Variation in Genome-Wide Levels of Meiotic Recombination Is Established at the Onset of Prophase in Mammalian Males

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Segregation of chromosomes during the first meiotic division relies on crossovers established during prophase. Although crossovers are strictly regulated so that at least one occurs per chromosome, individual variation in crossover levels is not uncommon. In an analysis of different inbred strains of male mice, we identified among-strain variation in the number of foci for the crossover-associated protein MLH1. We report studies of strains with “low” (CAST/EiJ), “medium” (C3H/HeJ), and “high” (C57BL/6J) genome-wide MLH1 values to define factors responsible for this variation. We utilized immunofluorescence to analyze the number and distribution of proteins that function at different stages in the recombination pathway: RAD51 and DMC1, strand invasion proteins acting shortly after double-strand break (DSB) formation, MSH4, part of the complex stabilizing double Holliday junctions, and the Bloom helicase BLM, thought to have anti-crossover activity. For each protein, we identified strain-specific differences that mirrored the results for MLH1; i.e., CAST/EiJ mice had the lowest values, C3H/HeJ mice intermediate values, and C57BL/6J mice the highest values. This indicates that differences in the numbers of DSBs (as identified by RAD51 and DMC1) are translated into differences in the number of crossovers, suggesting that variation in crossover levels is established by the time of DSB formation. However, DSBs per se are unlikely to be the primary determinant, since allelic variation for the DSB-inducing locus Spo11 resulted in differences in the numbers of DSBs but not the number of MLH1 foci. Instead, chromatin conformation appears to be a more important contributor, since analysis of synaptonemal complex length and DNA loop size also identified consistent strain-specific differences; i.e., crossover frequency increased with synaptonemal complex length and was inversely related to chromatin loop size. This indicates a relationship between recombination and chromatin compaction that may develop as DSBs form or earlier during establishment of the meiotic axis.

Vyšlo v časopise: Variation in Genome-Wide Levels of Meiotic Recombination Is Established at the Onset of Prophase in Mammalian Males. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004125
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004125

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1. RockmillB, RoederGS (1994) The yeast med1 mutant undergoes both meiotic homolog nondisjunction and precocious separation of sister chromatids. Genetics 136: 65–74.

2. MolnarM, ParisiS, KakiharaY, NojimaH, YamamotoA, et al. (2001) Characterization of rec7, an early meiotic recombination gene in Schizosaccharomyces pombe. Genetics 157: 519–532.

3. ZetkaMC, RoseAM (1995) Mutant rec-1 eliminates the meiotic pattern of crossing over in Caenorhabditis elegans. Genetics 141: 1339–1349.

4. HawleyRS, TheurkaufWE (1993) Requiem for distributive segregation: achiasmate segregation in Drosophila females. Trends Genet 9: 310–317.

5. HassoldT, HuntP (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2: 280–291.

6. CheungVG, BurdickJT, HirschmannD, MorleyM (2007) Polymorphic variation in human meiotic recombination. American journal of human genetics 80: 526–530.

7. CoopG, WenX, OberC, PritchardJK, PrzeworskiM (2008) High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319: 1395–1398.

8. KongA, ThorleifssonG, GudbjartssonDF, MassonG, SigurdssonA, et al. (2010) Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467: 1099–1103.

9. LynnA, KoehlerKE, JudisL, ChanER, CherryJP, et al. (2002) Covariation of synaptonemal complex length and mammalian meiotic exchange rates. Science 296: 2222–2225.

10. HassoldT, HansenT, HuntP, VandeVoortC (2009) Cytological studies of recombination in rhesus males. Cytogenetic and genome research 124: 132–138.

11. KoehlerKE, CherryJP, LynnA, HuntPA, HassoldTJ (2002) Genetic control of mammalian meiotic recombination. I. Variation in exchange frequencies among males from inbred mouse strains. Genetics 162: 297–306.

12. DumontBL, WhiteMA, SteffyB, WiltshireT, PayseurBA (2011) Extensive recombination rate variation in the house mouse species complex inferred from genetic linkage maps. Genome research 21: 114–125.

13. ChowdhuryR, BoisPR, FeingoldE, ShermanSL, CheungVG (2009) Genetic analysis of variation in human meiotic recombination. PLoS genetics 5: e1000648.

