{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPRDM9 is a meiosis‐specific zinc finger protein that plays a central role in specifying the locations of recombination hotspots in mammals. By binding specific DNA sequence motifs through its rapidly evolving tandem-repeat zinc finger domain, PRDM9 directs the deposition of histone modifications—most notably trimethylation of histone H3 lysine 4 (H3K4) and H3K36—at hotspot regions, thereby recruiting the recombination machinery to initiate programmed double‐strand breaks. Its sequence-specific binding not only defines the sites of recombination but also drives its own evolutionary turnover via a self-destructive biased gene conversion process, ultimately resulting in rapid shifts in hotspot usage between species and even among human populations. These properties explain its role in fertility, hybrid sterility, and reproductive isolation in model organisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical and structural studies have revealed that PRDM9 is a highly active histone methyltransferase with the capacity to catalyze mono-, di-, and trimethylation of H3K4 and H3K36 residues. Crystallographic analyses of its zinc finger domains have detailed how conserved and variant amino acids within these motifs mediate specific interactions with target DNA sequences, thereby explaining differences in hotspot activation among allelic variants. Moreover, population surveys show extensive diversity in the PRDM9 zinc finger arrays, with strong evidence for positive selection acting on the nucleotide contact residues. This diversity underlies differences in recombination landscapes—highlighting how distinct PRDM9 alleles can activate overlapping yet non-identical sets of hotspots."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent work has further expanded our understanding of PRDM9’s multifaceted role. Studies employing humanized mouse models and chromatin mapping have underscored its impact not only on the precise positioning of double-strand breaks but also on the regulation of hotspot activity and subsequent repair processes. Aberrant expression of PRDM9 has even been linked to genomic instability in cancers. Additionally, phylogenetic analyses have revealed its coevolution with accessory factors important for recombination, emphasizing that PRDM9 functions within an integrated network that governs the early stages of meiotic recombination and ensures proper chromosome segregation. These insights collectively reinforce the view of PRDM9 as a master regulator of the meiotic recombination landscape."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Toshinobu Miyamoto, Eitetsu Koh, Naoko Sakugawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Assist Reprod Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10815-008-9270-x"}], "href": "https://doi.org/10.1007/s10815-008-9270-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18941885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18941885"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "James H Thomas, Ryan O Emerson, Jay Shendure "}, {"type": "b", "children": [{"type": "t", "text": "Extraordinary molecular evolution in the PRDM9 fertility gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0008505"}], "href": "https://doi.org/10.1371/journal.pone.0008505"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20041164"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20041164"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Emil D Parvanov, Petko M Petkov, Kenneth Paigen "}, {"type": "b", "children": [{"type": "t", "text": "Prdm9 controls activation of mammalian recombination hotspots."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1181495"}], "href": "https://doi.org/10.1126/science.1181495"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20044538"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20044538"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "F Baudat, J Buard, C Grey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1183439"}], "href": "https://doi.org/10.1126/science.1183439"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20044539"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20044539"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Simon Myers, Rory Bowden, Afidalina Tumian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1182363"}], "href": "https://doi.org/10.1126/science.1182363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20044541"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20044541"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ingrid L Berg, Rita Neumann, Kwan-Wood G Lam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.658"}], "href": "https://doi.org/10.1038/ng.658"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20818382"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20818382"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ingrid L Berg, Rita Neumann, Shriparna Sarbajna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1109531108"}], "href": "https://doi.org/10.1073/pnas.1109531108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21750151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21750151"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Laure Ségurel, Ellen Miranda Leffler, Molly Przeworski "}, {"type": "b", "children": [{"type": "t", "text": "The case of the fickle fingers: how the PRDM9 zinc finger protein specifies meiotic recombination hotspots in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.1001211"}], "href": "https://doi.org/10.1371/journal.pbio.1001211"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22162947"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22162947"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Devki D Sukhtankar, Mei-Chuan Ko "}, {"type": "b", "children": [{"type": "t", "text": "Physiological function of gastrin-releasing peptide and neuromedin B receptors in regulating itch scratching behavior in the spinal cord of mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0067422"}], "href": "https://doi.org/10.1371/journal.pone.0067422"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23826298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23826298"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mohammad S Eram, Susan P Bustos, Evelyne Lima-Fernandes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.523183"}], "href": "https://doi.org/10.1074/jbc.M113.523183"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24634223"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24634223"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jerrod J Schwartz, David J Roach, James H Thomas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Primate evolution of the recombination regulator PRDM9."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms5370"}], "href": "https://doi.org/10.1038/ncomms5370"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25001002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25001002"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yann Lesecque, Sylvain Glémin, Nicolas Lartillot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The red queen model of recombination hotspots evolution in the light of archaic and modern human genomes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1004790"}], "href": "https://doi.org/10.1371/journal.pgen.1004790"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25393762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25393762"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Anamika Patel, John R Horton, Geoffrey G Wilson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for human PRDM9 action at recombination hot spots."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.274928.115"}], "href": "https://doi.org/10.1101/gad.274928.115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26833727"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26833727"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Benjamin Davies, Edouard Hatton, Nicolas Altemose, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature16931"}], "href": "https://doi.org/10.1038/nature16931"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26840484"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26840484"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Nicolas Altemose, Nudrat Noor, Emmanuelle Bitoun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.28383"}], "href": "https://doi.org/10.7554/eLife.28383"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29072575"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29072575"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Kenneth Paigen, Petko M Petkov "}, {"type": "b", "children": [{"type": "t", "text": "PRDM9 and Its Role in Genetic Recombination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tig.2017.12.017"}], "href": "https://doi.org/10.1016/j.tig.2017.12.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29366606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29366606"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Corinne Grey, Frédéric Baudat, Bernard de Massy "}, {"type": "b", "children": [{"type": "t", "text": "PRDM9, a driver of the genetic map."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1007479"}], "href": "https://doi.org/10.1371/journal.pgen.1007479"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30161134"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30161134"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Armande Ang Houle, Heather Gibling, Fabien C Lamaze, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "PRDM9"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " expression impacts the pan-cancer genomic landscape."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genome Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gr.231696.117"}], "href": "https://doi.org/10.1101/gr.231696.117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30341163"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30341163"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Daniel Wells, Emmanuelle Bitoun, Daniela Moralli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.53392"}], "href": "https://doi.org/10.7554/eLife.53392"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32744506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32744506"}]}]}]}