S1, S2A, S2B, S3A, S3B, S4, S5, S6, S7A, S7B Table S1 == References == == Associated Data == This section collects any data citations, data availability claims, or supplementary materials included in this article. == Supplementary Materials ==. the reductional department, unique to meiotic cells, homologous chromosomes segregate. This segregation requires the establishment of contacts between homologs that are mediated in most species by reciprocal recombination events known as crossing over (CO) (1). COs also increase genome diversity, thereby improving the efficacy of natural selection (2). The molecular process of CO formation involves a highly regulated pathway of induction of programmed DNA double strand breaks (DSBs) followed by their repair on the homolog (3). In yeastsSaccharomyces cerevisiaeandSchizosaccharomyces pombe, initiation sites have been mapped by the direct molecular detection of DSBs. These studies have shown that DSBs are not randomly distributed along chromosomes but occur in specific regions of the genome, in accordance to rules that are as yet poorly comprehended (4). A common chromatin feature, the trimethylation of lysine 4 of histone H3 (H3K4me3), defines yeast and mouse initiation sites (5, 6). In mammals, in most cases, the locations of initiation sites are deduced from mapping CO events. COs can be mapped at high resolution either by pedigree analysis, detection of recombinant molecules in gametes or by analysis of linkage disequibrium (LD) (7, 8). In humans, these approaches have shown that most COs are clustered in thin regions (12kb), called hotspots, that are predicted to be preferred initiation sites (9). On the basis of LD patterns, over 30, 000 hotspots have been recognized in the human being genome, spaced on average every 50100kb, often outside from genes and with highly variable levels of activity (10, 11). In addition , some hotspots show inter-individual variation in activity because shown by sperm typing studies (7) or pedigree analysis (12). LD-based hotspots were discovered to be highly enriched for a degenerate 13-mer motif (13). Moreover, in sperm typing studies, single nucleotide polymorphisms (SNPs) within this 13 bp motif were found to be associated with variation Desoxyrhaponticin of hotspot activity incis(14, 15). Genome-wide, the motif plays a role in approximately 40% of hotspots and is proposed to be involved in initiation specification or other Desoxyrhaponticin aspects of recombination activity (13). In mice, based on the analysis of a 25Mb interval on chromosome (chr. ) 1 (16) and several individual regions (17), initiation of meiotic recombination also appears to be clustered in small intervals. Recently, by comparing recombination activity between different mouse strains, a genetic locus responsible for the distribution of recombination in the genome was identified (18, 19), which potentially contributes, either directly or indirectly, to the specification of initiation sites in the genome. Specifically, the genetic background at this locus (wm7haplotype fromM. musculus molossinusorbhaplotype fromM. m. domesticusstrains C57BL/10 or C57BL/6) was found to affect recombination activity measured both chromosome-wide and at two individual hotspots (Psmb9on chr. 17 andHlx1on chr. 1). This locus (namedDsbc1) was mapped to a region between 10. 1 and 16. 8 Mb on mouse chr. 17 (18). == Prdm9, a candidate gene == Upon additional crossing, we refined theDsbc1locus to the 12. 2 to 16. 8 Mb region of mouse chr. 17 (supporting on-line text). This region contains thePrdm9gene coding for a protein with a SET-methyl transferase domain name and a tandem array of twelve C2-H2 zinc fingers. PRDM9 has been shown to tri-methylate H3K4 and is expressed specifically in germ cells during meiotic prophase (20). Strains with distinctDsbc1alleles (wm7orb) have different levels of H3K4me3 at the two recombination hotspots, Psmb9andHlx1. Specifically, a high level of H3K4me3 was correlated with large recombination activity Mouse monoclonal to Complement C3 beta chain at these hotspots (6). ThePrdm9gene is the only reported gene Desoxyrhaponticin encoding for a.