1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Genomics and Human Genetics
  4. Volume 24, 2023
  5. Article

Annual Review of Genomics and Human Genetics

Volume 24, 2023

Meiotic Chromosome Structure, the Synaptonemal Complex, and Infertility

Abstract

In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome axes. The mammalian SC comprises at least eight largely coiled-coil proteins that interact and self-assemble to generate a long, zipper-like structure that holds homologous chromosomes in close proximity and promotes the formation of genetic crossovers and accurate meiotic chromosome segregation. In recent years, numerous mutations in human SC genes have been associated with different types of male and female infertility. Here, we integrate structural information on the human SC with mouse and human genetics to describe the molecular mechanisms by which SC mutations can result in human infertility. We outline certain themes in which different SC proteins are susceptible to different types of disease mutation and how genetic variants with seemingly minor effects on SC proteins may act as dominant-negative mutations in which the heterozygous state is pathogenic.

Keyword(s): azoospermia, fertility, meiosis, primary ovarian failure, recurrent pregnancy loss, synaptonemal complex
Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-110122-090239
2023-08-25
2024-05-05
Loading full text...

Full text loading...

/deliver/fulltext/genom/24/1/annurev-genom-110122-090239.html?itemId=/content/journals/10.1146/annurev-genom-110122-090239&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Agostinho A, Kouznetsova A, Hernández-Hernández A, Bernhem K, Blom H et al. 2018. Sexual dimorphism in the width of the mouse synaptonemal complex. J. Cell Sci. 131:jcs212548
     [Google Scholar]
  2. 2.
    Agostinho A, Manneberg O, van Schendel R, Hernández-Hernández A, Kouznetsova A et al. 2016. High density of REC8 constrains sister chromatid axes and prevents illegitimate synaptonemal complex formation. EMBO Rep. 17:901–13
     [Google Scholar]
  3. 3.
    An M, Liu Y, Zhang M, Hu K, Jin Y et al. 2021. Targeted next-generation sequencing panel screening of 668 Chinese patients with non-obstructive azoospermia. J. Assist. Reprod. Genet. 38:1997–2005
     [Google Scholar]
  4. 4.
    Backwell L, Marsh JA. 2022. Diverse molecular mechanisms underlying pathogenic protein mutations: beyond the loss-of-function paradigm. Annu. Rev. Genom. Hum. Genet. 23:475–98
     [Google Scholar]
  5. 5.
    Baker SM, Plug AW, Prolla TA, Bronner CE, Harris AC et al. 1996. Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat. Genet. 13:336–42
     [Google Scholar]
  6. 6.
    Bao J, Vitting-Seerup K, Waage J, Tang C, Ge Y et al. 2016. UPF2-dependent nonsense-mediated mRNA decay pathway is essential for spermatogenesis by selectively eliminating longer 3′ UTR transcripts. PLOS Genet. 12:e1005863
     [Google Scholar]
  7. 7.
    Barchi M, Mahadevaiah S, Di Giacomo M, Baudat F, de Rooij DG et al. 2005. Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Mol. Cell. Biol. 25:7203–15
     [Google Scholar]
  8. 8.
    Barlow AL, Hultén MA. 1998. Crossing over analysis at pachytene in man. Eur. J. Hum. Genet. 6:350–58
     [Google Scholar]
  9. 9.
    Baudat F, Manova K, Yuen JP, Jasin M, Keeney S. 2000. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol. Cell 6:989–98
     [Google Scholar]
  10. 10.
    Beverley R, Snook ML, Brieño-Enríquez MA. 2021. Meiotic cohesin and variants associated with human reproductive aging and disease. Front. Cell Dev. Biol. 9:710033
     [Google Scholar]
  11. 11.
    Bisig CG, Guiraldelli MF, Kouznetsova A, Scherthan H, Höög C et al. 2012. Synaptonemal complex components persist at centromeres and are required for homologous centromere pairing in mouse spermatocytes. PLOS Genet. 8:e1002701
     [Google Scholar]
  12. 12.
    Biswas L, Tyc K, El Yakoubi W, Morgan K, Xing J, Schindler K. 2021. Meiosis interrupted: the genetics of female infertility via meiotic failure. Reproduction 161:R13–35
     [Google Scholar]
  13. 13.
    Biswas U, Hempel K, Llano E, Pendas A, Jessberger R. 2016. Distinct roles of meiosis-specific cohesin complexes in mammalian spermatogenesis. PLOS Genet. 12:e1006389
     [Google Scholar]
  14. 14.
    Biswas U, Stevense M, Jessberger R. 2018. SMC1α substitutes for many meiotic functions of SMC1β but cannot protect telomeres from damage. Curr. Biol. 28:249–61.e4
     [Google Scholar]
  15. 15.
    Bolcun-Filas E, Costa Y, Speed R, Taggart M, Benavente R et al. 2007. SYCE2 is required for synaptonemal complex assembly, double strand break repair, and homologous recombination. J. Cell Biol. 176:741–47
     [Google Scholar]
  16. 16.
    Bolcun-Filas E, Hall E, Speed R, Taggart M, Grey C et al. 2009. Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLOS Genet. 5:e1000393
     [Google Scholar]
  17. 17.
    Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC. 2014. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science 343:533–36
     [Google Scholar]
  18. 18.
