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Chromosoma

, Volume 128, Issue 3, pp 413–421 | Cite as

Maternal obesity enhances oocyte chromosome abnormalities associated with aging

  • Yan Yun
  • Zijie Wei
  • Neil HunterEmail author
Original Article

Abstract

Obesity is increasing globally, and maternal obesity has adverse effects on pregnancy outcomes and the long-term health of offspring. Maternal obesity has been associated with pregnancy failure through impaired oogenesis and embryogenesis. However, whether maternal obesity causes chromosome abnormalities in oocytes has remained unclear. Here we show that chromosome abnormalities are increased in the oocytes of obese mice fed a high-fat diet and identify weakened sister-chromatid cohesion as the likely cause. Numbers of full-grown follicles retrieved from obese mice were the same as controls and the efficiency of in vitro oocyte maturation remained high. However, chromosome abnormalities presenting in both metaphase-I and metaphase-II were elevated, most prominently the premature separation of sister chromatids. Weakened sister-chromatid cohesion in oocytes from obese mice was manifested both as the terminalization of chiasmata in metaphase-I and as increased separation of sister centromeres in metaphase II. Obesity-associated abnormalities were elevated in older mice implying that maternal obesity exacerbates the deterioration of cohesion seen with advancing age.

Keywords

Oocyte Meiosis Chromosome Aneuploidy Cohesin Maternal age effect Obesity High-fat diet Oxidative damage 

Notes

Acknowledgments

We thank Richard Shultz and members of the Hunter Lab for support and discussions. N.H. is an Investigator of the Howard Hughes Medical Institute, which also supported this study.

