Key Points
-
Meiosis is a defining event of mammalian gametogenesis, and errors of meiosis lead to infertility or aneuploidy.
-
Recombination, chromosome pairing and segregation are key events of meiosis that are coupled to each other.
-
Recombination is initiated by induction of genetically programmed double-strand breaks. These breaks are concentrated at 'hot spots' that are are genetically and epigenetically determined, and influence haplotype structure.
-
Meiotic recombination occurs between chromatids on homologous chromosomes and results in crossovers (at least one per chromosome) and non-crossover exchanges. Recombination between sister chromatids is suppressed.
-
The synaptonemal complex and sister-chromatid cohesion are essential for maintaining chromosome pairing and promoting recombination.
-
Rigorous assessment of meiotic events is crucial for the successful application of assisted reproductive technologies and efforts directed to in vitro derivation of gametes.
Abstract
Meiosis is an essential stage in gamete formation in all sexually reproducing organisms. Studies of mutations in model organisms and of human haplotype patterns are leading to a clearer understanding of how meiosis has adapted from yeast to humans, the genes that control the dynamics of chromosomes during meiosis, and how meiosis is tied to gametic success. Genetic disruptions and meiotic errors have important roles in infertility and the aetiology of developmental defects, especially aneuploidy. An understanding of the regulation of meiosis, coupled with advances in genomics, may ultimately allow us to diagnose the causes of meiosis-based infertilities, more wisely apply assisted reproductive technologies, and derive functional germ cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hassold, T., Hall, H. & Hunt, P. The origin of human aneuploidy: where we have been, where we are going. Hum. Mol. Genet. 16, R203–R208 (2007).
Hunter, N. Synaptonemal complexities and commonalities. Mol. Cell 12, 533–535 (2003).
Ward, J. O. et al. Toward the genetics of mammalian reproduction: induction and mapping of gametogenesis mutants in mice. Biol. Reprod. 69, 1615–1625 (2003).
Handel, M. A., Lessard, C., Reinholdt, L., Schimenti, J. & Eppig, J. J. Mutagenesis as an unbiased approach to identify novel contraceptive targets. Mol. Cell. Endocrinol. 250, 201–205 (2006).
O'Bryan, M. K. & Kretser, D. Mouse models for genes involved in impaired spermatogenesis. Int. J. Androl. 29, 76–89 (2006).
Kimura, Y., Tateno, H., Handel, M. A. & Yanagimachi, R. Factors affecting meiotic and developmental competence of primary spermatocyte nuclei injected into mouse oocytes. Biol. Reprod. 59, 871–877 (1998).
Kassir, Y. et al. Transcriptional regulation of meiosis in budding yeast. Int. Rev. Cytol. 224, 111–171 (2003).
Jambhekar, A. & Amon, A. Control of meiosis by respiration. Curr. Biol. 18, 969–975 (2008).
Kassir, Y., Granot, D. & Simchen, G. IME1, a positive regulator gene of meiosis in S. cerevisiae. Cell 52, 853–862 (1988).
Chu, S. et al. The transcriptional program of sporulation in budding yeast. Science 282, 699–705 (1998).
Mata, J., Lyne, R., Burns, G. & Bahler, J. The transcriptional program of meiosis and sporulation in fission yeast. Nature Genet. 32, 143–147 (2002).
Shinkai, Y. et al. A testicular germ cell-associated serine-threonine kinase, MAK, is dispensable for sperm formation. Mol. Cell Biol. 22, 3276–3280 (2002).
Schlecht, U. et al. Expression profiling of mammalian male meiosis and gametogenesis identifies novel candidate genes for roles in the regulation of fertility. Mol. Biol. Cell 15, 1031–1043 (2004).
Shima, J. E., McLean, D. J., McCarrey, J. R. & Griswold, M. D. The murine testicular transcriptome: characterizing gene expression in the testis during the progression of spermatogenesis. Biol. Reprod. 71, 319–330 (2004).