    Bollschweiler D, Radu L, Joudeh L, Plitzko JM, Henderson RM et al. 2019. Molecular architecture of the SYCP3 fibre and its interaction with DNA. Open Biol. 9:190094
     [Google Scholar]
  19. 19.
    Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E et al. 2009. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am. J. Hum. Genet. 84:14–20
     [Google Scholar]
  20. 20.
    Bühler M, Steiner S, Mohn F, Paillusson A, Mühlemann O. 2006. EJC-independent degradation of nonsense immunoglobulin-mu mRNA depends on 3′ UTR length. Nat. Struct. Mol. Biol. 13:462–64
     [Google Scholar]
  21. 21.
    Burgoyne PS, Mahadevaiah SK, Turner JMA. 2009. The consequences of asynapsis for mammalian meiosis. Nat. Rev. Genet. 10:207–16
     [Google Scholar]
  22. 22.
    Byers PH, Wallis GA, Willing MC. 1991. Osteogenesis imperfecta: translation of mutation to phenotype. J. Med. Genet. 28:433–42
     [Google Scholar]
  23. 23.
    Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL et al. 2014. Mutant cohesin in premature ovarian failure. N. Engl. J. Med. 370:943–49
     [Google Scholar]
  24. 24.
    Cahoon CK, Hawley RS. 2016. Regulating the construction and demolition of the synaptonemal complex. Nat. Struct. Mol. Biol. 23:369–77
     [Google Scholar]
  25. 25.
    Cloutier JM, Mahadevaiah SK, ElInati E, Nussenzweig A, Tóth A, Turner JMA. 2015. Histone H2AFX links meiotic chromosome asynapsis to prophase I oocyte loss in mammals. PLOS Genet. 11:e1005462
     [Google Scholar]
  26. 26.
    Costa Y, Speed R, Öllinger R, Alsheimer M, Semple CA et al. 2005. Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis. J. Cell Sci. 118:2755–62
     [Google Scholar]
  27. 27.
    Crichton JH, Dunce JM, Baarends WM, Davies OR, Adams IR. 2022. Parallel recruitment pathways contribute to synaptonemal complex assembly during mammalian meiosis. bioRxiv 2022.04.14.488335. https://doi.org/10.1101/2022.04.14.488335
  28. 28.
    Crichton JH, Dunce JM, Dunne OM, Salmon LJ, Devenney PS et al. 2023. Structural maturation of SYCP1-mediated meiotic chromosome synapsis by SYCE3. Nat. Struct. Mol. Biol. 30:188–99
     [Google Scholar]
  29. 29.
    Crichton JH, Read D, Adams IR. 2018. Defects in meiotic recombination delay progression through pachytene in Tex19.1−/− mouse spermatocytes. Chromosoma 127:437–59
     [Google Scholar]
  30. 30.
    Davies OR, Maman JD, Pellegrini L. 2012. Structural analysis of the human SYCE2-TEX12 complex provides molecular insights into synaptonemal complex assembly. Open Biol. 2:120099
     [Google Scholar]
  31. 31.
    de Boer E, Heyting C. 2006. The diverse roles of transverse filaments of synaptonemal complexes in meiosis. Chromosoma 115:220–34
     [Google Scholar]
  32. 32.
    de Vries FAT, de Boer E, van den Bosch M, Baarends WM, Ooms M et al. 2005. Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev. 19:1376–89
     [Google Scholar]
  33. 33.
    de Vries L, Behar DM, Smirin-Yosef P, Lagovsky I, Tzur S, Basel-Vanagaite L. 2014. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J. Clin. Endocrinol. Metab. 99:E2129–32
     [Google Scholar]
  34. 34.
    Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M. 2005. Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. PNAS 102:737–42
     [Google Scholar]
  35. 35.
    Dobson MJ, Pearlman RE, Karaiskakis A, Spyropoulos B, Moens PB. 1994. Synaptonemal complex proteins: occurrence, epitope mapping and chromosome disjunction. J. Cell Sci. 107:2749–60
     [Google Scholar]
  36. 36.
    Dunce JM, Dunne OM, Ratcliff M, Millán C, Madgwick S et al. 2018. Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly. Nat. Struct. Mol. Biol. 25:557–69
     [Google Scholar]
  37. 37.
    Dunce JM, Milburn AE, Gurusaran M, da Cruz I, Sen LT et al. 2018. Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1. Nat. Commun. 9:5355
     [Google Scholar]
  38. 38.
    Dunce JM, Salmon LJ, Davies OR. 2021. Structural basis of meiotic chromosome synaptic elongation through hierarchical fibrous assembly of SYCE2-TEX12. Nat. Struct. Mol. Biol. 28:681–93
     [Google Scholar]
  39. 39.
    Dunce JM, Salmon LJ, Davies OR. 2022. Coiled-coil structure of meiosis protein TEX12 and conformational regulation by its C-terminal tip. Commun Biol. 5:921
     [Google Scholar]
  40. 40.
    Dunne OM, Davies OR. 2019. A molecular model for self-assembly of the synaptonemal complex protein SYCE3. J. Biol. Chem. 294:9260–75
     [Google Scholar]
  41. 41.
    Dunne OM, Davies OR. 2019. Molecular structure of human synaptonemal complex protein SYCE1. Chromosoma 128:223–36
     [Google Scholar]
  42. 42.
    Eijpe M, Offenberg H, Jessberger R, Revenkova E, Heyting C. 2003. Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3. J. Cell Biol. 160:657–70
     [Google Scholar]
  43. 43.