References

  1. Angell RR (1991) Predivision in human oocytes at meiosis I: a mechanism for trisomy formation in man. Hum Genet 86:383–387CrossRefPubMedGoogle Scholar
  2. Angell RR, Xian J, Keith J, Ledger W, Baird DT (1994) First meiotic division abnormalities in human oocytes: mechanism of trisomy formation. Cytogenet Cell Genet 65:194–202CrossRefGoogle Scholar
  3. Ata B, Seyhan A, AI-Shalaty J, Escriva AM, Son WY, Tan SL (2013) Effect of body mass index on in vitro maturation treatment outcomes in women without polycystic ovarian syndrome. J IVF Reprod Med Genet 1:1CrossRefGoogle Scholar
  4. Bellver J, Ayllon Y, Ferrando M, Melo M, Goyri E, Pellicer A, Remohi J, Meseguer M (2010) Female obesity impairs in vitro fertilization outcome without affecting embryo quality. Fertil Steril 93:447–454CrossRefPubMedGoogle Scholar
  5. Bellver J, Pellicer A, Garcia-Velasco JA, Ballesteros A, Remohi J, Meseguer M (2013) Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors. Fertil Steril 100:1050–1058CrossRefPubMedGoogle Scholar
  6. Binder NK, Hannan NJ, Gardner DK (2012) Paternal diet-induced obesity retards early mouse embryo development, mitochondrial activity and pregnancy health. PLoS One 7:e52304CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boots CE, Boudoures A, Zhang W, Drury A, Moley KH (2016) Obesity-induced oocyte mitochondrial defects are partially prevented and rescued by supplementation with co-enzyme Q10 in a mouse model. Hum Reprod 31:2090–2097CrossRefPubMedPubMedCentralGoogle Scholar
  8. Broughton DE, Moley KH (2017) Obesity and female infertility: potential mediators of obesity's impact. Fertil Steril 107:840–847CrossRefPubMedGoogle Scholar
  9. Burkhardt S, Borsos M, Szydlowska A, Godwin J, Williams SA, Cohen PE, Hirota T, Saitou M, Tachibana-Konwalski K (2016) Chromosome cohesion established by Rec8-cohesin in fetal oocytes is maintained without detectable turnover in oocytes arrested for months in mice. Curr Biol 26:678–685CrossRefPubMedPubMedCentralGoogle Scholar
  10. Campbell JM, Lane M, Owens JA, Bakos HW (2015) Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis. Reprod BioMed Online 31:593–604CrossRefPubMedGoogle Scholar
  11. Cardozo E, Pavone ME, Hirshfeld-Cytron JE (2011) Metabolic syndrome and oocyte quality. Trends Endocrinol Metab 22:103–109CrossRefPubMedGoogle Scholar
  12. Cheng JM, Liu YX (2017) Age-related loss of cohesion: causes and effects. Int J Mol Sci 18Google Scholar
  13. Cheng PP, Xia JJ, Wang HL, Chen JB, Wang FY, Zhang Y, Huang X, Zhang QJ, Qi ZQ (2011) Islet transplantation reverses the effects of maternal diabetes on mouse oocytes. Reproduction 141:417–424CrossRefPubMedGoogle Scholar
  14. Cheng JM, Li J, Tang JX, Hao XX, Wang ZP, Sun TC, Wang XX, Zhang Y, Chen SR, Liu YX (2017) Merotelic kinetochore attachment in oocyte meiosis II causes sister chromatids segregation errors in aged mice. Cell Cycle 16:1404–1413CrossRefPubMedPubMedCentralGoogle Scholar
  15. Chiang T, Duncan FE, Schindler K, Schultz RM, Lampson MA (2010) Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr Biol 20:1522–1528CrossRefPubMedPubMedCentralGoogle Scholar
  16. Duncan FE, Hornick JE, Lampson MA, Schultz RM, Shea LD, Woodruff TK (2012) Chromosome cohesion decreases in human eggs with advanced maternal age. Aging Cell 11:1121–1124CrossRefPubMedPubMedCentralGoogle Scholar
  17. Dunn GA, Bale TL (2009) Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150:4999–5009CrossRefPubMedPubMedCentralGoogle Scholar
  18. Eknoyan G (2008) Adolphe Quetelet (1796-1874)--the average man and indices of obesity. Nephrol Dial Transplant 23:47–51CrossRefPubMedGoogle Scholar
  19. Finger BJ, Harvey AJ, Green MP, Gardner DK (2015) Combined parental obesity negatively impacts preimplantation mouse embryo development, kinetics, morphology and metabolism. Hum Reprod 30:2084–2096CrossRefPubMedGoogle Scholar
  20. Fullston T, Shehadeh H, Sandeman LY, Kang WX, Wu LL, Robker RL, McPherson NO, Lane M (2015) Female offspring sired by diet induced obese male mice display impaired blastocyst development with molecular alterations to their ovaries, oocytes and cumulus cells. J Assist Reprod Genet 32:725–735CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ge (2014) DNA methylation in oocytes and liver of female mice and their offspring: effects of high-fat-diet induced obesity. Environ Health Perspect 122:159–164CrossRefPubMedGoogle Scholar