Bowles, J. et al. Retinoid signaling determines germ cell fate in mice. Science 312, 596–600 (2006).
Koubova, J. et al. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc. Natl Acad. Sci. USA 103, 2474–2479 (2006). References 15 and 16 provided the first genetic and cellular evidence that indicated a role for RA in the induction of meiosis. The studies highlight the importance of gonadal somatic cells in determination of the sexually dimorphic temporal differences in the onset of meiosis.
Bowles, J. & Koopman, P. Retinoic acid, meiosis and germ cell fate in mammals. Development 134, 3401–3411 (2007).
Anderson, E. L. et al. Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc. Natl Acad. Sci. USA 105, 14976–14980 (2008).
Lin, Y., Gill, M. E., Koubova, J. & Page, D. C. Germ cell-intrinsic and -extrinsic factors govern meiotic initiation in mouse embryos. Science 322, 1685–1687 (2008).
Fledel-Alon, A. et al. Broad-scale recombination patterns underlying proper disjunction in humans. PLoS Genet. 5, e1000658 (2009).
Cromie, G. A. & Smith, G. R. Branching out: meiotic recombination and its regulation. Trends Cell Biol. 17, 448–455 (2007).
Murakami, H. & Keeney, S. Regulating the formation of DNA double-strand breaks in meiosis. Genes Dev. 22, 286–292 (2008).
Maleki, S., Neale, M. J., Arora, C., Henderson, K. A. & Keeney, S. Interactions between Mei4, Rec114, and other proteins required for meiotic DNA double-strand break formation in Saccharomyces cerevisiae. Chromosoma 116, 471–486 (2007).
Romanienko, P. J. & Camerini-Otero, R. D. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol. Cell 6, 975–987 (2000).
Baudat, F., Manova, K., Yuen, J. P., Jasin, M. & Keeney, S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol. Cell 6, 989–998 (2000).
Mahadevaiah, S. K. et al. Recombinational DNA double-strand breaks in mice precede synapsis. Nature Genet. 27, 271–276 (2001).
Libby, B. J., Reinholdt, L. G. & Schimenti, J. C. Positional cloning and characterization of Mei1, a vertebrate-specific gene required for normal meiotic chromosome synapsis in mice. Proc. Natl Acad. Sci. USA 100, 15706–15711 (2003).
Fukuda, T., Kugou, K., Sasanuma, H., Shibata, T. & Ohta, K. Targeted induction of meiotic double-strand breaks reveals chromosomal domain-dependent regulation of Spo11 and interactions among potential sites of meiotic recombination. Nucleic Acids Res. 36, 984–997 (2008).
Mets, D. G. & Meyer, B. J. Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure. Cell 139, 73–86 (2009).
Chen, S. Y. et al. Global analysis of the meiotic crossover landscape. Dev. Cell 15, 401–415 (2008).
Mancera, E., Bourgon, R., Brozzi, A., Huber, W. & Steinmetz, L. M. High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Nature 454, 479–485 (2008).
Borde, V. et al. Histone H3 lysine 4 trimethylation marks meiotic recombination initiation sites. EMBO J. 28, 99–111 (2009).
Buard, J., Barthes, P., Grey, C. & de Massy, B. Distinct histone modifications define initiation and repair of meiotic recombination in the mouse. EMBO J. 27, 2616–2624 (2009). References 32 and 33 report that recombination initiation sites (hot spots) have signature chromatin modifications — H3K4me3 2014 in yeast and mice. These studies define epigenetic characteristics of loci that are targets for SPO11-mediated DSB formation, and provide a framework for understanding the underlying signals and mechanisms of recombination site selection.
Kniewel, R. & Keeney, S. Histone methylation sets the stage for meiotic DNA breaks. EMBO J. 28, 81–83 (2009).
Shiroishi, T. et al. Recombinational hotspot specific to female meiosis in the mouse major histocompatibility complex. Immunogenetics 31, 79–88 (1990).
