Causes and consequences of chromosome segregation error in preimplantation embryos

Abstract

Errors in chromosome segregation are common during the mitotic divisions of preimplantation development in mammalian embryos, giving rise to so-called 'mosaic' embryos possessing a mixture of euploid and aneuploid cells. Mosaicism is widely considered to be detrimental to embryo quality and is frequently used as criteria to select embryos for transfer in human fertility clinics. However, despite the clear clinical importance, the underlying defects in cell division that result in mosaic aneuploidy remain elusive. In this review, we summarise recent findings from clinical and animal model studies that provide new insights into the fundamental mechanisms of chromosome segregation in the highly unusual cellular environment of early preimplantation development and consider recent clues as to why errors should commonly occur in this setting. We furthermore discuss recent evidence suggesting that mosaicism is not an irrevocable barrier to a healthy pregnancy. Understanding the causes and biological impacts of mosaic aneuploidy will be pivotal in the development and fine-tuning of clinical embryo selection methods.Reproduction (2018) 155 R63-R76

Segregating Chromosomes in the Mammalian Oocyte

“…The difference likely pertains to the observation that some SAC components assemble at the nucleus in interphase [92], such that bisection prior to germinal vesicle breakdown effectively concentrates SAC components, whereas bisection after germinal vesicle breakdown reduces cell volume without influencing SAC component concentrations [90,91]. Whether the effect of size will be more apparent in the human oocyte, which is approximately three to four times greater in volume than mouse, and whether the same principle causes the SAC to strengthen during early embryonic development, when cell divisions are also error prone and cells progressively decrease in size and nuclear-cytoplasmic ratio increases [93,94], will be interesting to determine.…”

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

“…Genetic surveys of in vitro fertilized (IVF) human embryos consistently reveal substantial levels of aneuploidy-whole chromosome gains and losses that trace their origins to diverse mechanisms of chromosome mis-segregation. These include (primarily maternal) meiotic mechanisms such as non-disjunction, precocious separation of sister chromatids, and reverse segregation (Ottolini et al 2015) , as well as mitotic mechanisms such as mitotic non-disjunction, anaphase lag, and endoreplication (Vázquez-Diez and FitzHarris 2018) . In contrast to meiotic errors, which uniformly affect all embryonic cells, mitotic errors generate chromosomal mosaicism, whereby different cells possess distinct chromosome complements.…”

Cycling through mammalian meiosis: B-type cyclins in oocytes

“…By age 42, the incidence of aneuploidy may increase up to 80%, according to (Capalbo et al, « Human Female Meiosis Revised »). Not all segregation errors are due to aberrant meiotic divisions though, and additionally, a high rate of segregation errors is observed in the following mitotic divisions at later stages of embryogenesis, up to the blastocyst stage (Schneider and Ellenberg 2019;Vázquez-Diez and FitzHarris 2018). Today, with more commonly used medically assisted reproduction and the increase of maternal age at first pregnancies, it is indispensable to gain a better comprehension of the regulatory mechanisms put in place to segregate the genetic material in meiosis and early mitotic divisions in the embryo.…”