title: Recombination regulator PRDM9 influences the instability of its own coding sequence in humans.
abstract: PRDM9 plays a key role in specifying meiotic recombination hotspot locations in humans and mice via recognition of hotspot sequence motifs by a variable tandem-repeat zinc finger domain in the protein. We now explore germ-line instability of this domain in humans. We show that repeat turnover is driven by mitotic and meiotic mutation pathways, the latter frequently resulting in substantial remodeling of zinc fingers. Turnover dynamics predict frequent allele switches in populations with correspondingly fast changes of the recombination landscape, fully consistent with the known rapid evolution of hotspot locations. We found variation in meiotic instability between men that correlated with PRDM9 status. One particular "destabilizer" variant caused hyperinstability not only of itself but also of otherwise-stable alleles in heterozygotes. PRDM9 protein thus appears to regulate the instability of its own coding sequence. However, destabilizer variants are strongly self-limiting in populations and probably have little impact on the evolution of the recombination landscape.
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom. ajj@le.ac.uk
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Jeffreys
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Cotton
authors.forename: Rita
authors.initials: R
authors.lastname: Neumann
authors.forename: Kwan-Wood Gabriel
authors.initials: KW
authors.lastname: Lam
mesh_terms: D005591:Chemical Fractionation; D003198:Computer Simulation; D043243:DNA Sequence, Unstable / Q000235:genetics*; D019143:Evolution, Molecular; D005828:Genetics, Population; D018095:Germ-Line Mutation / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics; D059645:Mutation Rate; D009841:Oligonucleotides / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D009841:Oligonucleotides; D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human