Shiroishi, T., Sagai, T. & Moriwaki, K. Hotspots of meiotic recombination in the mouse major histocompatibility complex. Genetica 88, 187–196 (1993).
Kelmenson, P. M. et al. A torrid zone on mouse chromosome 1 containing a cluster of recombinational hotspots. Genetics 169, 833–841 (2005).
Guillon, H., Baudat, F., Grey, C., Liskay, R. M. & de Massy, B. Crossover and noncrossover pathways in mouse meiosis. Mol. Cell 20, 563–573 (2005). This paper describes molecular analysis of CO and NCO events at a recombination hot spot in mice. The authors found there were different genetic requirements and recombinant product characteristics that led them to conclude that these two pathways are distinct.
Khil, P. P. & Camerini-Otero, R. D. Variation in patterns of human meiotic recombination. Genome Dyn. 5, 117–127 (2009).
Borts, R. H. The new yeast is a mouse! PLoS Biol. 7, e106 (2009).
Grey, C., Baudat, F. & de Massy, B. Genome-wide control of the distribution of meiotic recombination. PLoS Biol. 7, e35 (2009).
Parvanov, E. D., Ng, S. H., Petkov, P. M. & Paigen, K. Trans-regulation of mouse meiotic recombination hotspots by Rcr1. PLoS Biol. 7, e36 (2009). References 41 and 42 used classical genetic approaches to identify a locus on chromosome 17 that controls the location of recombination hot spots genome-wide. It is the first such gene identified in mammals.
Hayashi, K. & Matsui, Y. Meisetz, a novel histone tri-methyltransferase, regulates meiosis-specific epigenesis. Cell Cycle 5, 615–620 (2006).
Mihola, O., Trachtulec, Z., Vlcek, C., Schimenti, J. C. & Forejt, J. A mouse speciation gene encodes a meiotic histone H3 methyltransferase. Science 323, 373–375 (2009).
Coop, G., Wen, X., Ober, C., Pritchard, J. K. & Przeworski, M. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319, 1395–1398 (2008). The authors used high-resolution SNP analysis of human pedigrees to confirm that most COs occur at hot spots and that most of the hot spots correspond to linkage disequilibrium blocks. Furthermore, they found that hot spot usage was variable and had a genetic basis.
Kong, A. et al. Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319, 1398–1401 (2008). These authors measured meiotic recombination rates of men and women in many families and mapped a locus that controls genome-wide recombination rates. The most likely candidate gene is RNF212 , which encodes an orthologue of the yeast SC protein ZIP3 that seems to be an E3 SUMO ligase that is essential for proper crossing over.
Chowdhury, R., Bois, P. R., Feingold, E., Sherman, S. L. & Cheung, V. G. Genetic analysis of variation in human meiotic recombination. PLoS Genet. 5, e1000648 (2009).
Allers, T. & Lichten, M. Differential timing and control of noncrossover and crossover recombination during meiosis. Cell 106, 47–57 (2001).
Plug, A. W., Xu, J., Reddy, G., Golub, E. I. & Ashley, T. Presynaptic association of Rad51 protein with selected sites in meiotic chromatin. Proc. Natl Acad. Sci. USA 93, 5920–5924 (1996).
Niu, H. et al. Partner choice during meiosis is regulated by Hop1-promoted dimerization of Mek1. Mol. Biol. Cell 16, 5804–5818 (2005).
Carballo, J., Johnson, A., Sedgwick, S. & Cha, R. Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination. Cell 132, 758–770 (2008).
Fukuda, T., Daniel, K., Wojtasz, L., Toth, A. & Höög, C. A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes. Exp. Cell Res. 316, 158–171 (2010).
Wojtasz, L. et al. Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet. 5, e1000702 (2009).
Ghabrial, A. & Schüpbach, T. Activation of a meiotic checkpoint regulates translation of Gurken during Drosophila oogenesis. Nature Cell Biol. 1, 354–357 (1999).
