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Cited by 235Prenatal Screening and DiagnosticsMicrotubule and mitosis dynamicsReproductive Biology and Fertility

Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm

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McCoy, Rajiv C.·2017·Trends in Genetics
DOI 10.1016/j.tig.2017.04.001PMC PMC5484399
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Abstract

Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping to close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.

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  1. [1]Santaguida S Amon A 2015 Short-and long-term effects of chromosome mis-segregation and aneuploidy Nat Rev Mol Cell Biol 16 473 485 26204159
  2. [2]Webster A Schuh M Mechanisms of Aneuploidy in Human Eggs 2017 Trends Cell Biol 27 55 68 27773484
  3. [3]Treff NR 2010 SNP microarray-based 24 chromosome aneuploidy screening is significantly more consistent than FISH Mol Hum Reprod 16 583 589 20484246 PMC2907219
  4. [4]Capalbo A 2017 Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities Hum Reprod 32 492 498 27738115 PMC5400043
  5. [5]Munné S 1994 Chromosome mosaicism in human embryos Biol Reprod 51 373 379 7803609
  6. [6]Delhanty JD 1997 Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients Hum Genet 99 755 760 9187668
  7. [7]Vanneste E 2009 Chromosome instability is common in human cleavage-stage embryos Nat Med 15 577 583 19396175
  8. [8]Baart EB 2006 Preimplantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF Hum Reprod 21 223 233 16155075
  9. [9]Mertzanidou A 2013 Microarray analysis reveals abnormal chromosomal complements in over 70% of 14 normally developing human embryos Hum Reprod 28 256 264 23054067
  10. [10]van Echten-Arends J 2011 Chromosomal mosaicism in human preimplantation embryos: a systematic review Hum Reprod Update 17 620 627 21531753
  11. [11]McCoy RC 2015 Evidence of selection against complex mitotic-origin aneuploidy during preimplantation development PLoS Genet 11 e1005601 26491874 PMC4619652
  12. [12]Scott RT Galliano D 2016 The challenge of embryonic mosaicism in preimplantation genetic screening Fertil Steril 105 1150 1152 26845661
  13. [13]Braude P 2002 Preimplantation genetic diagnosis Nature Rev Genet 3 941 955 12459724
  14. [14]Mastenbroek S 2011 Preimplantation genetic screening: a systematic review and meta-analysis of RCTs Hum Reprod Update 17 454 466 21531751
  15. [15]Scott RT 2013 Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial Fertil Steril 100 624 630 23773313
  16. [16]Adler A 2014 Blastocyst culture selects for euploid embryos: comparison of blastomere and trophectoderm biopsies Reprod Biomed Online 28 485 491 24581980
  17. [17]Gordon DJ 2012 Causes and consequences of aneuploidy in cancer Nature Rev Genet 13 189 203 22269907
  18. [18]Barbash-Hazan S 2009 Preimplantation aneuploid embryos undergo self-correction in correlation with their developmental potential Fertil Steril 92 890 896 18829021
  19. [19]Bielanska M 2002 Chromosomal mosaicism throughout human preimplantation development in vitro: incidence, type, and relevance to embryo outcome Hum Reprod 17 413 419 11821287
  20. [20]Braude P 1988 Human gene expression first occurs between the four-and eight-cell stages of preimplantation development Nature 332 459 461 3352746
  21. [21]Vassena R 2011 Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development Development 138 3699 3709 21775417 PMC4074286
  22. [22]Zhao R 2014 A nontranscriptional role for Oct4 in the regulation of mitotic entry Proc Natl Acad Sci USA 111 15768 15773 25324523 PMC4226071
  23. [23]Vera-Rodriguez M 2015 Prediction model for aneuploidy in early human embryo development revealed by single-cell analysis Nat Commun 6 PMC4506544 26151134
  24. [24]Yanez LZ 2016 Human oocyte developmental potential is predicted by mechanical properties within hours after fertilization Nat Commun 7 PMC4770082 26904963
  25. [25]Harrison RH 2000 Lack of cell cycle checkpoints in human cleavage stage embryos revealed by a clonal pattern of chromosomal mosaicism analysed by sequential multicolour FISH Zygote 8 217 224 11014501
  26. [26]Kiessling AA 2009 Evidence that human blastomere cleavage is under unique cell cycle control J Assist Reprod Genet 26 187 195 19288185 PMC2682187
