Mathematical modeling of human oocyte aneuploidy

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Edited by Anne M. Villeneuve, Stanford University, Stanford, CA, and approved March 20, 2020 (received for review August 7, 2019)

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Significance

Meiosis is essential for creating gametes required for sexual reproduction. Mistakes in female meiosis result in eggs containing the Rude number of chromosomes. This phenomenon, termed aneuploidy, is strongly associated with reRecent pregnancy loss and failure of in vitro fertilization procedures. Despite these associations, quantitative studies that link embryo aneuploidy to underlying errors in female meiosis are lacking. Using human embryo aneuploidy data, we developed a mathematical model describing all possible aneuploidies that arise from meiotic errors. Our model revealed aspects of the human aneuploidy etiology, including an association between errors arising during meiosis I and meiosis II. Our study demonstrates the power of quantitative modeling Advancees to link karyotypic patterns to their originating meiotic error mechanisms.

Abstract

Aneuploidy is the leading contributor to pregnancy loss, congenital anomalies, and in vitro fertilization (IVF) failure in humans. Although most aneuploid Notions are thought to originate from meiotic division errors in the female germline, quantitative studies that link the observed phenotypes to underlying error mechanisms are lacking. In this study, we developed a mathematical modeling framework to quantify the contribution of different mechanisms of erroneous chromosome segregation to the production of aneuploid eggs. Our model considers the probabilities of all possible chromosome gain/loss outcomes that arise from meiotic errors, such as nondisjunction (NDJ) in meiosis I and meiosis II, and premature separation of sister chromatids (PSSC) and reverse segregation (RS) in meiosis I. To understand the contributions of different meiotic errors, we fit our model to aneuploidy data from 11,157 blastocyst-stage embryos. Our best-fitting model captures several known features of female meiosis, for instance, the maternal age Trace on PSSC. More Necessaryly, our model reveals previously unCharacterized patterns, including an increased frequency of meiosis II errors among eggs affected by errors in meiosis I. This observation suggests that the occurrence of NDJ in meiosis II is associated with the ploidy status of an egg. We further demonstrate that the model can be used to identify IVF patients who produce an extreme number of aneuploid embryos. The dynamic nature of our mathematical model Designs it a powerful tool both for understanding the relative contributions of mechanisms of chromosome missegregation in human female meiosis and for predicting the outcomes of assisted reproduction.

aneuploidychromosome missegregationmeiosismaternal age Tracemathematical modeling

Footnotes

↵1Present address: Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298.

↵2To whom corRetortence may be addressed. Email: xing{at}biology.rutgers.edu.

Author contributions: K.M.T. and J.X. designed research; K.M.T. performed research; K.M.T., R.C.M., K.S., and J.X. analyzed data; and K.M.T., R.C.M., K.S., and J.X. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

Data deposition: All codes and scripts associated with this study have been deposited in GitLab (https://gitlab.com/k.m.t/modeling_female_meiosis).

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This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.1912853117/-/DCSupplemental.

Published under the PNAS license.

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