Bhalla, N. & Dernburg, A. F. A conserved checkpoint monitors meiotic chromosome synapsis in Caenorhabditis elegans. Science 310, 1683–1686 (2005).
Roeder, G. S. Meiotic chromosomes: it takes two to tango. Genes Dev. 11, 2600–2621 (1997).
Roeder, G. S. & Bailis, J. M. The pachytene checkpoint. Trends Genet. 16, 395–403 (2000).
Wu, H. Y. & Burgess, S. M. Two distinct surveillance mechanisms monitor meiotic chromosome metabolism in budding yeast. Curr. Biol. 16, 2473–2479 (2006).
Li, X. C. & Schimenti, J. C. Mouse pachytene checkpoint 2 (Trip13) is required for completing meiotic recombination but not synapsis. PLoS Genet. 3, e130 (2007).
Barchi, M. et al. Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Mol. Cell Biol. 25, 7203–7215 (2005).
Kouznetsova, A. et al. BRCA1-mediated chromatin silencing is limited to oocytes with a small number of asynapsed chromosomes. J. Cell Sci. 122, 2446–2452 (2009).
Hunt, P. A. & Hassold, T. J. Sex matters in meiosis. Science 296, 2181–2183 (2002).
Turner, J. M., Mahadevaiah, S. K., Ellis, P. J., Mitchell, M. J. & Burgoyne, P. S. Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids. Dev. Cell 10, 521–529 (2006).
Turner, J. M. et al. Silencing of unsynapsed meiotic chromosomes in the mouse. Nature Genet. 37, 41–47 (2005).
Schimenti, J. Synapsis or silence. Nature Genet. 37, 11–13 (2005).
Smolka, M. B., Albuquerque, C. P., Chen, S. H. & Zhou, H. Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases. Proc. Natl Acad. Sci. USA 104, 10364–10369 (2007).
Scherthan, H. A bouquet makes ends meet. Nature Rev. Mol. Cell Biol. 2, 621–627 (2001).
Alsheimer, M. The dance floor of meiosis: evolutionary conservation of nuclear envelope attachments and dynamics of meiotic telomeres. Genome Dyn. 5, 81–93 (2009).
Hiraoka, Y. & Dernburg, A. F. The SUN rises on meiotic chromosome dynamics. Dev. Cell 17, 598–605 (2009). It is becoming increasingly apparent that the NE and cytoplasmic forces have facilitative roles in homologue pairing. This is a comprehensive review of recent and important work.
Penkner, A. M. et al. Meiotic chromosome homology search involves modifications of the nuclear envelope protein Matefin/SUN-1. Cell 139, 920–933 (2009).
Sato, A. et al. Cytoskeletal forces span the nuclear envelope to coordinate meiotic chromosome pairing and synapsis. Cell 139, 907–919 (2009).
Ding, X. et al. SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice. Dev. Cell 12, 863–872 (2007).
Chi, Y. H. et al. Requirement for Sun1 in the expression of meiotic reproductive genes and piRNA. Development 136, 965–973 (2009).
Paigen, K. et al. The recombinational anatomy of a mouse chromosome. PLoS Genet. 4, e1000119 (2008).
Liu, L. et al. Irregular telomeres impair meiotic synapsis and recombination in mice. Proc. Natl Acad. Sci. USA 101, 6496–6501 (2004).
de Boer, E. & Heyting, C. The diverse roles of transverse filaments of synaptonemal complexes in meiosis. Chromosoma 115, 220–234 (2006).
Costa, Y. & Cooke, H. J. Dissecting the mammalian synaptonemal complex using targeted mutations. Chromosome Res. 15, 579–589 (2007).
Yang, F. & Wang, P. J. The mammalian synaptonemal complex: a scaffold and beyond. Genome Dyn. 5, 69–80 (2009).
Suja, J. A. & Barbero, J. L. Cohesin complexes and sister chromatid cohesion in mammalian meiosis. Genome Dyn. 5, 94–116 (2009).
