". Genetics 189 (3): 685–94. November 2011. doi:10.1534/genetics.111.134130. PMID 22084420. 
  11. ↑ "A histone H3 methyltransferase controls epigenetic events required for meiotic prophase". Nature 438 (7066): 374–8. November 2005. doi:10.1038/nature04112. PMID 16292313. Bibcode: 2005Natur.438..374H. 
  12. ↑ "A mouse speciation gene encodes a meiotic histone H3 methyltransferase". Science 323 (5912): 373–5. January 2009. doi:10.1126/science.1163601. PMID 19074312. Bibcode: 2009Sci...323..373M. 
  13. ↑ "Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa". PLOS Genetics 5 (12): e1000753. December 2009. doi:10.1371/journal.pgen.1000753. PMID 19997497. 
  14. ↑ "PRDM9 points the zinc finger at meiotic recombination hotspots". Genome Biology 11 (2): 104. 2010-02-26. doi:10.1186/gb-2010-11-2-104. PMID 20210982. 
  15. ↑ "Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination". Science 327 (5967): 876–9. February 2010. doi:10.1126/science.1182363. PMID 20044541. Bibcode: 2010Sci...327..876M. 
  16. ↑ "PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice". Science 327 (5967): 836–40. February 2010. doi:10.1126/science.1183439. PMID 20044539. Bibcode: 2010Sci...327..836B. 
  17. ↑ "Prdm9 controls activation of mammalian recombination hotspots". Science 327 (5967): 835. February 2010. doi:10.1126/science.1181495. PMID 20044538. Bibcode: 2010Sci...327..835P. 
  18. ↑ "Genetic recombination is directed away from functional genomic elements in mice". Nature 485 (7400): 642–5. May 2012. doi:10.1038/nature11089. PMID 22660327. Bibcode: 2012Natur.485..642B. 
  19. ↑ "Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein". The Journal of Biological Chemistry 289 (17): 12177–88. April 2014. doi:10.1074/jbc.M113.523183. PMID 24634223. 
  20. ↑ "The Meiotic Recombination Activator PRDM9 Trimethylates Both H3K36 and H3K4 at Recombination Hotspots In Vivo". PLOS Genetics 12 (6): e1006146. June 2016. doi:10.1371/journal.pgen.1006146. PMID 27362481. 
  21. ↑ "Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice". Nature 530 (7589): 171–176. February 2016. doi:10.1038/nature16931. PMID 26840484. Bibcode: 2016Natur.530..171D. 
  22. ↑ "Genetics: Asymmetric breaks in DNA cause sterility". Nature 530 (7589): 167–8. February 2016. doi:10.1038/nature16870. PMID 26840487. Bibcode: 2016Natur.530..167F. 
  23. ↑ "Genome-wide analysis reveals novel molecular features of mouse recombination hotspots". Nature 472 (7343): 375–8. April 2011. doi:10.1038/nature09869. PMID 21460839. Bibcode: 2011Natur.472..375S. 
  24. ↑ 24.0 24.1 24.2 "The distribution and causes of meiotic recombination in the human genome". Biochemical Society Transactions 34 (Pt 4): 526–30. August 2006. doi:10.1042/BST0340526. PMID 16856851. 
  25. ↑ "Human genetics. Hidden features of human hotspots". Science 346 (6211): 808–9. November 2014. doi:10.1126/science.aaa0612. PMID 25395519. 
  26. ↑ 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. PMID 27362481. 

Further reading

External links

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



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