PR-domain 9 (Prdm9) is the first hybrid sterility gene identified in mammals. The incompatibility between Prdm9 from Mus musculus domesticus (Mmd; the B6 strain) and the Hstx2 region of chromosome (Chr) X from M. m. musculus (Mmm; the PWD strain) participates in the complete meiotic arrest of mouse intersubspecific (PWD×B6)F1 hybrid males. Other studies suggest that also semisterile intersubspecific hybrids are relevant for mouse speciation, but the genes responsible remain unknown. To investigate the causes of this semisterility, we analyzed the role of Prdm9 and Chr X in hybrids resulting from the crosses of PWK, another Mmm-derived inbred strain. We demonstrate that Prdm9 and Chr X control the partial meiotic arrest and reduced sperm count in (PWK×B6)F1 males. Asynapsis of heterosubspecific chromosomes and semisterility were partially suppressed by removal of the B6 allele of Prdm9. Polymorphisms between PWK and PWD on Chr X but not in the Prdm9 region were responsible for the modification of the outcome of Prdm9-Chr X F1 hybrid incompatibility. Furthermore, (PWK×B6)F1 hybrid males displayed delayed fertility dependent on the Prdm9 incompatibility. While the Drosophila hybrid sterility gene Overdrive causes both delayed fertility and increased transmission of its own chromosome to the offspring, the segregation of Chr X and the Prdm9 region from the mouse (PWK×B6)F1 males was normal. Our results indicate extended functional consequences of Prdm9-Chr X intersubspecific incompatibility on the fertility of hybrids and should influence the design of fertility analyses in hybrid zones and of laboratory crosses between Mmm and Mmd strains.

Department of Mouse Molecular Genetics Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic v v i Prague Czech Republic

Research Facility Studenec Institute of Vertebrate Biology Academy of Sciences of the Czech Republic Brno Czech Republic

Zobrazit více v PubMed

Haldane JBS (1922) Sex ratio and unisexual sterility in animal hybrids. J Genet 12: 101–109.

Ting CT, Tsaur SC, Wu ML, Wu CI (1998) A rapidly evolving homeobox at the site of a hybrid sterility gene. Science 282: 1501–1504. PubMed

Masly JP, Jones CD, Noor MA, Locke J, Orr HA (2006) Gene transposition as a cause of hybrid sterility in Drosophila . Science 313: 1448–1450. PubMed

Mihola O, Trachtulec Z, Vlcek C, Schimenti JC, Forejt J (2009) A mouse speciation gene encodes a meiotic histone H3 methyltransferase. Science 323: 373–375. PubMed

Phadnis N, Orr HA (2009) A single gene causes both male sterility and segregation distortion in Drosophila hybrids. Science 323: 376–379. PubMed PMC

Baird SJE, Macholan M (2012) What can the Mus musculus musculus/M. m. domesticus hybrid zone tell us about speciation? In: Baird SJE, Macholan M, Munclinger P, Pialek J, editors. Evolution of the House Mouse: Cambridge University Press. 334–372.

Forejt J, Pialek J, Trachtulec Z (2012) Hybrid male sterility genes in the mouse subspecific crosses. In: Baird SJE, Macholan M, Munclinger P, Pialek J, editors. Evolution of the House Mouse: Cambridge University Press. 482–503.

Dzur-Gejdosova M, Simecek P, Gregorova S, Bhattacharyya T, Forejt J (2012) Dissecting the genetic architecture of F1 hybrid sterility in house mice. Evolution 66: 3321–3335. PubMed

Bhattacharyya T, Gregorova S, Mihola O, Anger M, Sebestova J, et al. (2013) Mechanistic basis of infertility of mouse intersubspecific hybrids. Proc Natl Acad Sci U S A 110: E468–477. PubMed PMC

Bhattacharyya T, Reifova R, Gregorova S, Simecek P, Gergelits V, et al. (2014) X chromosome control of meiotic chromosome synapsis in mouse inter-subspecific hybrids. PLoS Genet 10: e1004088. PubMed PMC