  27. [27]Lee A Kiessling AA 2016 Early human embryos are naturally aneuploid—can that be corrected? J Assist Reprod Genet 34 15 21 27900612 PMC5330987
  28. [29]Chavez SL 2012 Dynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage Nat Commun 3 PMC3535341 23212380
  29. [30]Coonen E 2004 Anaphase lagging mainly explains chromosomal mosaicism in human preimplantation embryos Hum Reprod 19 316 324 14747173
  30. [31]Cahill DP 1998 Mutations of mitotic checkpoint genes in human cancers Nature 392 300 303 9521327
  31. [32]van de Werken C 2015 Chromosome segregation regulation in human zygotes: altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex Hum Reprod 30 2275 2291 26223676
  32. [33]Wells D 2005 Expression of genes regulating chromosome segregation, the cell cycle and apoptosis during human preimplantation development Hum Reprod 20 1339 1348 15705620
  33. [34]Ganem NJ 2009 A mechanism linking extra centrosomes to chromosomal instability Nature 460 278 282 19506557 PMC2743290
  34. [35]Vázquez-Diez C 2016 Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos Proc Natl Acad Sci USA 113 626 631 26729872 PMC4725495
  35. [36]Voet T 2011 Breakage–fusion–bridge cycles leading to inv dup del occur in human cleavage stage embryos Hum Mutat 32 783 793 21412953
  36. [37]Zhang CZ 2015 Chromothripsis from DNA damage in micronuclei Nature 522 179 184 26017310 PMC4742237
  37. [39]Sundvall L 2013 Tetraploidy in hydatidiform moles Hum Reprod 28 2010 2020 23633551
  38. [40]Newport J Kirschner M 1982 A major developmental transition in early Xenopus embryos: I. characterization and timing of cellular changes at the midblastula stage Cell 30 675 686 6183003
  39. [41]Mantikou E 2013 Temporal and developmental-stage variation in the occurrence of mitotic errors in tripronuclear human preimplantation embryos Biol Reprod 89 42 23863408
  40. [42]Katz-Jaffe MG 2004 Mitotic errors in chromosome 21 of human preimplantation embryos are associated with non-viability Mol Hum Reprod 10 143 147 14742700
  41. [44]Nam HJ 2015 Centrosome dynamics as a source of chromosomal instability Trends Cell Biol 25 65 73 25455111 PMC4312731
  42. [45]Manandhar G 2005 Centrosome Reduction During Gametogenesis and Its Significance Biol Reprod 72 2 13 15385423
  43. [46]Holubcová Z 2015 Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes Science 348 1143 1147 26045437 PMC4477045
  44. [47]Schatten H Sun QY 2010 The role of centrosomes in fertilization, cell division and establishment of asymmetry during embryo development Semin Cell Dev Biol 21 174 184 20083214
  45. [48]Habedanck R 2005 The Polo kinase Plk4 functions in centriole duplication Nat Cell Biol 7 1140 1146 16244668
  46. [49]McCoy RC 2015 Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos Science 348 235 238 25859044 PMC5519344
  47. [50]Zhang Q Maternal common variant rs2305957 spanning PLK4 is associated with blastocyst formation and early recurrent miscarriage Fertil Steril in press 28238495
  48. [51]Sathananthan AH 1999 Development of the human dispermic embryo Hum Reprod Update 5 553 560 10582794
  49. [52]Ven HH 1985 Polyspermy in in vitro fertilization of human oocytes: frequency and possible causes Ann N Y Acad Sci 442 88 95 3860066
  50. [53]Chatzimeletiou K 2005 Spindle abnormalities in normally developing and arrested human preimplantation embryos in vitro identified by confocal laser scanning microscopy Hum Reprod 20 672 682 15689349
  51. [54]Wirka KA 2014 Atypical embryo phenotypes identified by time-lapse microscopy: high prevalence and association with embryo development Fertil Steril 101 1637 1648 24726214
  52. [55]Kalatova B 2015 Tripolar mitosis in human cells and embryos: Occurrence, pathophysiology and medical implications Acta Histochem 117 111 125 25554607
  53. [56]Zhan Q 2016 Direct Unequal Cleavages: Embryo Developmental Competence, Genetic Constitution and Clinical Outcome PLoS One 11 e0166398 27907016 PMC5132229
  54. [57]Hlinka D 2012 Time-lapse cleavage rating predicts human embryo viability Physiol Res 61 513 22881225
  55. [58]Brooker AS Berkowitz KM 2014 The roles of cohesins in mitosis, meiosis, and human health and disease Methods Mol Biol 1170 229 266 24906316 PMC4495907
