Detailed FISH analysis of day 5 human embryos reveals the mechanisms leading to mosaic aneuploidy

Daphnis, D; Delhanty, Joy D. A.; Jerkovic, S.; Geyer, Joachim; Craft, Ian; Harper, Joyce

doi:10.1093/humrep/deh554

Cited by 107 publications

(69 citation statements)

References 45 publications

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“…This increased genetic variation in the organism has been suggested as a mechanism for evolutionary change (Gill et al 1995) but direct evidence for this hypothesis has been sparse. In human embryos, mosaic aneuploidy arising via nondisjunction of chromosomes during mitosis (Daphnis et al 2005) or via premature centromere division (Furukawa et al 2003) has mostly been associated with abnormal development. When based on adjusted euploid chromosome numbers, the level of aneuploidy in our study fell statistically significantly from the F 3 to the F 6 generation, but that trend toward genomic stability was not continued in the F 7 generation, and levels of aneuploidy remained overall relatively high (Figure 4).…”

Section: Somatic Mosaicism and Cytotypic Variation Is Prevalent In Eamentioning

confidence: 99%

Allopolyploidization Lays the Foundation for Evolution of Distinct Populations: Evidence From Analysis of SyntheticArabidopsisAllohexaploids

et al. 2012

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Polyploidization is an important mechanism for introducing diversity into a population and promoting evolutionary change. It is believed that most, if not all, angiosperms have undergone whole genome duplication events in their evolutionary history, which has led to changes in genome structure, gene regulation, and chromosome maintenance. Previous studies have shown that polyploidy can coincide with meiotic abnormalities and somatic cytogenetic mosaics in Arabidopsis allotetraploids, but it is unclear whether this phenomenon can contribute to novel diversity or act as a mechanism for speciation. In this study we tested the hypothesis that mosaic aneuploidy contributes to the formation of incipient diversity in neoallopolyploids. We generated a population of synthesized Arabidopsis allohexaploids and monitored karyotypic and phenotypic variation in this population over the first seven generations. We found evidence of sibling line-specific chromosome number variations and rapidly diverging phenotypes between lines, including flowering time, leaf shape, and pollen viability. Karyotypes varied between sibling lines and between cells within the same tissues. Cytotypic variation correlates with phenotypic novelty, and, unlike in allotetraploids, remains a major genomic destabilizing factor for at least the first seven generations. While it is still unclear whether new stable aneuploid lines will arise from these populations, our data are consistent with the notion that somatic aneuploidy, especially in higher level allopolyploids, can act as an evolutionary relevant mechanism to induce rapid variation not only during the initial allopolyploidization process but also for several subsequent generations. This process may lay the genetic foundation for multiple, rather than just a single, new species. P OLYPLOIDY is a major force in shaping angiosperm evolution and plant biodiversity (Ohno 1970;Stebbins 1971;Hegarty and Hiscock 2008;Leitch and Leitch 2008;Buggs et al. 2011). Polyploids are organisms with two or more complete sets of chromosomes. Polyploidy is frequent in nature and evidence shows that most, if not all, angiosperms have undergone at least one ancient genome doubling event in their evolutionary history (Bowers et al. 2003;Blanc and Wolfe 2004;Cui et al. 2006;Soltis and Soltis 2009;Jiao et al. 2011). Two major forms of polyploidy exist: autopolyploidy, which describes multiple genomes derived from a single species, and allopolyploidy, which refers to species in which genome doubling occurred concomitantly with the hybridization of two or more species.Newly formed allopolyploids (neoallopolyploids) are subject to multiple changes from their progenitors in response to genome duplication, including structural chromosomal change, aneuploidy, genome rearrangement, epigenetic remodeling, and transcriptional change (Madlung et al. 2002;Henry et al. 2005;Huettel et al. 2008;Lim et al. 2008;Wright et al. 2009;Salmon et al. 2010;Chen 2010). Plants are generally quite plastic and can tolerate variation in the...

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Section: Somatic Mosaicism and Cytotypic Variation Is Prevalent In Eamentioning

confidence: 99%

Allopolyploidization Lays the Foundation for Evolution of Distinct Populations: Evidence From Analysis of SyntheticArabidopsisAllohexaploids

et al. 2012

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“…In all cases, evidence suggests that these repair pathways are coupled to covalent-modifications of chromatin (Berardi et al, 2004;Wuebbles and Jones, 2004). Many oocytes and embryos (notably in the human) also display aneuploidy, which may be exacerbated by in vitro culture (Daphnis et al, 2005;Jakobsen et al, 2006).…”