Revenkova, E. et al. Cohesin SMC1β is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nature Cell Biol. 6, 555–562 (2004). This paper provides genetic and cellular evidence for the important role of meiosis-specific cohesin molecules in chromosome behaviour during meiosis.
Bannister, L. A., Reinholdt, L. G., Munroe, R. J. & Schimenti, J. C. Positional cloning and characterization of mouse mei8, a disrupted allele of the meiotic cohesin Rec8. Genesis 40, 184–194 (2004).
Xu, H., Beasley, M. D., Warren, W. D., van der Horst, G. T. & McKay, M. J. Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev. Cell 8, 949–961 (2005).
Yuan, L. et al. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol. Cell 5, 73–83 (2000).
Yuan, L. et al. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296, 1115–1118 (2002).
Yang, F. et al. Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J. Cell Biol. 173, 497–507 (2006).
de Vries, F. A. et al. Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev. 19, 1376–1389 (2005).
Bolcun-Filas, E. et al. Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLoS Genet. 5, e1000393 (2009).
Bolcun-Filas, E. et al. SYCE2 is required for synaptonemal complex assembly, double strand break repair, and homologous recombination. J. Cell Biol. 176, 741–747 (2007).
Hamer, G. et al. Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J. Cell Sci. 121, 2445–2451 (2008).
Phillips, C. M. et al. Identification of chromosome sequence motifs that mediate meiotic pairing and synapsis in C. elegans. Nature Cell Biol. 11, 934–942 (2009).
Pearlman, R. E., Tsao, N. & Moens, P. B. Synaptonemal complexes from DNase-treated rat pachytene chromosomes contain (GT)n and LINE/SINE sequences. Genetics 130, 865–872 (1992).
Hernández-Hernández, A. et al. Differential distribution and association of repeat DNA sequences in the lateral element of the synaptonemal complex in rat spermatocytes. Chromosoma 117, 77–87 (2008).
Sourirajan, A. & Lichten, M. Polo-like kinase Cdc5 drives exit from pachytene during budding yeast meiosis. Genes Dev. 22, 2627–2632 (2008).
Jordan, P. et al. Ipl1/Aurora B kinase coordinates synaptonemal complex disassembly with cell cycle progression and crossover formation in budding yeast. Genes Dev. 23, 2237–2251 (2009).
Dix, D. J. et al. HSP70-2 is required for desynapsis of synaptonemal complexes during meiotic prophase in juvenile and adult mouse spermatocytes. Development 124, 4595–4603 (1997).
Dix, D. J. et al. Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc. Natl Acad. Sci. USA 93, 3264–3268 (1996).
Sun, F. & Handel, M. A. Regulation of the meiotic prophase I to metaphase I transition in mouse spermatocytes. Chromosoma 117, 471–485 (2008).
Zhu, D. H., Dix, D. J. & Eddy, E. M. HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes. Development 124, 3007–3014 (1997).
Hsieh, M., Zamah, A. M. & Conti, M. Epidermal growth factor-like growth factors in the follicular fluid: role in oocyte development and maturation. Semin. Reprod. Med. 27, 52–61 (2009).
Viera, A. et al. Condensin I reveals new insights on mouse meiotic chromosome structure and dynamics. PLoS ONE 2, e783 (2007).
Holt, J. E. & Jones, K. T. Control of homologous chromosome division in the mammalian oocyte. Mol. Hum. Reprod. 15, 139–147 (2009).
Vogt, E., Kirsch-Volders, M., Parry, J. & Eichenlaub-Ritter, U. Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error. Mutat. Res. 651, 14–29 (2008).
Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev. Genet. 2, 280–291 (2001).
Hunt, P. A. & Hassold, T. J. Human female meiosis: what makes a good egg go bad? Trends Genet. 24, 86–93 (2008).
LeMaire-Adkins, R. & Hunt, P. A. Nonrandom segregation of the mouse univalent X chromosome: evidence of spindle-mediated meiotic drive. Genetics 156, 775–783 (2000).
