title: PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans.
abstract: PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling. We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Subtle changes within the zinc finger array can create hot-spot nonactivating or enhancing variants and can even trigger the appearance of a new hot spot, suggesting that PRDM9 is a major global regulator of hot spots in humans. Variation at the PRDM9 locus also influences aspects of genome instability-specifically, a megabase-scale rearrangement underlying two genomic disorders as well as minisatellite instability-implicating PRDM9 as a risk factor for some pathological genome rearrangements.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Berg
authors.forename: Rita
authors.initials: R
authors.lastname: Neumann
authors.forename: Kwan-Wood G
authors.initials: KW
authors.lastname: Lam
authors.forename: Shriparna
authors.initials: S
authors.lastname: Sarbajna
authors.forename: Linda
authors.initials: L
authors.lastname: Odenthal-Hesse
authors.forename: Celia A
authors.initials: CA
authors.lastname: May
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Jeffreys
mesh_terms: D000483:Alleles; D000818:Animals; D015321:Gene Rearrangement; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D042822:Genomic Instability; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D011995:Recombination, Genetic / Q000235:genetics*; D013094:Spermatozoa
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human
references.citation: Science. 2010 Feb 12;327(5967):835
references.pmid: 20044538
references.citation: Nat Genet. 1992 Dec;2(4):292-300
references.pmid: 1303282
references.citation: Science. 2008 Mar 7;319(5868):1398-401
references.pmid: 18239089
references.citation: Am J Hum Genet. 2003 Jun;72(6):1436-47
references.pmid: 12748906
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10471-6
references.pmid: 18650392
references.citation: Mol Cell. 1998 Aug;2(2):267-73
references.pmid: 9734365
references.citation: Am J Hum Genet. 2006 Nov;79(5):890-902
references.pmid: 17033965
references.citation: Hum Mol Genet. 2006 May 1;15(9):1401-11
references.pmid: 16543360
references.citation: Am J Hum Genet. 2000 Sep;67(3):763-8
references.pmid: 10903930
references.citation: EMBO J. 1998 Jun 15;17(12):3495-502
references.pmid: 9628885
references.citation: Nat Genet. 2002 Jul;31(3):267-71
references.pmid: 12089523
references.citation: Nat Genet. 1994 Feb;6(2):136-45
references.pmid: 8162067
references.citation: Science. 2006 Feb 17;311(5763):971
references.pmid: 16484486
references.citation: Hum Mol Genet. 2005 Aug 1;14(15):2277-87
references.pmid: 15987698
references.citation: PLoS Genet. 2009 Sep;5(9):e1000648
references.pmid: 19763160
references.citation: Nature. 2010 Apr 1;464(7289):704-12
references.pmid: 19812545
references.citation: Science. 2010 Feb 12;327(5967):876-9
references.pmid: 20044541
references.citation: Nat Rev Genet. 2010 Mar;11(3):221-33
references.pmid: 20168297
references.citation: Annu Rev Biophys Biomol Struct. 2000;29:183-212
references.pmid: 10940247
references.citation: Nat Genet. 2001 Oct;29(2):139-40
references.pmid: 11586296
references.citation: Hum Mol Genet. 1999 May;8(5):879-88
references.pmid: 10196378
references.citation: Nat Genet. 2008 Sep;40(9):1124-9
references.pmid: 19165926
references.citation: Nat Genet. 2008 Jan;40(1):90-5
references.pmid: 18059269
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: Hum Mol Genet. 2000 Mar 22;9(5):725-33
references.pmid: 10749979
references.citation: Nat Genet. 2009 May;41(5):625-9
references.pmid: 19349985
references.citation: Science. 2010 Feb 12;327(5967):836-40
references.pmid: 20044539
references.citation: Nature. 2005 Nov 17;438(7066):374-8
references.pmid: 16292313
references.citation: Nat Genet. 1994 Oct;8(2):162-70
references.pmid: 7842015
references.citation: Nature. 2001 May 10;411(6834):199-204
references.pmid: 11346797