    Fan S, Jiao Y, Khan R, Jiang X, Javed AR et al. 2021. Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans. Am. J. Hum. Genet. 108:324–36
     [Google Scholar]
  44. 44.
    Fanourgakis G, Lesche M, Akpinar M, Dahl A, Jessberger R. 2016. Chromatoid body protein TDRD6 supports long 3′ UTR triggered nonsense mediated mRNA decay. PLOS Genet. 12:e1005857
     [Google Scholar]
  45. 45.
    Feng J, Fu S, Cao X, Wu H, Lu J et al. 2017. Synaptonemal complex protein 2 (SYCP2) mediates the association of the centromere with the synaptonemal complex. Protein Cell 8:538–43
     [Google Scholar]
  46. 46.
    Feng K, Ge H, Chen H, Cui C, Zhang S et al. 2022. Novel exon mutation in SYCE1 gene is associated with non-obstructive azoospermia. J. Cell. Mol. Med. 26:1245–52
     [Google Scholar]
  47. 47.
    Fraune J, Alsheimer M, Volff J-N, Busch K, Fraune S et al. 2012. Hydra meiosis reveals unexpected conservation of structural synaptonemal complex proteins across metazoans. PNAS 109:16588–93
     [Google Scholar]
  48. 48.
    Fraune J, Brochier-Armanet C, Alsheimer M, Benavente R. 2013. Phylogenies of central element proteins reveal the dynamic evolutionary history of the mammalian synaptonemal complex: ancient and recent components. Genetics 195:781–93
     [Google Scholar]
  49. 49.
    Fraune J, Brochier-Armanet C, Alsheimer M, Volff J-N, Schücker K, Benavente R. 2016. Evolutionary history of the mammalian synaptonemal complex. Chromosoma 125:355–60
     [Google Scholar]
  50. 50.
    Fuchs E. 1994. Intermediate filaments and disease: mutations that cripple cell strength. J. Cell Biol. 125:511–16
     [Google Scholar]
  51. 51.
    Garner KEL, Salter A, Lau CK, Gurusaran M, Villemant C et al. 2022. The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein. bioRxiv 2022.04.13.488131. https://doi.org/10.1101/2022.04.13.488131
  52. 52.
    Geisinger A, Benavente R. 2016. Mutations in genes coding for synaptonemal complex proteins and their impact on human fertility. Cytogenet. Genome Res. 150:77–85
     [Google Scholar]
  53. 53.
    Geoffroy-Siraudin C, Aknin-Seiffer I, Metzler-Guillemain C, Ghalamoun-Slaimi R, Bonzi MF et al. 2007. Meiotic abnormalities in patients bearing complete AZFc deletion of Y chromosome. Hum. Reprod. 22:1567–72
     [Google Scholar]
  54. 54.
    Gerasimavicius L, Livesey BJ, Marsh JA. 2022. Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure. Nat. Commun. 13:3895
     [Google Scholar]
  55. 55.
    Gilissen C, Hoischen A, Brunner HG, Veltman JA. 2012. Disease gene identification strategies for exome sequencing. Eur. J. Hum. Genet. 20:490–97
     [Google Scholar]
  56. 56.
    Gómez-H L, Felipe-Medina N, Sánchez-Martín M, Davies OR, Ramos I et al. 2016. C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility. Nat. Commun. 7:13298
     [Google Scholar]
  57. 57.
    Grey C, de Massy B. 2021. Chromosome organization in early meiotic prophase. Front. Cell Dev. Biol. 9:688878
     [Google Scholar]
  58. 58.
    Gryaznova Y, Keating L, Touati SA, Cladière D, El Yakoubi W et al. 2021. Kinetochore individualization in meiosis I is required for centromeric cohesin removal in meiosis II. EMBO J. 40:e106797
     [Google Scholar]
  59. 59.
    Gurkan H, Aydin F, Kadıoglu A, Palanduz S. 2013. Investigation of mutations in the synaptonemal complex protein 3 (SYCP3) gene among azoospermic infertile male patients in the Turkish population. Andrologia 45:92–100
     [Google Scholar]
  60. 60.
    Hamer G, Gell K, Kouznetsova A, Novak I, Benavente R, Höög C. 2006. Characterization of a novel meiosis-specific protein within the central element of the synaptonemal complex. J. Cell Sci. 119:4025–32
     [Google Scholar]
  61. 61.
    Hamer G, Wang H, Bolcun-Filas E, Cooke HJ, Benavente R, Höög C. 2008. Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J. Cell Sci. 121:2445–51
     [Google Scholar]
  62. 62.
    Hanna CW, Blair JD, Stephenson MD, Robinson WP. 2012. Absence of SYCP3 mutations in women with recurrent miscarriage with at least one trisomic miscarriage. Reprod. BioMed. Online 24:251–53
     [Google Scholar]
  63. 63.
    Hernández-López D, Geisinger A, Trovero MF, Santiñaque FF, Brauer M et al. 2020. Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice. Mol. Hum. Reprod. 26:485–97
     [Google Scholar]
  64. 64.
    Heyting C, Dietrich AJ, Moens PB, Dettmers RJ, Offenberg HH et al. 1989. Synaptonemal complex proteins. Genome 31:81–87
     [Google Scholar]
  65. 65.
    Hodges CA, LeMaire-Adkins R, Hunt PA. 2001. Coordinating the segregation of sister chromatids during the first meiotic division: evidence for sexual dimorphism. J. Cell Sci. 114:2417–26
     [Google Scholar]
  66. 66.
