Hybrid sterility is one of the reproductive isolation mechanisms leading to speciation. Prdm9, the only known vertebrate hybrid-sterility gene, causes failure of meiotic chromosome synapsis and infertility in male hybrids that are the offspring of two mouse subspecies. Within species, Prdm9 determines the sites of programmed DNA double-strand breaks (DSBs) and meiotic recombination hotspots. To investigate the relation between Prdm9-controlled meiotic arrest and asynapsis, we inserted random stretches of consubspecific homology on several autosomal pairs in sterile hybrids, and analyzed their ability to form synaptonemal complexes and to rescue male fertility. Twenty-seven or more megabases of consubspecific (belonging to the same subspecies) homology fully restored synapsis in a given autosomal pair, and we predicted that two or more DSBs within symmetric hotspots per chromosome are necessary for successful meiosis. We hypothesize that impaired recombination between evolutionarily diverged chromosomes could function as one of the mechanisms of hybrid sterility occurring in various sexually reproducing species.

Faculty of Science Charles University Prague Czech Republic

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Vestec Czech Republic

Zobrazit více v PubMed

Altemose N, Noor N, Bitoun E, Tumian A, Imbeault M, Chapman JR, Aricescu AR, Myers SR. A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis. eLife. 2017;6:e28383. doi: 10.7554/eLife.28383. PubMed DOI PMC

Anderson LK, Reeves A, Webb LM, Ashley T. Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. Genetics. 1999;151:1569–1648. PubMed PMC

Baker CL, Petkova P, Walker M, Flachs P, Mihola O, Trachtulec Z, Petkov PM, Paigen K. Multimer formation explains allelic suppression of prdm9 recombination hotspots. PLOS Genetics. 2015;11:e1005512. doi: 10.1371/journal.pgen.1005512. PubMed DOI PMC

Bates D, Machler M, Bolker B, Walker S. lme4: Linear mixed-effects models using Eigen and S4_. R package version 1.1-82015 http://CRAN.R- project.org/package=lme4%3E

Bhattacharyya T, Gregorova S, Mihola O, Anger M, Sebestova J, Denny P, Simecek P, Forejt J. Mechanistic basis of infertility of mouse intersubspecific hybrids. PNAS. 2013;110:E468–E477. doi: 10.1073/pnas.1219126110. PubMed DOI PMC

Bhattacharyya T, Reifova R, Gregorova S, Simecek P, Gergelits V, Mistrik M, Martincova I, Pialek J, Forejt J. X chromosome control of meiotic chromosome synapsis in mouse inter-subspecific hybrids. PLoS Genetics. 2014;10:e1004088. doi: 10.1371/journal.pgen.1004088. PubMed DOI PMC

Boulton A, Myers RS, Redfield RJ. The hotspot conversion paradox and the evolution of meiotic recombination. PNAS. 1997;94:8058–8063. doi: 10.1073/pnas.94.15.8058. PubMed DOI PMC

Brunschwig H, Levi L, Ben-David E, Williams RW, Yakir B, Shifman S. Fine-scale maps of recombination rates and hotspots in the mouse genome. Genetics. 2012;191:757–764. doi: 10.1534/genetics.112.141036. PubMed DOI PMC

Burgoyne PS, Mahadevaiah SK, Turner JM. The consequences of asynapsis for mammalian meiosis. Nature Reviews Genetics. 2009;10:207–216. doi: 10.1038/nrg2505. PubMed DOI

Chakraborty U, Alani E. Understanding how mismatch repair proteins participate in the repair/anti-recombination decision. FEMS Yeast Research. 2016;16:fow071. doi: 10.1093/femsyr/fow071. PubMed DOI PMC

Chaumeil J, Augui S, Chow JC, Heard E. Combined immunofluorescence, RNA fluorescent in situ hybridization, and DNA fluorescent in situ hybridization to study chromatin changes, transcriptional activity, nuclear organization, and X-chromosome inactivation. Methods in Molecular Biology. 2008;463:297–308. doi: 10.1007/978-1-59745-406-3_18. PubMed DOI

Civetta A. Misregulation of gene expression and sterility in interspecies hybrids: causal links and alternative hypotheses. Journal of Molecular Evolution. 2016;82:176–182. doi: 10.1007/s00239-016-9734-z. PubMed DOI

Coyne JA, Orr HA. Speciation. Sunderland, Massachusetts: Sinauer Associates; 2004.

Davies B, Hatton E, Altemose N, Hussin JG, Pratto F, Zhang G, Hinch AG, Moralli D, Biggs D, Diaz R, Preece C, Li R, Bitoun E, Brick K, Green CM, Camerini-Otero RD, Myers SR, Donnelly P. Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice. Nature. 2016;530:171–176. doi: 10.1038/nature16931. PubMed DOI PMC

Dobzhansky T. Genetics and the Origin of Species. New York: Columbia University; 1951.