Pardo-Manuel de Villena, F. P. M. & Sapienza, C. Female meiosis drives karyotypic evolution in mammals. Genetics 159, 1179–1189 (2001).
Pardo-Manuel de Villena, F. & Sapienza, C. Nonrandom segregation during meiosis: the unfairness of females. Mamm. Genome 12, 331–339 (2001).
Mailhes, J. B. Faulty spindle checkpoint and cohesion protein activities predispose oocytes to premature chromosome separation and aneuploidy. Environ. Mol. Mutagen. 49, 642–658 (2008).
Hodges, C. A., Revenkova, E., Jessberger, R., Hassold, T. J. & Hunt, P. A. SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nature Genet. 37, 1351–1355 (2005).
Leland, S. et al. Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Proc. Natl Acad. Sci. USA 106, 12776–12781 (2009).
Duncan, F. E., Chiang, T., Schultz, R. M. & Lampson, M. A. Evidence that a defective spindle assembly checkpoint is not the primary cause of maternal age-associated aneuploidy in mouse eggs. Biol. Reprod. 81, 768–776 (2009).
Miyamoto, T. et al. Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest. J. Assist. Reprod. Genet. 25, 553–557 (2008).
Miyamoto, T. et al. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362, 1714–1719 (2003).
Sato, H. et al. Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest. J. Hum. Genet. 51, 533–540 (2006).
Mandon-Pepin, B. et al. Human infertility: meiotic genes as potential candidates. Gynecol. Obstet. Fertil. 30, 817–821 (2002).
Bannister, L. et al. A dominant, recombination-defective allele of Dmc1 causing male-specific sterility. PLoS Biol. 5, e105 (2007).
Lupski, J. R. & Stankiewicz, P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 1, e49 (2005).
Lange, J. et al. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palidromes. Cell 138, 855–869 (2009). This paper provides an elegant analysis that demonstrates that the homologous recombination that maintains human Y chromosome palindromes can lead to genetic disorders of sex determination and differentiation and Turner syndrome.
Hubner, K. et al. Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256 (2003).
Toyooka, Y., Tsunekawa, N., Akasu, R. & Noce, T. Embryonic stem cells can form germ cells in vitro. Proc. Natl Acad. Sci. USA 100, 11457–11462 (2003).
Geijsen, N. et al. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 427, 148–154 (2004).
Nayernia, K. et al. In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev. Cell 11, 125–132 (2006).
Aflatoonian, B. et al. In vitro post-meiotic germ cell development from human embryonic stem cells. Hum. Reprod. 24, 3150–3159 (2009).
Kee, K., Angeles, V. T., Flores, M., Nguyen, H. N. & Reijo Pera, R. A. Human DAZL, DAZ, and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462, 222–225 (2009).
Nicholas, C. R., Haston, K. M., Grewall, A. K., Longacre, T. A. & Reijo Pera, R. A. Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility. Hum. Mol. Genet. 18, 4376–4389 (2009).
Kubota, H. & Brinster, R. L. Culture of rodent spermatogonial stem cells, male germline stem cells of the postnatal animal. Methods Cell Biol. 86, 59–84 (2008).
Morelli, M. A. & Cohen, P. E. Not all germ cells are created equal: aspects of sexual dimorphism in mammalian meiosis. Reproduction 130, 761–781 (2005).
Holloway, J. K., Booth, J., Edelmann, W., McGowan, C. H. & Cohen, P. E. MUS81 generates a subset of MLH1–MLH3-independent crossovers in mammalian meiosis. PLoS Genet. 4, e1000186 (2008).
Acknowledgements
The authors thank P. Cohen, J. Eppig, K. Paigen and L. Reinholdt for comments on the manuscript. We apologize to authors whose papers could not be cited owing to space limitations.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
OMIM
FURTHER INFORMATION
Glossary
- Disjunction
-
The separation of chromosomes or chromatids during anaphase of mitosis or meiosis. The failure of chromosomes to separate at anaphase is called non-disjunction.