    Hodges CA, Revenkova E, Jessberger R, Hassold TJ, Hunt PA. 2005. SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat. Genet. 37:1351–55
     [Google Scholar]
  67. 67.
    Holloway JK, Booth J, Edelmann W, McGowan CH, Cohen PE. 2008. MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLOS Genet. 4:e1000186
     [Google Scholar]
  68. 68.
    Horn HF, Kim DI, Wright GD, Wong ESM, Stewart CL et al. 2013. A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton. J. Cell Biol. 202:1023–39
     [Google Scholar]
  69. 69.
    Hou D, Yao C, Xu B, Luo W, Ke H et al. 2022. Variations of C14ORF39 and SYCE1 identified in idiopathic premature ovarian insufficiency and nonobstructive azoospermia. J. Clin. Endocrinol. Metab. 107:724–34
     [Google Scholar]
  70. 70.
    Houston BJ, Riera-Escamilla A, Wyrwoll MJ, Salas-Huetos A, Xavier MJ et al. 2021. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships. Hum. Reprod. Update 28:15–29
     [Google Scholar]
  71. 71.
    Huang N, Wen Y, Guo X, Li Z, Dai J et al. 2015. A screen for genomic disorders of infertility identifies MAST2 duplications associated with nonobstructive azoospermia in humans. Biol. Reprod. 93:61
     [Google Scholar]
  72. 72.
    Huang Y, Tian R, Xu J, Ji Z, Zhang Y et al. 2022. Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia. BMC Med. Genom. 15:137
     [Google Scholar]
  73. 73.
    Hug N, Longman D, Cáceres JF. 2016. Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res. 44:1483–95
     [Google Scholar]
  74. 74.
    Hunter N. 2015. Meiotic recombination: the essence of heredity. Cold Spring Harb. Perspect. Biol. 7:a016618
     [Google Scholar]
  75. 75.
    Ishiguro K, Kim J, Fujiyama-Nakamura S, Kato S, Watanabe Y. 2011. A new meiosis-specific cohesin complex implicated in the cohesin code for homologous pairing. EMBO Rep. 12:267–75
     [Google Scholar]
  76. 76.
    Jones SH, Wilkinson M. 2017. RNA decay, evolution, and the testis. RNA Biol. 14:146–55
     [Google Scholar]
  77. 77.
    Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J et al. 2020. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–43
     [Google Scholar]
  78. 78.
    Kasak L, Laan M. 2021. Monogenic causes of non-obstructive azoospermia: challenges, established knowledge, limitations and perspectives. Hum. Genet. 140:135–54
     [Google Scholar]
  79. 79.
    Kee K, Angeles VT, Flores M, Nguyen HN, Reijo Pera RA. 2009. Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462:222–25
     [Google Scholar]
  80. 80.
    Kherraf Z-E, Cazin C, Bouker A, Fourati Ben Mustapha S, Hennebicq S et al. 2022. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia. Am. J. Hum. Genet. 109:508–17
     [Google Scholar]
  81. 81.
    Kouznetsova A, Benavente R, Pastink A, Höög C. 2011. Meiosis in mice without a synaptonemal complex. PLOS ONE 6:e28255
     [Google Scholar]
  82. 82.
    Kouznetsova A, Novak I, Jessberger R, Höög C. 2005. SYCP2 and SYCP3 are required for cohesin core integrity at diplotene but not for centromere cohesion at the first meiotic division. J. Cell Sci. 118:2271–78
     [Google Scholar]
  83. 83.
    Kouznetsova A, Wang H, Bellani M, Camerini-Otero RD, Jessberger R, Höög C. 2009. BRCA1-mediated chromatin silencing is limited to oocytes with a small number of asynapsed chromosomes. J. Cell Sci. 122:2446–52
     [Google Scholar]
  84. 84.
    Krausz C, Riera-Escamilla A. 2018. Genetics of male infertility. Nat. Rev. Urol. 15:369–84
     [Google Scholar]
  85. 85.
    Krausz C, Riera-Escamilla A, Moreno-Mendoza D, Holleman K, Cioppi F et al. 2020. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men. Genet. Med. 22:1956–66
     [Google Scholar]
  86. 86.
    Kudo NR, Anger M, Peters AHFM, Stemmann O, Theussl H-C et al. 2009. Role of cleavage by separase of the Rec8 kleisin subunit of cohesin during mammalian meiosis I. J. Cell Sci. 122:2686–98
     [Google Scholar]
  87. 87.
    Kudo NR, Wassmann K, Anger M, Schuh M, Wirth KG et al. 2006. Resolution of chiasmata in oocytes requires separase-mediated proteolysis. Cell 126:135–46
     [Google Scholar]
  88. 88.
    Kurosaki T, Popp MW, Maquat LE. 2019. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat. Rev. Mol. Cell Biol. 20:406–20
     [Google Scholar]
  89. 89.
    Lammers JH, Offenberg HH, van Aalderen M, Vink AC, Dietrich AJ, Heyting C. 1994. The gene encoding a major component of the lateral elements of synaptonemal complexes of the rat is related to X-linked lymphocyte-regulated genes. Mol. Cell. Biol. 14:1137–46
     [Google Scholar]
  90. 90.
    Le Hir H, Gatfield D, Izaurralde E, Moore MJ 2001. The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J. 20:4987–97
     [Google Scholar]
  91. 91.
