Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development.
Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring duri...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-10-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4619652?pdf=render |
| _version_ | 1818285284516691968 |
|---|---|
| author | Rajiv C McCoy Zachary P Demko Allison Ryan Milena Banjevic Matthew Hill Styrmir Sigurjonsson Matthew Rabinowitz Dmitri A Petrov |
| author_facet | Rajiv C McCoy Zachary P Demko Allison Ryan Milena Banjevic Matthew Hill Styrmir Sigurjonsson Matthew Rabinowitz Dmitri A Petrov |
| author_sort | Rajiv C McCoy |
| collection | DOAJ |
| description | Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4-8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility. |
| first_indexed | 2024-12-13T01:06:15Z |
| format | Article |
| id | doaj.art-302e7261c8504e16a09a097e6af752b3 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T01:06:15Z |
| publishDate | 2015-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-302e7261c8504e16a09a097e6af752b32022-12-22T00:04:33ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-10-011110e100560110.1371/journal.pgen.1005601Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development.Rajiv C McCoyZachary P DemkoAllison RyanMilena BanjevicMatthew HillStyrmir SigurjonssonMatthew RabinowitzDmitri A PetrovWhole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4-8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility.http://europepmc.org/articles/PMC4619652?pdf=render |
| spellingShingle | Rajiv C McCoy Zachary P Demko Allison Ryan Milena Banjevic Matthew Hill Styrmir Sigurjonsson Matthew Rabinowitz Dmitri A Petrov Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. PLoS Genetics |
| title | Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. |
| title_full | Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. |
| title_fullStr | Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. |
| title_full_unstemmed | Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. |
| title_short | Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. |
| title_sort | evidence of selection against complex mitotic origin aneuploidy during preimplantation development |
| url | http://europepmc.org/articles/PMC4619652?pdf=render |
| work_keys_str_mv | AT rajivcmccoy evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT zacharypdemko evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT allisonryan evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT milenabanjevic evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT matthewhill evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT styrmirsigurjonsson evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT matthewrabinowitz evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment AT dmitriapetrov evidenceofselectionagainstcomplexmitoticoriginaneuploidyduringpreimplantationdevelopment |