Abstract
Meiotic crossover (CO) recombination establishes physical linkages between homologous chromosomes that are required for their proper segregation into developing gametes, and promotes genetic diversity by shuffling genetic material between parental chromosomes. COs require the formation of double strand breaks (DSBs) to create the substrate for strand exchange. DSBs occur in small intervals called hotspots1,2,3 and significant variation in hotspot usage exists between and among individuals4. This variation is thought to reflect differences in sequence identity and chromatin structure, DNA topology and/ or chromosome domain organization1,5,6,7,8,9. Chromosomes show different frequencies of nondisjunction (NDJ)10, reflecting inherent differences in meiotic crossover control, yet the underlying basis of these differences remains elusive. Here we show that a novel chromatin factor, X non-disjunction factor 1 (xnd-1), is responsible for the global distribution of COs in C. elegans. xnd-1 is also required for formation of double-strand breaks (DSBs) on the X, but surprisingly XND-1 protein is autosomally enriched. We show that xnd-1 functions independently of genes required for X chromosome-specific gene silencing, revealing a novel pathway that distinguishes the X from autosomes in the germ line, and further show that xnd-1 exerts its effects on COs, at least in part, by modulating levels of H2A lysine 5 acetylation.
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Acknowledgements
We thank J. Bembenek, A. Bortvin, G. Deshpande, M. Halpern, V. Jantsch, A. MacQueen and D. Mets for comments on the manuscript; the Koshland lab and Baltimore Area Worm Club for discussions; M. Siddiqi for microscopy support. We are indebted to the Caenorhabditis Genetics Center and the C. elegans Knockout Consortium for worm stocks and Y. Kohara for cDNAs. This work was supported by the Carnegie Institution of Washington, NIH K01AG031296, and MWRI start-up funds to J.L.Y. D.L.B. was supported by a Canada Research Chair and a grant from NSERC.
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C.R.W. performed RNAi screen, SNP analysis, FISH and immunofluorescence. L.K. and D.L.B. identified xnd-1 as a HIM mutant, created co-suppression lines, and determined hatching rates and embryonic lethality. J.L.Y. prepared samples for immunofluorescence, isolated protein for antibody production and performed confocal microscopy. C.R.W. and J.L.Y. designed experiments, analysed data, and wrote the paper.
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Supplementary Information
This file contains Supplementary Figures 1-7 with legends Supplementary Tables 1-6, legends for Supplementary Movies 1-3 and additional references. (PDF 8507 kb)
Supplementary Movie 1
This movie shows a 3D reconstruction of confocal stocks of a wild type gonad revealing RAD-51 foci on the X chromosome indicating the formation of DSBs on the X - see Supplementary Information file for full legend. (MOV 5771 kb)
Supplementary Movie 2
This movie shows a 3D reconstruction of confocal stocks of a xnd-1 mutant gonad revealing the absence of RAD-51 foci on the X chromosome, revealing the lack of DSBs on a fraction of X chromosomes in the mutant - see Supplementary Information file for full legend. (MOV 4182 kb)
Supplementary Movie 3
This movie shows a 3D reconstruction of confocal stacks from wild type gonads showing the enrichment of XND-1 protein on autosomes - see Supplementary Information file for full legend. (MOV 7313 kb)
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Wagner, C., Kuervers, L., Baillie, D. et al. xnd-1 regulates the global recombination landscape in Caenorhabditis elegans. Nature 467, 839–843 (2010). https://doi.org/10.1038/nature09429
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DOI: https://doi.org/10.1038/nature09429
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