14. Fledel-AlonA, LefflerEM, GuanY, StephensM, CoopG, et al. (2011) Variation in human recombination rates and its genetic determinants. PloS one 6: e20321.

15. MatiseTC, ChenF, ChenW, De La VegaFM, HansenM, et al. (2007) A second-generation combined linkage physical map of the human genome. Genome Res 17: 1783–1786.

16. MartiniE, DiazRL, HunterN, KeeneyS (2006) Crossover homeostasis in yeast meiosis. Cell 126: 285–295.

17. ColeF, KauppiL, LangeJ, RoigI, WangR, et al. (2012) Homeostatic control of recombination is implemented progressively in mouse meiosis. Nature cell biology 14: 424–430.

18. KongA, ThorleifssonG, StefanssonH, MassonG, HelgasonA, et al. (2008) Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319: 1398–1401.

19. ReynoldsA, QiaoH, YangY, ChenJK, JacksonN, et al. (2013) RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis. Nature Genetics 45: 269–278.

20. BakerSM, PlugAW, ProllaTA, BronnerCE, HarrisAC, et al. (1996) Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over [see comments]. Nat Genet 13: 336–342.

21. MassonJY, WestSC (2001) The Rad51 and Dmc1 recombinases: a non-identical twin relationship. Trends in biochemical sciences 26: 131–136.

22. Santucci-DarmaninS, WalpitaD, LespinasseF, DesnuelleC, AshleyT, et al. (2000) MSH4 acts in conjunction with MLH1 during mammalian meiosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14: 1539–1547.

23. JessopL, RockmillB, RoederGS, LichtenM (2006) Meiotic chromosome synapsis-promoting proteins antagonize the anti-crossover activity of sgs1. PLoS genetics 2: e155.

24. KeeneyS, GirouxCN, KlecknerN (1997) Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88: 375–384.

25. KeeneyS, BaudatF, AngelesM, ZhouZH, CopelandNG, et al. (1999) A mouse homolog of the Saccharomyces cerevisiae meiotic recombination DNA transesterase Spo11p. Genomics 61: 170–182.

26. AndersonLK, ReevesA, WebbLM, AshleyT (1999) Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. Genetics 151: 1569–1579.

27. SvetlanovA, BaudatF, CohenPE, de MassyB (2008) Distinct functions of MLH3 at recombination hot spots in the mouse. Genetics 178: 1937–1945.

28. SheridanSD, YuX, RothR, HeuserJE, SehornMG, et al. (2008) A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments. Nucleic acids research 36: 4057–4066.

29. MoensPB, KolasNK, TarsounasM, MarconE, CohenPE, et al. (2002) The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. Journal of cell science 115: 1611–1622.

30. TarsounasM, MoritaT, PearlmanRE, MoensPB (1999) RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes. J Cell Biol 147: 207–220.

31. BarchiM, MahadevaiahS, Di GiacomoM, BaudatF, de RooijDG, et al. (2005) Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Molecular and cellular biology 25: 7203–7215.

32. CallenderTL, HollingsworthNM (2010) Mek1 suppression of meiotic double-strand break repair is specific to sister chromatids, chromosome autonomous and independent of Rec8 cohesin complexes. Genetics 185: 771–782.

33. BornerGV, KlecknerN, HunterN (2004) Crossover/noncrossover differentiation, synaptonemal complex formation, and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117: 29–45.

34. BellaniMA, RomanienkoPJ, CairattiDA, Camerini-OteroRD (2005) SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm-/- spermatocytes. Journal of cell science 118: 3233–3245.

35. BarchiM, RoigI, Di GiacomoM, de RooijDG, KeeneyS, et al. (2008) ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes. PLoS genetics 4: e1000076.

36. BakerSM, BronnerCE, ZhangL, PlugAW, RobatzekM, et al. (1995) Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell 82: 309–319.

37. YuanL, LiuJG, HojaMR, WilbertzJ, NordqvistK, et al. (2002) Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296: 1115–1118.

38. BaudatF, ManovaK, YuenJP, JasinM, KeeneyS (2000) Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking spo11. Mol Cell 6: 989–998.

39. EdelmannW, CohenPE, KneitzB, WinandN, LiaM, et al. (1999) Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nature Genetics 21: 123–127.

