title: Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.
abstract: Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape.
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Baker
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Petkova
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Walker
authors.affiliation: Laboratory of Germ Cell Development, Division BIOCEV, Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, v. v. i., Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Flachs
authors.affiliation: Laboratory of Germ Cell Development, Division BIOCEV, Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, v. v. i., Prague, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Mihola
authors.affiliation: Laboratory of Germ Cell Development, Division BIOCEV, Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, v. v. i., Prague, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Trachtulec
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Petko M
authors.initials: PM
authors.lastname: Petkov
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Paigen
mesh_terms: D000483:Alleles; D000818:Animals; D004249:DNA Damage; D004303:Dosage Compensation, Genetic; D057809:HEK293 Cells; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D040641:Quantitative Trait Loci; D011995:Recombination, Genetic
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human