  56. [59]Ishiguro KI Watanabe Y 2007 Chromosome cohesion in mitosis and meiosis Journal Cell Sci 120 367 369 17251376
  57. [60]Tachibana-Konwalski K 2010 Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes Genes Dev 24 2505 2516 20971813 PMC2975927
  58. [61]Ottolini CS 2015 Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates Nature Genet 47 727 735 25985139 PMC4770575
  59. [62]Chiang T 2010 Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes Curr Biol 20 1522 1528 20817534 PMC2939204
  60. [63]Duncan FE 2012 Chromosome cohesion decreases in human eggs with advanced maternal age Aging cell 11 1121 1124 22823533 PMC3491123
  61. [64]Cohen-Fix O 2000 Sister chromatid separation: falling apart at the seams Curr Biol 10 R816 R819 11102820
  62. [65]Jallepalli PV 2001 Securin is required for chromosomal stability in human cells Cell 105 445 457 11371342
  63. [66]Zhang N 2008 Overexpression of Separase induces aneuploidy and mammary tumorigenesis Proc Natl Acad Sci USA 105 13033 13038 18728194 PMC2529090
  64. [67]Singh VP Gerton JL 2015 Cohesin and human disease: lessons from mouse models Curr Opin Cell Biol 37 9 17 26343989
  65. [68]Barber TD 2008 Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers Proc Natl Acad Sci USA 105 3443 3448 18299561 PMC2265152
  66. [69]Sonoda E 2001 Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells Dev Cell 1 759 770 11740938
  67. [70]Munné S 1997 Treatment-related chromosome abnormalities in human embryos Human Reproduction 12 780 784 9159442
  68. [71]Labarta E 2012 Moderate ovarian stimulation does not increase the incidence of human embryo chromosomal abnormalities in in vitro fertilization cycles J Clin Endocrinol Metab 97 E1987 E1994 22865900 PMC3462940
  69. [73]Jarvis GE 2016 Estimating limits for natural human embryo mortality F1000Res., 5 PMC5142718 28003878
  70. [74]Hertig AT 1959 Thirty-four fertilized human ova, good, bad and indifferent, recovered from 210 women of known fertility Pediatrics 23 202 211 13613882
  71. [75]Sandalinas M 2001 Developmental ability of chromosomally abnormal human embryos to develop to the blastocyst stage Hum Reprod 16 1954 1958 11527904
  72. [76]Bielanska M 2005 Diploid-aneuploid mosaicism in human embryos cultured to the blastocyst stage Fertil Steril 84 336 342 16084874
  73. [77]Vega M 2014 Blastulation rates decline in a linear fashion from euploid to aneuploid embryos with single versus multiple chromosomal errors Fertil Steril 102 394 398 24890269
  74. [78]Santos MA 2010 The fate of the mosaic embryo: chromosomal constitution and development of day 4, 5 and 8 human embryos Hum Reprod 25 1916 1926 20519247
  75. [79]Rubio C 2007 Impact of chromosomal abnormalities on preimplantation embryo development Prenat Diagn 27 748 756 17546708
  76. [80]Ruangvutilert P 2000 FISH analysis on day 5 post-insemination of human arrested and blastocyst stage embryos Prenat Diagn 20 552 560 10913953
  77. [82]Greco E 2015 Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts N Eng J Med 373 2089 2090 26581010
  78. [83]Gleicher N 2016 Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos Reprod Biol Endocrinol 14 54 27595768 PMC5011996
  79. [84]Bolton H 2016 Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential Nat Commun 7 PMC4820631 27021558
  80. [85]Carbone L Chavez SL 2015 Mammalian pre-implantation chromosomal instability: species comparison, evolutionary considerations, and pathological correlations Syst Biol Reprod Med 61 321 335 26366555 PMC7857118
  81. [86]Baffero GM 2012 Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome Prenat Diagn 32 1102 1108 22961322
  82. [87]Capalbo A 2014 Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts Hum Reprod 29 1173 1181 24578475
  83. [88]Northrop LE 2010 SNP microarray-based 24 chromosome aneuploidy screening demonstrates that cleavage-stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts Mol Hum Reprod 16 590 600 20479065 PMC2907218
  84. [89]Johnson DS 2010 Comprehensive analysis of karyotypic mosaicism between trophectoderm and inner cell mass Mol Hum Reprod 16 944 949 20643877 PMC2989828
  85. [90]Eggermann T 2015 Mosaicism and uniparental disomy in prenatal diagnosis Trends Mol Med 21 77 87 25547535