40. BadgeRM, YardleyJ, JeffreysAJ, ArmourJA (2000) Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic recombination. Human Molecular Genetics 9: 1239–1244.

41. LienS, SzydaJ, SchechingerB, RappoldG, ArnheimN (2000) Evidence for heterogeneity in recombination in the human pseudoautosomal region: high resolution analysis by sperm typing and radiation-hybrid mapping. American journal of human genetics 66: 557–566.

42. JeffreysAJ, MurrayJ, NeumannR (1998) High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Mol Cell 2: 267–273.

43. JeffreysAJ, MayCA (2004) Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nature Genetics 36: 151–156.

44. McVeanGA, MyersSR, HuntS, DeloukasP, BentleyDR, et al. (2004) The fine-scale structure of recombination rate variation in the human genome. Science 304: 581–584.

45. MyersS, BottoloL, FreemanC, McVeanG, DonnellyP (2005) A fine-scale map of recombination rates and hotspots across the human genome. Science 310: 321–324.

46. BaudatF, BuardJ, GreyC, Fledel-AlonA, OberC, et al. (2010) PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327: 836–840.

47. BergIL, NeumannR, LamKW, SarbajnaS, Odenthal-HesseL, et al. (2010) PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nature Genetics 42: 859–863.

48. ParvanovED, PetkovPM, PaigenK (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327: 835.

49. StefanssonH, HelgasonA, ThorleifssonG, SteinthorsdottirV, MassonG, et al. (2005) A common inversion under selection in Europeans. Nature Genetics 37: 129–137.

50. HinchAG, TandonA, PattersonN, SongY, RohlandN, et al. (2011) The landscape of recombination in African Americans. Nature 476: 170–175.

51. MurdochB, OwenN, ShirleyS, CrumbS, BromanKW, et al. (2010) Multiple loci contribute to genome-wide recombination levels in male mice. Mammalian genome : official journal of the International Mammalian Genome Society 21: 550–555.

52. DumontBL, PayseurBA (2011) Genetic analysis of genome-scale recombination rate evolution in house mice. PLoS Genet 7: e1002116.

53. MoensPB, MarconE, ShoreJS, KochakpourN, SpyropoulosB (2007) Initiation and resolution of interhomolog connections: crossover and non-crossover sites along mouse synaptonemal complexes. Journal of cell science 120: 1017–1027.

54. RosuS, LibudaDE, VilleneuveAM (2011) Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number. Science 334: 1286–1289.

55. GruhnJ, RubioC, BromanK, HuntP, HassoldT (2013) Cytological studies of human meiosis: sex-specific differences in recombination originate at, or prior to, establishment of double-strand breaks. PloS one 8(12): e85075.

56. SmagulovaF, GregorettiIV, BrickK, KhilP, Camerini-OteroRD, et al. (2011) Genome-wide analysis reveals novel molecular features of mouse recombination hotspots. Nature 472: 375–378.

57. BrickK, SmagulovaF, KhilP, Camerini-OteroRD, PetukhovaGV (2012) Genetic recombination is directed away from functional genomic elements in mice. Nature 485: 642–645.

58. de La Casa-EsperonE, Loredo-OstiJC, Pardo-Manuel de VillenaF, BriscoeTL, MaletteJM, et al. (2002) X chromosome effect on maternal recombination and meiotic drive in the mouse. Genetics 161: 1651–1659.

59. RoyoH, PolikiewiczG, MahadevaiahSK, ProsserH, MitchellM, et al. (2010) Evidence that meiotic sex chromosome inactivation is essential for male fertility. Current biology : CB 20: 2117–2123.

60. AdelmanCA, PetriniJH (2008) ZIP4H (TEX11) deficiency in the mouse impairs meiotic double strand break repair and the regulation of crossing over. PLoS genetics 4: e1000042.

61. PetersAH, PlugAW, van VugtMJ, de BoerP (1997) A drying-down technique for the spreading of mammalian meiocytes from the male and female germline. Chromosome Res 5: 66–68.

62. NovakI, WangH, RevenkovaE, JessbergerR, ScherthanH, et al. (2008) Cohesin Smc1beta determines meiotic chromatin axis loop organization. The Journal of cell biology 180: 83–90.