    Lee C-Y, Horn HF, Stewart CL, Burke B, Bolcun-Filas E et al. 2015. Mechanism and regulation of rapid telomere prophase movements in mouse meiotic chromosomes. Cell Rep. 11:551–63
     [Google Scholar]
  92. 92.
    Lee J, Hirano T. 2011. RAD21L, a novel cohesin subunit implicated in linking homologous chromosomes in mammalian meiosis. J. Cell Biol. 192:263–76
     [Google Scholar]
  93. 93.
    Lee J, Iwai T, Yokota T, Yamashita M. 2003. Temporally and spatially selective loss of Rec8 protein from meiotic chromosomes during mammalian meiosis. J. Cell Sci. 116:2781–90
     [Google Scholar]
  94. 94.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E et al. 2016. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–91
     [Google Scholar]
  95. 95.
    Lenzi ML, Smith J, Snowden T, Kim M, Fishel R et al. 2005. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis I in human oocytes. Am. J. Hum. Genet. 76:112–27
     [Google Scholar]
  96. 96.
    Li XC, Bolcun-Filas E, Schimenti JC. 2011. Genetic evidence that synaptonemal complex axial elements govern recombination pathway choice in mice. Genetics 189:71–82
     [Google Scholar]
  97. 97.
    Liu JG, Yuan L, Brundell E, Björkroth B, Daneholt B, Höög C. 1996. Localization of the N-terminus of SCP1 to the central element of the synaptonemal complex and evidence for direct interactions between the N-termini of SCP1 molecules organized head-to-head. Exp. Cell Res. 226:11–19
     [Google Scholar]
  98. 98.
    Llano E, Herrán Y, García-Tuñón I, Gutiérrez-Caballero C, de Álava E et al. 2012. Meiotic cohesin complexes are essential for the formation of the axial element in mice. J. Cell Biol. 197:877–85
     [Google Scholar]
  99. 99.
    Lu J, Gu Y, Feng J, Zhou W, Yang X, Shen Y. 2014. Structural insight into the central element assembly of the synaptonemal complex. Sci. Rep. 4:7059
     [Google Scholar]
  100. 100.
    Lykke-Andersen J, Shu MD, Steitz JA. 2001. Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science 293:1836–39
     [Google Scholar]
  101. 101.
    Lynn A, Koehler KE, Judis L, Chan ER, Cherry JP et al. 2002. Covariation of synaptonemal complex length and mammalian meiotic exchange rates. Science 296:2222–25
     [Google Scholar]
  102. 102.
    MacGregor IA, Adams IR, Gilbert N. 2019. Large-scale chromatin organisation in interphase, mitosis and meiosis. Biochem. J. 476:2141–56
     [Google Scholar]
  103. 103.
    Mahadevaiah SK, Bourc'his D, de Rooij DG, Bestor TH, Turner JMA, Burgoyne PS. 2008. Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. J. Cell Biol. 182:263–76
     [Google Scholar]
  104. 104.
    Mahadevaiah SK, Turner JM, Baudat F, Rogakou EP, de Boer P et al. 2001. Recombinational DNA double-strand breaks in mice precede synapsis. Nat. Genet. 27:271–76
     [Google Scholar]
  105. 105.
    Maor-Sagie E, Cinnamon Y, Yaacov B, Shaag A, Goldsmidt H et al. 2015. Deleterious mutation in SYCE1 is associated with non-obstructive azoospermia. J. Assist. Reprod. Genet. 32:887–91
     [Google Scholar]
  106. 106.
    Marcet-Ortega M, Pacheco S, Martínez-Marchal A, Castillo H, Flores E et al. 2017. p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes. PLOS Genet. 13:e1006845
     [Google Scholar]
  107. 107.
    Martinez G, Coutton C, Loeuillet C, Cazin C, Muroňová J et al. 2022. Oligogenic heterozygous inheritance of sperm abnormalities in mouse. eLife 11:e75373
     [Google Scholar]
  108. 108.
    Martínez J, Bonache S, Carvajal A, Bassas L, Larriba S. 2007. Mutations of SYCP3 are rare in infertile Spanish men with meiotic arrest. Fertil. Steril. 88:988–89
     [Google Scholar]
  109. 109.
    Mengoli V, Jonak K, Lyzak O, Lamb M, Lister LM et al. 2021. Deprotection of centromeric cohesin at meiosis II requires APC/C activity but not kinetochore tension. EMBO J. 40:e106812
     [Google Scholar]
  110. 110.
    Meuwissen RL, Offenberg HH, Dietrich AJ, Riesewijk A, van Iersel M, Heyting C. 1992. A coiled-coil related protein specific for synapsed regions of meiotic prophase chromosomes. EMBO J. 11:5091–100
     [Google Scholar]
  111. 111.
    Miyamoto T, Hasuike S, Yogev L, Maduro MR, Ishikawa M et al. 2003. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362:1714–19
     [Google Scholar]
  112. 112.
    Mizutani E, Suzumori N, Ozaki Y, Oseto K, Yamada-Namikawa C et al. 2011. SYCP3 mutation may not be associated with recurrent miscarriage caused by aneuploidy. Hum. Reprod. 26:1259–66
     [Google Scholar]
  113. 113.
    Moens PB, Kolas NK, Tarsounas M, Marcon E, Cohen PE, Spyropoulos B. 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. J. Cell Sci. 115:1611–22
     [Google Scholar]
  114. 114.