Section: Role Of Nucleic Acid Damage In Determining Zygote Viabilitymentioning

confidence: 99%

The quiet embryo hypothesis: Molecular characteristics favoring viability

Baumann

Morris

Sreenan

et al. 2007

Molecular Reproduction Devel

158

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It has been proposed that the viability of early mammalian embryos is associated with a metabolism that is ''quiet'' rather than ''active'' (Leese HJ, 2002:BioEssays 24:845-849). The data on which this hypothesis was based were largely drawn from measurements on the depletion and appearance of amino acids from the culture medium. Data on the de novo synthesis of protein in in vivo-and in vitro-derived bovine embryos, as determined from the flux of radiolabeled methionine, have provided further support of the hypothesis and are interpreted to provide a new set of testable propositions that could illuminate the molecular basis of the quiet metabolism phenotype. The propositions are based on the premise that the extent of DNA damage, and the RNA and protein content of the immature oocyte, are key factors in determining whether the zygote progresses to the blastocyst stage. We propose that stochastic events and environmental stresses determine whether the condition of the genome, transcriptome, and proteome of the zygote will support development. Several molecular components are identified that may determine the viability of a zygote, and we speculate that the cellular response to unfavorable events or excessive DNA damage may be the premature activation of the embryonic genome and of apoptosis. Mol. Reprod. Dev. 74: 1345

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“…Recently, Lavon et al reported derivation of euploid HESCs from aneuploid embryos; their results suggest that in vitro selection may occur in favor of euploid cells [23]. Aneuploidy and chromosomal mosaicism are often found in poor-quality embryos [24], yet all of the cell lines derived by our group from poor-quality embryos thus far display a normal karyotype. Our results indicate that the process of HESC derivation rigorously selects for normal ploidy.…”

Section: Discussionmentioning

confidence: 71%

A Modified Culture Medium Increases Blastocyst Formation and the Efficiency of Human Embryonic Stem Cell Derivation from Poor-Quality Embryos

Fan

Luo

Chen

et al. 2010

Journal of Reproduction and Development

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Abstract. Human embryonic stem cells (HESCs) are defined as self-renewing cells that retain their ability to differentiate into all cell types of the body. They have enormous potential in medical applications and as a model for early human development. There is a need for derivation of new HESC lines to meet emerging requirements for their use in cell replacement therapies, disease modeling, and basic research. Here, we describe a modified culture medium containing human recombinant leukemia inhibitory factor and human basic fibroblast growth factor that significantly increases the number of human blastocysts formed and their quality, as well as the efficiency of HESC derivation from poor-quality embryos. Culturing poor-quality embryos in modified medium resulted in a two-fold increase in the blastocyst formation rate and a seven-fold increase over the derivation efficiency in conventional medium. We derived 15 HESC lines from poor-quality embryos cultured in modified culture medium and two HESC lines from quality embryos cultured in conventional culture medium. All cell lines shared typical human pluripotent stem cell features including similar morphology, normal karyotypes, expression of alkaline phosphatase, pluripotency genes, such as Oct4, and cell surface markers (SSEA-4, TRA-1-60, TRA-1-81), the ability to form teratomas in SCID mice, and the ability to differentiate into cells of three embryonic germ layers in vitro. Our data suggest that poor-quality embryos that have reached the blastocyst stage in our modified culture medium are a robust source for normal HESC line derivation. Key words: Derivation, Human embryonic stem cells, Modified culture medium, Poor-quality embryos (J. Reprod. Dev. 56: [533][534][535][536][537][538][539] 2010) uman embryonic stem cell (HESC) lines are typically derived from the inner cell masses (ICM) of blastocyst-stage embryos [1]. HESCs are self-renewing and have the ability to differentiate into all cell types. These characteristics provide HESCs with great potential for use in modern regenerative medicine and cell-based drug discovery.Currently, the vast majority of HESC lines are derived from surplus cryopreserved embryos for in vitro fertilization (IVF) treatments [1,2]. These embryos are developed to the blastocyst stage using in vitro culture prior to being plated for derivation purposes. However, the use of embryos and derivation of HESCs for research and eventual medical application has resulted in polarized ethical debates [3], since the process involves the destruction of viable developing human embryos [1]. Therefore, it is difficult to obtain good quality embryos for research purposes. During the IVF process, only a small number of all IVF zygotes will develop successfully to the blastocyst stage [3,4]. Most of these embryos display abnormal or delayed cell division, frequently accompanied by cellular fragmentation and developmental arrest before the blastocyst stage [4,5]. These embryos, which display poor morphology, are routinely discarded because they are ...

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Detailed FISH analysis of day 5 human embryos reveals the mechanisms leading to mosaic aneuploidy

Abstract: Post-zygotic chromosome loss was the most common mechanism leading to aneuploidy mosaicism for both groups, followed by chromosome gain, with fewer examples of mitotic non-disjunction.

Cited by 107 publications

References 45 publications

Allopolyploidization Lays the Foundation for Evolution of Distinct Populations: Evidence From Analysis of SyntheticArabidopsisAllohexaploids

Allopolyploidization Lays the Foundation for Evolution of Distinct Populations: Evidence From Analysis of SyntheticArabidopsisAllohexaploids

The quiet embryo hypothesis: Molecular characteristics favoring viability

A Modified Culture Medium Increases Blastocyst Formation and the Efficiency of Human Embryonic Stem Cell Derivation from Poor-Quality Embryos

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