Dzur-Gejdosova M, Simecek P, Gregorova S, Bhattacharyya T, Forejt J. Dissecting the genetic architecture of F1 hybrid sterility in house mice. Evolution. 2012;66:3321–3335. doi: 10.1111/j.1558-5646.2012.01684.x. PubMed DOI

Finsterbusch F, Ravindranathan R, Dereli I, Stanzione M, Tränkner D, Tóth A. Alignment of homologous chromosomes and effective repair of programmed dna double-strand breaks during mouse meiosis require the minichromosome maintenance domain containing 2 (MCMDC2) protein. PLOS Genetics. 2016;12:e1006393. doi: 10.1371/journal.pgen.1006393. PubMed DOI PMC

Flachs P, Mihola O, Simeček P, Gregorová S, Schimenti JC, Matsui Y, Baudat F, de Massy B, Piálek J, Forejt J, Trachtulec Z. Interallelic and intergenic incompatibilities of the Prdm9 (Hst1) gene in mouse hybrid sterility. PLoS Genetics. 2012;8:e1003044. doi: 10.1371/journal.pgen.1003044. PubMed DOI PMC

Forejt J, Iványi P. Genetic studies on male sterility of hybrids between laboratory and wild mice (Mus musculus L.) Genetical Research. 1974;24:189–206. doi: 10.1017/S0016672300015214. PubMed DOI

Forejt J, Pialek J, Trachtulec Z. In: Evolution of the House Mouse. Macholan M, Baird S. J. E, Muclinger P, Pialek J, editors. Cambridge: Cambridge University Press; 2012. Hybrid male sterility genes in the mouse subspecific crosses; pp. 482–503. DOI

Forejt J. In: Chromosomes Today. Bennett M, Gropp A, Wolf U, editors. London: Geroge Allen and Unwin; 1984. X-inactivation and its role in male sterility; pp. 117–127. DOI

Forejt J. Hybrid sterility in the mouse. Trends in Genetics. 1996;12:412–417. doi: 10.1016/0168-9525(96)10040-8. PubMed DOI

Forsdyke DR. Speciation: goldschmidt’s chromosomal heresy, once supported by gould and dawkins, is again reinstated. Biological Theory. 2017;12:4–12. doi: 10.1007/s13752-016-0257-z. DOI

Gregorová S, Divina P, Storchova R, Trachtulec Z, Fotopulosova V, Svenson KL, Donahue LR, Paigen B, Forejt J. Mouse consomic strains: exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies. Genome Research. 2008;18:509–515. doi: 10.1101/gr.7160508. PubMed DOI PMC

Gregorová S, Forejt J. PWD/Ph and PWK/Ph inbred mouse strains of Mus m. musculus subspecies-a valuable resource of phenotypic variations and genomic polymorphisms. Folia Biologica. 2000;46:31–41. PubMed

Gregorová S, Mnuková-Fajdelová M, Trachtulec Z, Capková J, Loudová M, Hoglund M, Hamvas R, Lehrach H, Vincek V, Klein J, Forejt J. Sub-milliMorgan map of the proximal part of mouse Chromosome 17 including the hybrid sterility 1 gene. Mammalian Genome. 1996;7:107–113. doi: 10.1007/s003359900029. PubMed DOI

Greig D, Travisano M, Louis EJ, Borts RH. A role for the mismatch repair system during incipient speciation in Saccharomyces. Journal of Evolutionary Biology. 2003;16:429–437. doi: 10.1046/j.1420-9101.2003.00546.x. PubMed DOI

Haldane JBS. Sex ratio and unisexual sterility in hybrid animals. Journal of Genetics. 1922;12:101–109. doi: 10.1007/BF02983075. DOI

Hall LL, Carone DM, Gomez AV, Kolpa HJ, Byron M, Mehta N, Fackelmayer FO, Lawrence JB. Stable C0T-1 repeat RNA is abundant and is associated with euchromatic interphase chromosomes. Cell. 2014;156:907–919. doi: 10.1016/j.cell.2014.01.042. PubMed DOI PMC

Hayashi K, Yoshida K, Matsui Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature. 2005;438:374–378. doi: 10.1038/nature04112. PubMed DOI

Hunter N, Chambers SR, Louis EJ, Borts RH. The mismatch repair system contributes to meiotic sterility in an interspecific yeast hybrid. The EMBO Journal. 1996;15:1726–1733. PubMed PMC