  22. Goncalves LF, Machado TQ, Castro-Pinheiro C, de Souza NG, Oliveira KJ, Fernandes-Santos C (2017) Ageing is associated with brown adipose tissue remodelling and loss of white fat browning in female C57BL/6 mice. Int J Exp Pathol 98:100–108CrossRefPubMedPubMedCentralGoogle Scholar
  23. Han LS, Wang HC, Li L, Li XY, Ge J, Reiter RJ, Wang Q (2017) Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway. J Pineal Res 63. doi:  https://doi.org/10.1111/jpi.12431
  24. Han LS, Ren C, Li L, Li XY, Ge J, Wang HC, Miao YL, Guo XJ, Moley KH, Shu WJ, Wang Q (2018) Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes (vol 50, pg 432, 2018). Nat Genet 50:768–768CrossRefPubMedGoogle Scholar
  25. Hauf S, Biswas A, Langegger M, Kawashima SA, Tsukahara T, Watanabe Y (2007) Aurora controls sister kinetochore mono-orientation and homolog bi-orientation in meiosis-I. EMBO J 26:4475–4486CrossRefPubMedPubMedCentralGoogle Scholar
  26. Herbert M, Kalleas D, Cooney D, Lamb M, Lister L (2015) Meiosis and maternal aging: insights from aneuploid oocytes and trisomy births. Cold Spring Harb Perspect Biol 7:a017970CrossRefPubMedPubMedCentralGoogle Scholar
  27. Heydemann A (2016) An overview of murine high fat diet as a model for type 2 diabetes mellitus. J Diabetes Res 2016:1–14Google Scholar
  28. Hirose Y, Suzuki R, Ohba T, Hinohara Y, Matsuhara H, Yoshida M, Itabashi Y, Murakami H, Yamamoto A (2011) Chiasmata promote monopolar attachment of sister chromatids and their co-segregation toward the proper pole during meiosis I. PLoS Genet 7:e1001329CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hodges CA, Revenkova E, Jessberger R, Hassold TJ, Hunt PA (2005) SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat Genet 37:1351–1355CrossRefPubMedGoogle Scholar
  30. Holt JE, Jones KT (2009) Control of homologous chromosome division in the mammalian oocyte. Mol Hum Reprod 15:139–147CrossRefPubMedGoogle Scholar
  31. Hou YJ, Zhu CC, Duan X, Liu HL, Wang Q, Sun SC (2016) Both diet and gene mutation induced obesity affect oocyte quality in mice. Sci Rep 6:18858CrossRefPubMedPubMedCentralGoogle Scholar
  32. Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, Thomas S, Thomas BF, Hassold TJ (2003) Bisphenol a exposure causes meiotic aneuploidy in the female mouse. Curr Biol 13:546–553CrossRefPubMedGoogle Scholar
  33. Hunter N (2017) Oocyte quality control: causes, mechanisms, and consequences. Cold Spring Harb Symp Quant Biol 82:235–247CrossRefGoogle Scholar
  34. Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR, McConnell J (2010) Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS One 5:e10074CrossRefPubMedPubMedCentralGoogle Scholar
  35. Jagiello G, Fang JS (1979) Analyses of diplotene chiasma frequencies in mouse oocytes and spermatocytes in relation to ageing and sexual dimorphism. Cytogenet Cell Genet 23:53–60CrossRefPubMedGoogle Scholar
  36. Jessberger R (2012) Age-related aneuploidy through cohesion exhaustion. EMBO Rep 13:539–546CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jia Z, Feng Z, Wang L, Li H, Wang H, Xu D, Zhao X, Feng D, Feng X (2018) Resveratrol reverses the adverse effects of a diet-induced obese murine model on oocyte quality and zona pellucida softening. Food Funct 9:2623–2633CrossRefPubMedGoogle Scholar
  38. Jones KT, Lane SI (2013) Molecular causes of aneuploidy in mammalian eggs. Development 140:3719–3730CrossRefGoogle Scholar
  39. Jungheim ES, Schoeller EL, Marquard KL, Louden ED, Schaffer JE, Moley KH (2010) Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology 151:4039–4046Google Scholar
  40. Jungheim ES, Schon SB, Schulte MB, DeUgarte DA, Fowler SA, Tuuli MG (2013) IVF outcomes in obese donor oocyte recipients: a systematic review and meta-analysis. Hum Reprod 28:2720–2727CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kitajima TS, Sakuno T, Ishiguro K, Iemura S, Natsume T, Kawashima SA, Watanabe Y (2006) Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature 441:46–52CrossRefGoogle Scholar
  42. Kudo NR, Wassmann K, Anger M, Schuh M, Wirth KG, Xu H, Helmhart W, Kudo H, McKay M, Maro B, Ellenberg J, de Boer P, Nasmyth K (2006) Resolution of chiasmata in oocytes requires separase-mediated proteolysis. Cell 126:135–146CrossRefPubMedGoogle Scholar
  43. Kouznetsova A, Lister L, Nordenskjold M, Herbert M, Hoog C (2007) Bi-orientation of achiasmatic chromosomes in meiosis I oocytes contributes to aneuploidy in mice. Nature Genetics 39: 966-968Google Scholar
