title: PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination.
abstract: Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we measured activity of the Prdm9Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced experimentally. Comparing these two strains, we find that haplotype differences at hotspots lead to qualitative and quantitative changes in PRDM9 binding and activity. Using Mus spretus as an outlier, we found most variants affecting PRDM9Cst binding arose and were fixed in M.m. castaneus, suppressing hotspot activity. Furthermore, M.m. castaneus×M.m. domesticus F1 hybrids exhibit novel hotspots, with large haplotype biases in both PRDM9 binding and chromatin modification. These novel hotspots represent sites of historic evolutionary erosion that become activated in hybrids due to crosstalk between one parent's Prdm9 allele and the opposite parent's chromosome. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion.
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; Okayama University, Graduate School of Natural Science and Technology, Okayama, Okayama, Japan.
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kajita
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: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Saxl
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Raghupathy
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Kwangbom
authors.initials: K
authors.lastname: Choi
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: D000818:Animals; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005785:Gene Conversion; D006239:Haplotypes; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D059765:Homologous Recombination; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D059372:Nucleotide Motifs
chemical_list: D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; C534829:prdm9 protein, mouse