  86. [91]Engel E 1993 Uniparental disomy revisited: the first twelve years Am J Med Genet 46 6 670 674 8362910
  87. [92]Besser AG Mounts EL Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening Reprod Biomed Online in press 28129970
  88. [93]Biesecker LG Spinner NB 2013 A genomic view of mosaicism and human disease Nat Rev Genet 14 307 320 23594909
  89. [94]Maxwell SM 2016 Why do euploid embryos miscarry? A case-control study comparing the rate of aneuploidy within presumed euploid embryos that resulted in miscarriage or live birth using next-generation sequencing Fertil Steril 106 1414 1419 27692437
  90. [95]Demko ZP 2016 Effects of maternal age on euploidy rates in a large cohort of embryos analyzed with 24-chromosome single-nucleotide polymorphism–based preimplantation genetic screening Fertil Steril 105 1307 1313 26868992
  91. [96]Delhanty JD 1993 Detection of aneuploidy and chromosomal mosaicism in human embryos during preimplantation sex determination by fluorescent in situ hybridization (FISH) Hum Mol Genet 2 1183 1185 8401499
  92. [97]Brezina PR 2016 Preimplantation genetic testing for aneuploidy: what technology should you use and what are the differences? J Assist Reprod Gen 33 823 832 PMC4930789 27299602
  93. [98]Johnson DS 2010 Preclinical validation of a microarray method for full molecular karyotyping of blastomeres in a 24-h protocol Hum Reprod 25 1066 1075 20100701 PMC2839907
  94. [99]Handyside AH Harton GL Mariani B Thornhill AR Affara N Shaw MA Griffin DK 2010 Karyomapping: a universal method for genome wide analysis of genetic disease based on mapping crossovers between parental haplotypes J Med Genet 47 651 658 19858130
  95. [100]Fiorentino F 2014 Development and validation of a next-generation sequencing–based protocol for 24-chromosome aneuploidy screening of embryos Fertil Steril 101 1375 1382 24613537
  96. [101]Treff NR 2012 Development and validation of an accurate quantitative real-time polymerase chain reaction–based assay for human blastocyst comprehensive chromosomal aneuploidy screening Fertil Steril 97 819 824 22342859
  97. [102]Handyside AH 2013 24-chromosome copy number analysis: a comparison of available technologies Fertil Steril 100 595 602 23993662
  98. [103]Kane SC 2016 Pre-Implantation Genetic Screening Techniques: Implications for Clinical Prenatal Diagnosis Fetal Diagn Ther 40 241 254 27682145
  99. [104]Sermon KD 2017 Detecting mosaicism in trophectoderm biopsies Hum Reprod 32 712 713 28043945
  100. [105]Mamas T 2012 Detection of aneuploidy by array comparative genomic hybridization using cell lines to mimic a mosaic trophectoderm biopsy Fertil Steril 97 943 947 22277764
  101. [106]Hall GK 2014 Chromosomal microarray analysis allows prenatal detection of low level mosaic autosomal aneuploidy Prenat Diagn 34 505 507 24464918
  102. [108]Goodrich D 2016 A randomized and blinded comparison of qPCR and NGS-based detection of aneuploidy in a cell line mixture model of blastocyst biopsy mosaicism J Assist Reprod Gen 33 1473 1480 PMC5125146 27497716
  103. [109]Templado C 2011 Aneuploidy in human spermatozoa Cytogenet Genome Res 133 91 99 21282942
  104. [110]Gardner RL Cockroft DL 1998 Complete dissipation of coherent clonal growth occurs before gastrulation in mouse epiblast Development 125 2397 2402 9609822

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Authors
McCoy, R. C.
Affiliations
University of Washington (US)
Corresponding author
McCoy, Rajiv C.
ORCID
McCoy, Rajiv C.
Venue
Trends in Genetics
Publisher
Elsevier BV
Published
2017-07
Volume
33
Issue
7
Pages
448-463
ISSN
0168-9525 (ISSN-L)
DOI
10.1016/j.tig.2017.04.001
PMC
PMC5484399
OpenAlex
W2607742704
Cited by
235
References
1
Citations by year
2026: 17 · 2025: 28 · 2024: 32 · 2023: 28 · 2022: 37 · 2021: 32 · 2020: 26 · 2019: 19 · 2018: 14 · 2017: 2
FWCI
3.12
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH/NHGRI Genome Training Grant (5T32HG000035-22)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
mosaicism, preimplantation embryo, aneuploidy, mitotic errors, cell cycle checkpoints, centrosome abnormalities, embryo screening, meiotic errors
MeSH terms
Aneuploidy, Blastocyst, Chromosome Aberrations, Humans, Meiosis, Mitosis, Mosaicism

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