  44. Lacefield S, Murray AW (2007) The spindle checkpoint rescues the meiotic segregation of chromosomes whose crossovers are far from the centromere. Nature Genetics 39: 1273-1277Google Scholar
  45. Lashen H, Fear K, Sturdee DW (2004) Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Hum Reprod 19:1644–1646CrossRefPubMedGoogle Scholar
  46. Lister LM, Kouznetsova A, Hyslop LA, Kalleas D, Pace SL, Barel JC, Nathan A, Floros V, Adelfalk C, Watanabe Y, Jessberger R, Kirkwood TB, Hoog C, Herbert M (2010) Age-related meiotic segregation errors in mammalian oocytes are preceded by depletion of cohesin and Sgo2. Curr Biol 20:1511–1521CrossRefGoogle Scholar
  47. Luke B, Brown MB, Stern JE, Missmer SA, Fujimoto VY, Leach R, Grp ASW (2011) Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates. Hum Reprod 26:245–252CrossRefPubMedGoogle Scholar
  48. Luzzo KM, Wang Q, Purcell SH, Chi M, Jimenez PT, Grindler N, Schedl T, Moley KH (2012) High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One 7:e49217CrossRefPubMedPubMedCentralGoogle Scholar
  49. MacLennan M, Crichton JH, Playfoot CJ, Adams IR (2015) Oocyte development, meiosis and aneuploidy. Semin Cell Dev Biol 45:68–76CrossRefPubMedPubMedCentralGoogle Scholar
  50. McPherson NO, Bell VG, Zander-Fox DL, Fullston T, Wu LL, Robker RL, Lane M (2015) When two obese parents are worse than one! Impacts on embryo and fetal development. Am J Physiol Endocrinol Metab 309:E568–E581CrossRefPubMedGoogle Scholar
  51. Mihalas BP, Bromfield EG, Sutherland JM, De Iuliis GN, McLaughlin EA, Aitken RJ, Nixon B (2018) Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. J Biol Chem 293:18944–18964CrossRefPubMedGoogle Scholar
  52. Minge CE, Bennett BD, Norman RJ, Robker RL (2008) Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality. Endocrinology 149:2646–2656CrossRefPubMedGoogle Scholar
  53. Nagaoka SI, Hassold TJ, Hunt PA (2012) Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet 13:493–504CrossRefPubMedPubMedCentralGoogle Scholar
  54. Nagaoka SI, Hodges CA, Albertini DF, Hunt PA (2011) Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Current Biology 21: 651-657.Google Scholar
  55. Ottolini CS, Newnham LJ, Capalbo A, Natesan SA, Joshi HA, Cimadomo D, Griffin DK, Sage K, Summers MC, Thornhill AR, Housworth E, Herbert AD, Rienzi L, Ubaldi FM, Handyside AH, Hoffmann ER (2015) Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates. Nat Genet 47:727–735CrossRefPubMedPubMedCentralGoogle Scholar
  56. Ozekinci M, Seven A, Olgan S, Sakinci M, Keskin U, Akar ME, Ceyhan ST, Ergun A (2015) Does obesity have detrimental effects on IVF treatment outcomes? BMC Womens Health 15:61CrossRefPubMedPubMedCentralGoogle Scholar
  57. Patel J, Tan SL, Hartshorne GM, McAinsh AD (2015) Unique geometry of sister kinetochores in human oocytes during meiosis I may explain maternal age-associated increases in chromosomal abnormalities. Biol Open 5:178–184CrossRefPubMedGoogle Scholar
  58. Perkins AT, Das TM, Panzera LC, Bickel SE (2016) Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors. Proc Natl Acad Sci U S A 113:E6823–E6830CrossRefPubMedPubMedCentralGoogle Scholar
  59. Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, Reimold M, Haring HU, Claussen CD, Stefan N (2010) Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 59:1789–1793CrossRefPubMedPubMedCentralGoogle Scholar
  60. Qiao H, Rao H, Yun Y, Sandhu S, Fong JH, Sapre M, Nguyen M, Tham A, Van BW, Chng TYH, Lee A, Hunter N (2018) Impeding DNA break repair enables oocyte quality control. Mol Cell 72:211–221 e213CrossRefPubMedPubMedCentralGoogle Scholar
  61. Reichman R, Alleva B, Smolikove S (2017) Prophase I: preparing chromosomes for segregation in the developing oocyte. Results Probl Cell Differ 59:125–173CrossRefPubMedGoogle Scholar
  62. Revenkova E, Herrmann K, Adelfalk C, Jessberger R (2010) Oocyte cohesin expression restricted to predictyate stages provides full fertility and prevents aneuploidy. Curr Biol 20:1529–1533CrossRefPubMedPubMedCentralGoogle Scholar
  63. Saben JL, Boudoures AL, Asghar Z, Thompson A, Drury A, Zhang W, Chi M, Cusumano A, Scheaffer S, Moley KH (2016) Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations. Cell Rep 16:1–8CrossRefPubMedPubMedCentralGoogle Scholar
  64. Sakakibara Y, Hashimoto S, Nakaoka Y, Kouznetsova A, Hoog C, Kitajima TS (2015) Bivalent separation into univalents precedes age-related meiosis I errors in oocytes. Nature Communications 6:7550.Google Scholar