    Moses MJ. 1956. Chromosomal structures in crayfish spermatocytes. J. Biophys. Biochem. Cytol. 2:215–18
     [Google Scholar]
  115. 115.
    Moses MJ. 1968. Synaptinemal complex. Annu. Rev. Genet. 2:363–412
     [Google Scholar]
  116. 116.
    Nabi S, Askari M, Rezaei-Gazik M, Salehi N, Almadani N et al. 2022. A rare frameshift mutation in SYCP1 is associated with human male infertility. Mol. Hum. Reprod. 28:gaac009
     [Google Scholar]
  117. 117.
    Naro C, Jolly A, Di Persio S, Bielli P, Setterblad N et al. 2017. An orchestrated intron retention program in meiosis controls timely usage of transcripts during germ cell differentiation. Dev. Cell 41:82–93.e4
     [Google Scholar]
  118. 118.
    Offenberg HH, Schalk JA, Meuwissen RL, van Aalderen M, Kester HA et al. 1998. SCP2: a major protein component of the axial elements of synaptonemal complexes of the rat. Nucleic Acids Res. 26:2572–79
     [Google Scholar]
  119. 119.
    Oldenkamp R, Rowland BD. 2022. A walk through the SMC cycle: from catching DNAs to shaping the genome. Mol. Cell 82:1616–30
     [Google Scholar]
  120. 120.
    Ollinger R, Alsheimer M, Benavente R. 2005. Mammalian protein SCP1 forms synaptonemal complex-like structures in the absence of meiotic chromosomes. Mol. Biol. Cell 16:212–17
     [Google Scholar]
  121. 121.
    Ortiz R, Echeverría OM, Ubaldo E, Carlos A, Scassellati C, Vázquez-Nin GH. 2002. Cytochemical study of the distribution of RNA and DNA in the synaptonemal complex of guinea-pig and rat spermatocytes. Eur. J. Histochem. 46:133–42
     [Google Scholar]
  122. 122.
    Oud MS, Ramos L, O'Bryan MK, McLachlan RI, Okutman Ö et al. 2017. Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia. Hum. Mutat. 38:1592–605
     [Google Scholar]
  123. 123.
    Oud MS, Smits RM, Smith HE, Mastrorosa FK, Holt GS et al. 2022. A de novo paradigm for male infertility. Nat. Commun. 13:154
     [Google Scholar]
  124. 124.
    Pacheco S, Marcet-Ortega M, Lange J, Jasin M, Keeney S, Roig I. 2015. The ATM signaling cascade promotes recombination-dependent pachytene arrest in mouse spermatocytes. PLOS Genet. 11:e1005017
     [Google Scholar]
  125. 125.
    Pashaei M, Rahimi Bidgoli MM, Zare-Abdollahi D, Najmabadi H, Haji-Seyed-Javadi R et al. 2020. The second mutation of SYCE1 gene associated with autosomal recessive nonobstructive azoospermia. J. Assist. Reprod. Genet. 37:451–58
     [Google Scholar]
  126. 126.
    Pelttari J, Hoja MR, Yuan L, Liu JG, Brundell E et al. 2001. A meiotic chromosomal core consisting of cohesin complex proteins recruits DNA recombination proteins and promotes synapsis in the absence of an axial element in mammalian meiotic cells. Mol. Cell. Biol. 21:5667–77
     [Google Scholar]
  127. 127.
    Plug AW, Xu J, Reddy G, Golub EI, Ashley T. 1996. Presynaptic association of Rad51 protein with selected sites in meiotic chromatin. PNAS 93:5920–24
     [Google Scholar]
  128. 128.
    Prieto I, Pezzi N, Buesa JM, Kremer L, Barthelemy I et al. 2002. STAG2 and Rad21 mammalian mitotic cohesins are implicated in meiosis. EMBO Rep. 3:543–50
     [Google Scholar]
  129. 129.
    Prieto I, Suja JA, Pezzi N, Kremer L, Martínez-A C et al. 2001. Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I. Nat. Cell Biol. 3:761–66
     [Google Scholar]
  130. 130.
    Qiao H, Chen JK, Reynolds A, Höög C, Paddy M, Hunter N. 2012. Interplay between synaptonemal complex, homologous recombination, and centromeres during mammalian meiosis. PLOS Genet. 8:e1002790
     [Google Scholar]
  131. 131.
    Reichmann J, Dobie K, Lister LM, Crichton JH, Best D et al. 2020. Tex19.1 inhibits the N-end rule pathway and maintains acetylated SMC3 cohesin and sister chromatid cohesion in oocytes. J. Cell Biol. 219:e201702123
     [Google Scholar]
  132. 132.
    Reijo R, Lee TY, Salo P, Alagappan R, Brown LG et al. 1995. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat. Genet. 10:383–93
     [Google Scholar]
  133. 133.
    Revenkova E, Eijpe M, Heyting C, Gross B, Jessberger R. 2001. Novel meiosis-specific isoform of mammalian SMC1. Mol. Cell. Biol. 21:6984–98
     [Google Scholar]
  134. 134.
    Revenkova E, Eijpe M, Heyting C, Hodges CA, Hunt PA et al. 2004. Cohesin SMC1β is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat. Cell Biol. 6:555–62
     [Google Scholar]
  135. 135.