Ishiguro K, Kim J, Shibuya H, Hernández-Hernández A, Suzuki A, Fukagawa T, Shioi G, Kiyonari H, Li XC, Schimenti J, Höög C, Watanabe Y. Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes. Genes & Development. 2014;28:594–607. doi: 10.1101/gad.237313.113. PubMed DOI PMC

Kauppi L, Barchi M, Lange J, Baudat F, Jasin M, Keeney S. Numerical constraints and feedback control of double-strand breaks in mouse meiosis. Genes & Development. 2013;27:873–886. doi: 10.1101/gad.213652.113. PubMed DOI PMC

Lange J, Yamada S, Tischfield SE, Pan J, Kim S, Zhu X, Socci ND, Jasin M, Keeney S. The landscape of mouse meiotic double-strand break formation, processing, and repair. Cell. 2016;167:695–708. doi: 10.1016/j.cell.2016.09.035. PubMed DOI PMC

Larson EL, Keeble S, Vanderpool D, Dean MD, Good JM. The composite regulatory basis of the large X-effect in mouse speciation. Molecular Biology and Evolution. 2016;34:msw243. doi: 10.1093/molbev/msw243. PubMed DOI PMC

Liti G, Barton DB, Louis EJ. Sequence diversity, reproductive isolation and species concepts in Saccharomyces. Genetics. 2006;174:839–850. doi: 10.1534/genetics.106.062166. PubMed DOI PMC

Mack KL, Nachman MW. Gene regulation and speciation. Trends in Genetics. 2017;33:68–80. doi: 10.1016/j.tig.2016.11.003. PubMed DOI PMC

Mahadevaiah SK, Bourc'his D, de Rooij DG, Bestor TH, Turner JM, Burgoyne PS. Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. The Journal of Cell Biology. 2008;182:263–276. doi: 10.1083/jcb.200710195. PubMed DOI PMC

Mahadevaiah SK, Costa Y, Turner JM. Using RNA FISH to study gene expression during mammalian meiosis. Methods in Molecular Biology. 2009;558:433–444. doi: 10.1007/978-1-60761-103-5_25. PubMed DOI

Maheshwari S, Barbash DA. The genetics of hybrid incompatibilities. Annual Review of Genetics. 2011;45:331–355. doi: 10.1146/annurev-genet-110410-132514. PubMed DOI

Masly JP, Jones CD, Noor MA, Locke J, Orr HA. Gene transposition as a cause of hybrid sterility in Drosophila. Science. 2006;313:1448–1450. doi: 10.1126/science.1128721. PubMed DOI

Mihola O, Trachtulec Z, Vlcek C, Schimenti JC, Forejt J. A mouse speciation gene encodes a meiotic histone H3 methyltransferase. Science. 2009;323:373–375. doi: 10.1126/science.1163601. PubMed DOI

Muggeo VM. Estimating regression models with unknown break-points. Statistics in Medicine. 2003;22:3055–3071. doi: 10.1002/sim.1545. PubMed DOI

Muggeo VMR, Ferrara G. Fitting generalized linear models with unspecified link function: A P-spline approach. Computational Statistics & Data Analysis. 2008;52:2529–2537. doi: 10.1016/j.csda.2007.08.011. DOI

Muller H, Pontecorvo G. Recessive genes causing interspecific sterility and other disharmonies between Drosophila melanogaster and simulans. Genetics. 1942;27:157

Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science. 2010;327:876–879. doi: 10.1126/science.1182363. PubMed DOI PMC

Orr HA. Dobzhansky, Bateson, and the genetics of speciation. Genetics. 1996;144:1331–1335. PubMed PMC

Orr HA. The genetic basis of reproductive isolation: insights from Drosophila. PNAS. 2005;102:6522–6526. doi: 10.1073/pnas.0501893102. PubMed DOI PMC

Parvanov ED, Petkov PM, Paigen K. Prdm9 controls activation of mammalian recombination hotspots. Science. 2010;327:835. doi: 10.1126/science.1181495. PubMed DOI PMC

Phadnis N, Orr HA. A single gene causes both male sterility and segregation distortion in Drosophila hybrids. Science. 2009;323:376–379. doi: 10.1126/science.1163934. PubMed DOI PMC

Powers NR, Parvanov ED, Baker CL, Walker M, Petkov PM, Paigen K. The meiotic recombination activator prdm9 trimethylates both h3k36 and h3k4 at recombination hotspots in vivo. PLOS Genetics. 2016;12:e1006146. doi: 10.1371/journal.pgen.1006146. PubMed DOI PMC

Presgraves DC. Sex chromosomes and speciation in Drosophila. Trends in Genetics. 2008;24:336–343. doi: 10.1016/j.tig.2008.04.007. PubMed DOI PMC