  65. Sakuno T, Tanaka K, Hauf S, Watanabe Y (2011) Repositioning of aurora B promoted by chiasmata ensures sister chromatid mono-orientation in meiosis I. Developmental Cell 21:534-545.Google Scholar
  66. Selesniemi K, Lee HJ, Muhlhauser A, Tilly JL (2011) Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A 108:12319–12324CrossRefPubMedPubMedCentralGoogle Scholar
  67. Severson AF, Meyer BJ (2014) Divergent kleisin subunits of cohesin specify mechanisms to tether and release meiotic chromosomes. eLife 3:e03467CrossRefPubMedPubMedCentralGoogle Scholar
  68. Shomper M, Lappa C, FitzHarris G (2014) Kinetochore microtubule establishment is defective in oocytes from aged mice. Cell Cycle 13:1171–1179CrossRefPubMedPubMedCentralGoogle Scholar
  69. Snider AP, Wood JR (2019) Obesity induces ovarian inflammation and reduces oocyte quality. Reproduction.  https://doi.org/10.1530/REP-18-0583
  70. Speed RM (1977) The effects of ageing on the meiotic chromosomes of male and female mice. Chromosoma 64:241–254CrossRefPubMedGoogle Scholar
  71. Tachibana-Konwalski K, Godwin J, van der Weyden L, Champion L, Kudo NR, Adams DJ, Nasmyth K (2010) Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. Genes Dev 24:2505–2516CrossRefPubMedPubMedCentralGoogle Scholar
  72. Tachibana-Konwalski K, Godwin J, Borsos M, Rattani A, Adams DJ, Nasmyth K (2013) Spindle assembly checkpoint of oocytes depends on a kinetochore structure determined by cohesin in meiosis I. Curr Biol 23:2534–2539CrossRefPubMedPubMedCentralGoogle Scholar
  73. Tsutsumi M, Fujiwara R, Nishizawa H, Ito M, Kogo H, Inagaki H, Ohye T, Kato T, Fujii T, Kurahashi H (2014) Age-related decrease of meiotic cohesins in human oocytes. PLoS One 9:e96710CrossRefPubMedPubMedCentralGoogle Scholar
  74. Wang Q, Ratchford AM, Chi MMY, Schoeller E, Frolova A, Schedl T, Moley KH (2009) Maternal diabetes causes mitochondrial dysfunction and meiotic defects in murine oocytes. Mol Endocrinol 23:1603–1612CrossRefPubMedPubMedCentralGoogle Scholar
  75. Watanabe Y (2012) Geometry and force behind kinetochore orientation: lessons from meiosis. Nat Rev Mol Cell Biol 13:370–382CrossRefPubMedGoogle Scholar
  76. Watkins AJ, Dias I, Tsuro H, Allen D, Emes RD, Moreton J, Wilson R, Ingram RJM, Sinclair KD (2018) Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc Natl Acad Sci U S A 115:10064–10069CrossRefPubMedPubMedCentralGoogle Scholar
  77. Wu LLY, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, Robker RL (2010) High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology 151:5438–5445CrossRefPubMedGoogle Scholar
  78. Wu LL, Russell DL, Wong SL, Chen M, Tsai TS, St John JC, Norman RJ, Febbraio MA, Carroll J, Robker RL (2015) Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors. Development 142:681–691CrossRefPubMedGoogle Scholar
  79. Yun Y, Lane SI, Jones KT (2014) Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes. Development 141:199–208CrossRefPubMedPubMedCentralGoogle Scholar
  80. Zhang D, Zhu Y, Gao H, Zhou B, Zhang R, Wang T, Ding G, Qu F, Huang H, Lu X (2010) Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro fertilisation: a cohort study of 2628 Chinese women. Gynecol Endocrinol 26:325–332CrossRefPubMedGoogle Scholar
  81. Zhang JJ, Feret M, Chang L, Yang M, Merhi Z (2015a) Obesity adversely impacts the number and maturity of oocytes in conventional IVF not in minimal stimulation IVF. Gynecol Endocrinol 31:409–413CrossRefPubMedGoogle Scholar
  82. Zhang L, Han L, Ma R, Hou X, Yu Y, Sun S, Xu Y, Schedl T, Moley KH, Wang Q (2015b) Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes. Cell Cycle 14:2959–2968CrossRefPubMedPubMedCentralGoogle Scholar
  83. Zhao LH, Lu TF, Gao L, Fu XW, Zhu SE, Hou YP (2017) Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice. J Anim Sci Biotechnol 8:62.  https://doi.org/10.1186/s40104-017-0195-z CrossRefPubMedPubMedCentralGoogle Scholar
  84. Zielinska AP, Holubcova Z, Blayney M, Elder K, Schuh M (2015) Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect. eLife 4:e11389CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Howard Hughes Medical InstituteUniversity of California, DavisDavisUSA
  2. 2.Department of Microbiology & Molecular GeneticsUniversity of California, DavisDavisUSA
  3. 3.Department of Molecular & Cellular BiologyUniversity of California, DavisDavisUSA
  4. 4.Department of Cell Biology & Human AnatomyUniversity of California, DavisDavisUSA

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