- Aneuploidy
-
The presence of an abnormal number of chromosomes, either more or less than the diploid number. It is associated with cell and organismal inviability, birth defects and cancer.
- Chromatid
-
An identical copy of a chromosome that is created through DNA replication. The two sister chromatids of a chromosome each become a chromosome when their centromeres are separated in mitosis or in the second meiotic division.
- Synapsis
-
The intimate apposition that occurs after pairing of homologous chromosomes along their length during prophase I of meiosis; synapsis is mediated by a proteinaceous structure, the synaptonemal complex.
- Double-strand break
-
A serious form of DNA damage that is created enzymatically during meiosis and that stimulates repair by crossover or non-crossover recombination.
- Induced pluripotent stem cells
-
These are derived from somatic cells by 'reprogramming' or de-differentiation triggered by the transfection of pluripotency genes, which alters the somatic cells to a state that is similar to that of embryonic stem cells.
- Cohesins
-
Multi-protein complexes that maintain tight association (cohesion) of sister chromatids.
- Resection
-
In the context of recombination, strand-biased enzymatic removal of nucleotides at the site of a double-strand break. In most recombination models, resection occurs in the 5′ to 3′ direction.
- Gene conversion
-
Originally coined to describe non-Mendelian segregation of alleles obtained from a single meiosis, this typically (but not always) refers to a non-reciprocal form of non-crossover recombination that results in the alteration of the sequence of a gene (or DNA sequence) to that of its homologue. In ectopic gene conversion, the donor and recipient DNA strands are not allelic copies of the same locus.
- Checkpoint
-
A mechanism that monitors the fidelity of cellular events and triggers cell cycle arrest and possibly apoptosis when errors are not corrected. In meiosis, unrepaired DNA damage and synapsis failure trigger checkpoints that can halt meiotic progression.
- Piwi-interacting RNAs
-
Small germ-cell RNAs that interact with PIWI proteins. They are thought to be involved in the repression of retrotransposon expression during gametogenesis.
- Interference
-
A phenomenon in which the occurrence of a crossover recombination at one position on a chromosome suppresses the frequency of additional, nearby crossovers; inhibition decreases with physical distance.
- Bivalent
-
Two paired or synapsed homologous chromosomes, each formed of two sister chromatids.
- Dictyate
-
A 'resting' stage at the end of the first meiotic prophase. It is at the end of diplonema but before the resumption of meiosis and the onset of progress to metaphase of the first meiotic division.
- Anastral spindle
-
A spindle formed without centrosomes (microtubule- organizing centres) or the astral microtubules that usually surround the centrioles at spindle poles.
- Univalent
-
An unpaired chromosome at metaphase I: usually one that has failed to synapse or recombine with its homologue.
- Acrocentric chromosome
-
A chromosome with a centromere near to one end so that one arm is very short.
- Isodicentric chromosome
-
A cytogenetically anomalous chromosome characterized by the presence of two centromeres, with additional, identical copies of DNA segments joined end to end.
Rights and permissions
About this article
Cite this article
Handel, M., Schimenti, J. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11, 124–136 (2010). https://doi.org/10.1038/nrg2723
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrg2723
This article is cited by
-
Genomic evidence for human-mediated introgressive hybridization and selection in the developed breed
BMC Genomics (2024)
-
A loss-of-function variant in ZCWPW1 causes human male infertility with sperm head defect and high DNA fragmentation
Reproductive Health (2024)
-
The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis
Nature Communications (2023)
-
The proper interplay between the expression of Spo11 splice isoforms and the structure of the pseudoautosomal region promotes XY chromosomes recombination
Cellular and Molecular Life Sciences (2023)
-
A Novel Frameshift Microdeletion of the TEX12 Gene Caused Infertility in Two Brothers with Nonobstructive Azoospermia
Reproductive Sciences (2023)