Presgraves DC. Darwin and the origin of interspecific genetic incompatibilities. The American Naturalist. 2010;176:S45–S60. doi: 10.1086/657058. PubMed DOI

Rayssiguier C, Thaler DS, Radman M. The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants. Nature. 1989;342:396–401. doi: 10.1038/342396a0. PubMed DOI

Scherthan H, Schöfisch K, Dell T, Illner D. Contrasting behavior of heterochromatic and euchromatic chromosome portions and pericentric genome separation in pre-bouquet spermatocytes of hybrid mice. Chromosoma. 2014;123:609–624. doi: 10.1007/s00412-014-0479-4. PubMed DOI PMC

Smagulova F, Brick K, Pu Y, Camerini-Otero RD, Petukhova GV. The evolutionary turnover of recombination hot spots contributes to speciation in mice. Genes & Development. 2016;30:266–280. doi: 10.1101/gad.270009.115. PubMed DOI PMC

Stambuk S, Radman M. Mechanism and control of interspecies recombination in Escherichia coli. I. Mismatch repair, methylation, recombination and replication functions. Genetics. 1998;150:533–542. PubMed PMC

Ting CT, Tsaur SC, Wu ML, Wu CI. A rapidly evolving homeobox at the site of a hybrid sterility gene. Science. 1998;282:1501–1504. doi: 10.1126/science.282.5393.1501. PubMed DOI

Trachtulec Z, Mnuková-Fajdelová M, Hamvas RM, Gregorová S, Mayer WE, Lehrach HR, Vincek V, Forejt J, Klein J. Isolation of candidate hybrid sterility 1 genes by cDNA selection in a 1.1 megabase pair region on mouse chromosome 17. Mammalian Genome. 1997;8:312–316. doi: 10.1007/s003359900430. PubMed DOI

Turner JM, Mahadevaiah SK, Fernandez-Capetillo O, Nussenzweig A, Xu X, Deng CX, Burgoyne PS. Silencing of unsynapsed meiotic chromosomes in the mouse. Nature Genetics. 2005;37:41–47. doi: 10.1038/ng1484. PubMed DOI

Wojtasz L, Cloutier JM, Baumann M, Daniel K, Varga J, Fu J, Anastassiadis K, Stewart AF, Reményi A, Turner JM, Tóth A. Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms. Genes & Development. 2012;26:958–973. doi: 10.1101/gad.187559.112. PubMed DOI PMC

Yamada S, Kim S, Tischfield SE, Jasin M, Lange J, Keeney S. Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice. Cell Cycle. 2017;16:1870–1884. doi: 10.1080/15384101.2017.1361065. PubMed DOI PMC

Zhang L, Sun T, Woldesellassie F, Xiao H, Tao Y. Sex ratio meiotic drive as a plausible evolutionary mechanism for hybrid male sterility. PLOS Genetics. 2015;11:e1005073. doi: 10.1371/journal.pgen.1005073. PubMed DOI PMC

Zickler D, Kleckner N. Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harbor Perspectives in Biology. 2015;7:a016626. doi: 10.1101/cshperspect.a016626. PubMed DOI PMC

A Minimal Hybrid Sterility Genome Assembled by Chromosome Swapping Between Mouse Subspecies (Mus musculus)

Natural variation in the zinc-finger-encoding exon of Prdm9 affects hybrid sterility phenotypes in mice

Mechanisms of Intrinsic Postzygotic Isolation: From Traditional Genic and Chromosomal Views to Genomic and Epigenetic Perspectives

Meiotic Recognition of Evolutionarily Diverged Homologs: Chromosomal Hybrid Sterility Revisited

Genic and chromosomal components of Prdm9-driven hybrid male sterility in mice (Mus musculus)

Sex chromosomes in meiotic, hemiclonal, clonal and polyploid hybrid vertebrates: along the 'extended speciation continuum'

Rat PRDM9 shapes recombination landscapes, duration of meiosis, gametogenesis, and age of fertility

Chromosome-wide characterization of meiotic noncrossovers (gene conversions) in mouse hybrids

Prdm9 Intersubspecific Interactions in Hybrid Male Sterility of House Mouse

Parthenogenesis as a Solution to Hybrid Sterility: The Mechanistic Basis of Meiotic Distortions in Clonal and Sterile Hybrids

Copy-number variation introduced by long transgenes compromises mouse male fertility independently of pachytene checkpoints

Genomic Structure of Hstx2 Modifier of Prdm9-Dependent Hybrid Male Sterility in Mice

Cisplatin-induced DNA double-strand breaks promote meiotic chromosome synapsis in PRDM9-controlled mouse hybrid sterility