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Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

BACKGROUND: The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and stillbirth following natural conception as well as in vitro fertilization (IVF). Preimplantation genetic tes...

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Autores principales: McCoy, Rajiv C., Summers, Michael C., McCollin, Abeo, Ottolini, Christian S., Ahuja, Kamal, Handyside, Alan H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544495/
https://www.ncbi.nlm.nih.gov/pubmed/37779206
http://dx.doi.org/10.1186/s13073-023-01231-1
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author McCoy, Rajiv C.
Summers, Michael C.
McCollin, Abeo
Ottolini, Christian S.
Ahuja, Kamal
Handyside, Alan H.
author_facet McCoy, Rajiv C.
Summers, Michael C.
McCollin, Abeo
Ottolini, Christian S.
Ahuja, Kamal
Handyside, Alan H.
author_sort McCoy, Rajiv C.
collection PubMed
description BACKGROUND: The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and stillbirth following natural conception as well as in vitro fertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stage in vitro, while the others arrest at cleavage to late morula or early blastocyst stages. METHODS: To achieve a more complete view of the impacts of aneuploidy, we applied low-coverage sequencing-based PGT-A to a large series (n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time-lapse imaging (n = 843). RESULTS: The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20 to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos. CONCLUSIONS: We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryos in vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01231-1.
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spelling pubmed-105444952023-10-03 Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos McCoy, Rajiv C. Summers, Michael C. McCollin, Abeo Ottolini, Christian S. Ahuja, Kamal Handyside, Alan H. Genome Med Research BACKGROUND: The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and stillbirth following natural conception as well as in vitro fertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stage in vitro, while the others arrest at cleavage to late morula or early blastocyst stages. METHODS: To achieve a more complete view of the impacts of aneuploidy, we applied low-coverage sequencing-based PGT-A to a large series (n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time-lapse imaging (n = 843). RESULTS: The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20 to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos. CONCLUSIONS: We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryos in vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01231-1. BioMed Central 2023-10-02 /pmc/articles/PMC10544495/ /pubmed/37779206 http://dx.doi.org/10.1186/s13073-023-01231-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
McCoy, Rajiv C.
Summers, Michael C.
McCollin, Abeo
Ottolini, Christian S.
Ahuja, Kamal
Handyside, Alan H.
Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
title Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
title_full Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
title_fullStr Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
title_full_unstemmed Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
title_short Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
title_sort meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544495/
https://www.ncbi.nlm.nih.gov/pubmed/37779206
http://dx.doi.org/10.1186/s13073-023-01231-1
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