    Reynolds N, Collier B, Maratou K, Bingham V, Speed RM et al. 2005. Dazl binds in vivo to specific transcripts and can regulate the pre-meiotic translation of Mvh in germ cells. Hum. Mol. Genet. 14:3899–909
     [Google Scholar]
  136. 136.
    Riera-Escamilla A, Enguita-Marruedo A, Moreno-Mendoza D, Chianese C, Sleddens-Linkels E et al. 2019. Sequencing of a “mouse azoospermia” gene panel in azoospermic men: identification of RNF212 and STAG3 mutations as novel genetic causes of meiotic arrest. Hum. Reprod. 34:978–88
     [Google Scholar]
  137. 137.
    Rinaldi VD, Bolcun-Filas E, Kogo H, Kurahashi H, Schimenti JC. 2017. The DNA damage checkpoint eliminates mouse oocytes with chromosome synapsis failure. Mol. Cell 67:1026–36.e2
     [Google Scholar]
  138. 138.
    Robert T, Nore A, Brun C, Maffre C, Crimi B et al. 2016. The TopoVIB-like protein family is required for meiotic DNA double-strand break formation. Science 351:943–49
     [Google Scholar]
  139. 139.
    Romanienko PJ, Camerini-Otero RD. 2000. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol. Cell 6:975–87
     [Google Scholar]
  140. 140.
    Roos A, von Kaisenberg CS, Eggermann T, Schwanitz G, Löffler C et al. 2013. Analysis of SYCP3 encoding synaptonemal complex protein 3 in human aneuploidies. Arch. Gynecol. Obstet. 288:1153–58
     [Google Scholar]
  141. 141.
    Rosario R, Adams IR, Anderson RA. 2016. Is there a role for DAZL in human female fertility?. Mol. Hum. Reprod. 22:377–83
     [Google Scholar]
  142. 142.
    Rosario R, Smith RWP, Adams IR, Anderson RA. 2017. RNA immunoprecipitation identifies novel targets of DAZL in human foetal ovary. Mol. Hum. Reprod. 23:177–86
     [Google Scholar]
  143. 143.
    Sánchez-Sáez F, Gómez-H L, Dunne OM, Gallego-Páramo C, Felipe-Medina N et al. 2020. Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility. Sci. Adv. 6:eabb1660
     [Google Scholar]
  144. 144.
    Sandhu S, Sou IF, Hunter JE, Salmon L, Wilson CL et al. 2021. Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12. Commun. Biol. 4:1371
     [Google Scholar]
  145. 145.
    Sazegari A, Kalantar SM, Pashaiefar H, Mohtaram S, Honarvar N et al. 2014. The T657C polymorphism on the SYCP3 gene is associated with recurrent pregnancy loss. J. Assist. Reprod. Genet. 31:1377–81
     [Google Scholar]
  146. 146.
    Schalk JA, Dietrich AJ, Vink AC, Offenberg HH, van Aalderen M, Heyting C. 1998. Localization of SCP2 and SCP3 protein molecules within synaptonemal complexes of the rat. Chromosoma 107:540–48
     [Google Scholar]
  147. 147.
    Schilit SLP, Menon S, Friedrich C, Kammin T, Wilch E et al. 2020. SYCP2 translocation-mediated dysregulation and frameshift variants cause human male infertility. Am. J. Hum. Genet. 106:41–57
     [Google Scholar]
  148. 148.
    Schmekel K, Meuwissen RL, Dietrich AJ, Vink AC, van Marle J et al. 1996. Organization of SCP1 protein molecules within synaptonemal complexes of the rat. Exp. Cell Res. 226:20–30
     [Google Scholar]
  149. 149.
    Schmekel K, Skoglund U, Daneholt B. 1993. The three-dimensional structure of the central region in a synaptonemal complex: a comparison between rat and two insect species, Drosophila melanogaster and Blaps cribrosa. Chromosoma 102:682–92
     [Google Scholar]
  150. 150.
    Schramm S, Fraune J, Naumann R, Hernandez-Hernandez A, Höög C et al. 2011. A novel mouse synaptonemal complex protein is essential for loading of central element proteins, recombination, and fertility. PLOS Genet. 7:e1002088
     [Google Scholar]
  151. 151.
    Schücker K, Holm T, Franke C, Sauer M, Benavente R. 2015. Elucidation of synaptonemal complex organization by super-resolution imaging with isotropic resolution. PNAS 112:2029–33
     [Google Scholar]
  152. 152.
    Shibuya H, Hernández-Hernández A, Morimoto A, Negishi L, Höög C, Watanabe Y. 2015. MAJIN links telomeric DNA to the nuclear membrane by exchanging telomere cap. Cell 163:1252–66
     [Google Scholar]
  153. 153.
    Shum EY, Jones SH, Shao A, Dumdie J, Krause MD et al. 2016. The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated RNA decay. Cell 165:382–95
     [Google Scholar]
  154. 154.
    Sibley CR, Blazquez L, Ule J. 2016. Lessons from non-canonical splicing. Nat. Rev. Genet. 17:407–21
     [Google Scholar]
  155. 155.
    Solari AJ. 1980. Synaptosomal complexes and associated structures in microspread human spermatocytes. Chromosoma 81:315–37
     [Google Scholar]
  156. 156.
    Spindler M-C, Filbeck S, Stigloher C, Benavente R. 2019. Quantitative basis of meiotic chromosome synapsis analyzed by electron tomography. Sci. Rep. 9:16102
     [Google Scholar]
  157. 157.
    Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. 2005. SYCP3 mutations are uncommon in patients with azoospermia. Fertil. Steril. 84:1019–20
     [Google Scholar]
  158. 158.
    Stouffs K, Vandermaelen D, Tournaye H, Liebaers I, Lissens W. 2011. Mutation analysis of three genes in patients with maturation arrest of spermatogenesis and couples with recurrent miscarriages. Reprod. BioMed. Online 22:65–71
     [Google Scholar]
  159. 159.
    Syrjänen JL, Heller I, Candelli A, Davies OR, Peterman EJG et al. 2017. Single-molecule observation of DNA compaction by meiotic protein SYCP3. eLife 6:e22582
     [Google Scholar]
  160. 160.
    Syrjänen JL, Pellegrini L, Davies OR. 2014. A molecular model for the role of SYCP3 in meiotic chromosome organisation. eLife 3:e02963
     [Google Scholar]
  161. 161.
    Tachibana-Konwalski K, Godwin J, van der Weyden L, Champion L, Kudo NR et al. 2010. Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. Genes Dev. 24:2505–16
     [Google Scholar]
  162. 162.
    Tarsounas M, Morita T, Pearlman RE, Moens PB. 1999. RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes. J. Cell Biol. 147:207–20
     [Google Scholar]
  163. 163.
    Tease C, Hultén MA. 2004. Inter-sex variation in synaptonemal complex lengths largely determine the different recombination rates in male and female germ cells. Cytogenet. Genome Res. 107:208–15
     [Google Scholar]
  164. 164.
    Tucker EJ, Bell KM, Robevska G, van den Bergen J, Ayers KL et al. 2022. Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes. Eur. J. Hum. Genet. 30:219–28
     [Google Scholar]
  165. 165.
    Turner JMA, 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
     [Google Scholar]
  166. 166.
    van der Bijl N, Röpke A, Biswas U, Wöste M, Jessberger R et al. 2019. Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest. Hum. Reprod. 34:2112–19
     [Google Scholar]
  167. 167.
    Veitia RA. 2020. Primary ovarian insufficiency, meiosis and DNA repair. Biomed. J. 43:115–23
     [Google Scholar]
  168. 168.
    Voelkel-Meiman K, Cheng S-Y, Morehouse SJ, MacQueen AJ. 2016. Synaptonemal complex proteins of budding yeast define reciprocal roles in MutSγ-mediated crossover formation. Genetics 203:1091–103
     [Google Scholar]
  169. 169.
    Voelkel-Meiman K, Cheng S-Y, Parziale M, Morehouse SJ, Feil A et al. 2019. Crossover recombination and synapsis are linked by adjacent regions within the N terminus of the Zip1 synaptonemal complex protein. PLOS Genet. 15:e1008201
     [Google Scholar]
  170. 170.
    Wang H, Höög C. 2006. Structural damage to meiotic chromosomes impairs DNA recombination and checkpoint control in mammalian oocytes. J. Cell Biol. 173:485–95
     [Google Scholar]
  171. 171.
    West AM, Rosenberg SC, Ur SN, Lehmer MK, Ye Q et al. 2019. A conserved filamentous assembly underlies the structure of the meiotic chromosome axis. eLife 8:e40372
     [Google Scholar]
  172. 172.
    Westergaard M, von Wettstein D. 1972. The synaptinemal complex. Annu. Rev. Genet. 6:71–110
     [Google Scholar]
  173. 173.
    Yang F, De La Fuente R, Leu NA, Baumann C, McLaughlin KJ, Wang PJ. 2006. Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J. Cell Biol. 173:497–507
     [Google Scholar]
  174. 174.
    Yatsenko SA, Rajkovic A. 2019. Genetics of human female infertility. Biol. Reprod. 101:549–66
     [Google Scholar]
  175. 175.
    Yuan L, Liu JG, Hoja MR, Wilbertz J, Nordqvist K, Höög C. 2002. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296:1115–18
     [Google Scholar]
  176. 176.
    Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B, Höög C. 2000. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol. Cell 5:73–83
     [Google Scholar]
  177. 177.
    Yuan L, Pelttari J, Brundell E, Björkroth B, Zhao J et al. 1998. The synaptonemal complex protein SCP3 can form multistranded, cross-striated fibers in vivo. J. Cell Biol. 142:331–39
     [Google Scholar]
  178. 178.
    Zhang F, Liu M, Gao J. 2022. Alterations in synaptonemal complex coding genes and human infertility. Int. J. Biol. Sci. 18:1933–43
     [Google Scholar]
  179. 179.
    Zhe J, Ye D, Chen X, Liu Y, Zhou X et al. 2020. Consanguineous Chinese familial study reveals that a gross deletion that includes the SYCE1 gene region is associated with premature ovarian insufficiency. Reprod. Sci. 27:461–67
     [Google Scholar]
  180. 180.
    Zickler D, Kleckner N. 2015. Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harb. Perspect. Biol. 7:a016626
     [Google Scholar]
/content/journals/10.1146/annurev-genom-110122-090239
Loading
Meiotic Chromosome Structure, the Synaptonemal Complex, and Infertility
Annual Review of Genomics and Human Genetics 24, 35 (2023); https://doi.org/10.1146/annurev-genom-110122-090239
/content/journals/10.1146/annurev-genom-110122-090239
/content/journals/10.1146/annurev-genom-110122-090239
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error