Forejt J, Ivanyi P (1974) Genetic studies on male sterility of hybrids between laboratory and wild mice (Mus musculus L.). Genet Res 24: 189–206. PubMed

Gregorova S, Mnukova-Fajdelova M, Trachtulec Z, Capkova J, Loudova M, et al. (1996) Sub-milliMorgan map of the proximal part of mouse Chromosome 17 including the hybrid sterility 1 gene. Mamm Genome 7: 107–113. PubMed

Trachtulec Z, Vincek V, Hamvas RM, Forejt J, Lehrach H, et al. (1994) Physical map of mouse chromosome 17 in the region relevant for positional cloning of the Hybrid sterility 1 gene. Genomics 23: 132–137. PubMed

Forejt J, Trachtulec Z, Hamvas R (1999) Mouse chromosome 17. Mamm Genome 10: 958. PubMed

Mihola O, Forejt J, Trachtulec Z (2007) Conserved alternative and antisense transcripts at the programmed cell death 2 locus. BMC Genomics 8: 20. PubMed PMC

Trachtulec Z, Vlcek C, Mihola O, Gregorova S, Fotopulosova V, et al. (2008) Fine haplotype structure of a chromosome 17 region in the laboratory and wild mouse. Genetics 178: 1777–1784. PubMed PMC

Hayashi K, Yoshida K, Matsui Y (2005) A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature 438: 374–378. PubMed

Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, et al. (2010) PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327: 836–840. PubMed PMC

Parvanov ED, Petkov PM, Paigen K (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327: 835. PubMed PMC

Brick K, Smagulova F, Khil P, Camerini-Otero RD, Petukhova GV (2012) Genetic recombination is directed away from functional genomic elements in mice. Nature 485: 642–645. PubMed PMC

Bateson W (1909) Heredity and variation in modern lights. In: Steward AC, editor. Darwin and modern science. Cambridge, U.K: Cambridge Univ. Press. 85–101.

Dobzhansky T (1937). Genetics and the origin of species. New York: Columbia Univ. Press.

Muller HJ (1942) Isolating mechanisms, evolution, and temperature. Biological Symposia. Lancaster: Jaques Cattell Press. 71–125.

Flachs P, Mihola O, Simecek P, Gregorova S, Schimenti JC, et al. (2012) Interallelic and intergenic incompatibilities of the Prdm9 (Hst1) gene in mouse hybrid sterility. PLoS Genet 8: e1003044. PubMed PMC

Payseur BA, Krenz JG, Nachman MW (2004) Differential patterns of introgression across the X chromosome in a hybrid zone between two species of house mice. Evolution 58: 2064–2078. PubMed

Janousek V, Wang L, Luzynski K, Dufkova P, Vyskocilova MM, et al. (2012) Genome-wide architecture of reproductive isolation in a naturally occurring hybrid zone between Mus musculus musculus and M. m. domesticus . Mol Ecol 21: 3032–3047. PubMed PMC

Yoshiki A, Moriwaki K, Sakakura T, Kusakabe M (1993) Histological studies on male-sterility of hybrids between laboratory and wild mouse strains. Development Growth & Differentiation 35: 271–281. PubMed

Britton-Davidian J, Fel-Clair F, Lopez J, Alibert P, Boursot P (2005) Postzygotic isolation between the two European subspecies of the house mouse: estimates from fertility patterns in wild and laboratory-bred hybrids. Biol J Lin Soc 84: 379–393.

Good JM, Handel MA, Nachman MW (2008) Asymmetry and polymorphism of hybrid male sterility during the early stages of speciation in house mice. Evolution 62: 50–65. PubMed PMC

White MA, Steffy B, Wiltshire T, Payseur BA (2011) Genetic dissection of a key reproductive barrier between nascent species of house mice. Genetics 189: 289–304. PubMed PMC

Oka A, Mita A, Sakurai-Yamatani N, Yamamoto H, Takagi N, et al. (2004) Hybrid breakdown caused by substitution of the X chromosome between two mouse subspecies. Genetics 166: 913–924. PubMed PMC

Storchova R, Gregorova S, Buckiova D, Kyselova V, Divina P, et al. (2004) Genetic analysis of X-linked hybrid sterility in the house mouse. Mamm Genome 15: 515–524. PubMed

Oka A, Aoto T, Totsuka Y, Takahashi R, Ueda M, et al. (2007) Disruption of genetic interaction between two autosomal regions and the X chromosome causes reproductive isolation between mouse strains derived from different subspecies. Genetics 175: 185–197. PubMed PMC

Oka A, Mita A, Takada Y, Koseki H, Shiroishi T (2010) Reproductive isolation in hybrid mice due to spermatogenesis defects at three meiotic stages. Genetics 186: 339–351. PubMed PMC

Albrechtova J, Albrecht T, Baird SJ, Macholan M, Rudolfsen G, et al. (2012) Sperm-related phenotypes implicated in both maintenance and breakdown of a natural species barrier in the house mouse. Proc R Soc B 279: 4803–4810. PubMed PMC

Turner LM, Schwahn DJ, Harr B (2012) Reduced male fertility is common but highly variable in form and severity in a natural house mouse hybrid zone. Evolution 66: 443–458. PubMed

Gregorova S, Forejt J (2000) PWD/Ph and PWK/Ph inbred mouse strains of Mus m. musculus subspecies–a valuable resource of phenotypic variations and genomic polymorphisms. Folia Biol (Praha) 46: 31–41. PubMed

Keane TM, Goodstadt L, Danecek P, White MA, Wong K, et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477: 289–294. PubMed PMC

Pialek J, Vyskocilova M, Bimova B, Havelkova D, Pialkova J, et al. (2008) Development of unique house mouse resources suitable for evolutionary studies of speciation. J Hered 99: 34–44. PubMed

Yang H, Wang JR, Didion JP, Buus RJ, Bell TA, et al. (2011) Subspecific origin and haplotype diversity in the laboratory mouse. Nat Genet 43: 648–655. PubMed PMC

Gregorova S, Divina P, Storchova R, Trachtulec Z, Fotopulosova V, et al. (2008) Mouse consomic strains: exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies. Genome Res 18: 509–515. PubMed PMC

Turner JM, Mahadevaiah SK, Fernandez-Capetillo O, Nussenzweig A, Xu X, et al. (2005) Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 37: 41–47. PubMed

Anderson LK, Reeves A, Webb LM, Ashley T (1999) Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. Genetics 151: 1569–1579. PubMed PMC

McKee BD, Handel MA (1993) Sex chromosomes, recombination, and chromatin conformation. Chromosoma 102: 71–80. PubMed

Vyskocilova M, Trachtulec Z, Forejt J, Pialek J (2005) Does geography matter in hybrid sterility in house mice? Biol J Lin Soc 84: 663–674.

Vyskocilova M, Prazanova G, Pialek J (2009) Polymorphism in hybrid male sterility in wild-derived Mus musculus musculus strains on proximal chromosome 17. Mamm Genome 20: 83–91. PubMed

Dufkova P, Macholan M, Pialek J (2011) Inference of selection and stochastic effects in the house mouse hybrid zone. Evolution 65: 993–1010. PubMed

Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, et al. (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36: 1133–1137. PubMed

Frank SA (1991) Divergence of meiotic drive-suppression systems as an explanation for sex-biased hybrid sterility and inviability. Evolution 45: 262–267. PubMed

Hurst LD, Pomiankowski A (1991) Causes of sex ratio bias may account for unisexual sterility in hybrids: a new explanation of Haldane’s rule and related phenomena. Genetics 128: 841–858. PubMed PMC

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

Prdm9 deficiency of rat oocytes causes synapsis among non-homologous chromosomes and aneuploidy

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

Bardet-Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self-tolerance

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

Histone methyltransferase PRDM9 is not essential for meiosis in male mice

Hybrid Sterility Locus on Chromosome X Controls Meiotic Recombination Rate in Mouse

Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots