The Human Cleavage Stage Embryo Is a Cradle of Chromosomal Rearrangements

Abstract

The first cell cycles following in vitro fertilization (IVF) of human gametes are prone to chromosome instability. Many, but often not all, blastomeres of an embryo acquire a genetic makeup during cleavage that is not representative of the original zygotic genome. Whole chromosomes are missegregated, but also structural rearrangements of chromosomes do occur in human cleavage stage embryogenesis following IVF. Analysis of pre- and postnatal DNA samples indicates that the in vivo human conceptions also endure instability of chromosome number and structure during cleavage of the fertilized oocyte. This embryonic chromosome instability not necessarily undermines normal human development, but may lead to a spectrum of conditions, including loss of conception, genetic disease and genetic variation development. In this review, the structural instability of chromosomes during human cleavage stage embryogenesis is catalogued, channeled into etiologic models and linked to genomic profiles of healthy and diseased newborns.

Non-meiotic chromosome instability in human immature oocytes

“…35 Accordingly, early in embryogenesis (from week 9 to the 5th month), during the formation of germ cells, a very active cell proliferation takes place, and this could lead to a certain level of genetic instability, reminding what has been observed in some tumours. 36 All of the ends of the segmental imbalances found in this study, except À8p12, are located close to previously described fragile sites of the genome. 37 Specifically, one of the most active fragile sites, FRA3G, located at 3p14.2, has also been found in this work.…”

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

“…With the ability to perform a low-resolution genome-wide survey of either single blastomeres from a three-day-old embryo or by the study of several cells from the trophectoderm of a five-or six-day-old blastocyst, it has become evident that in addition to the common occurrence of aneuploidy within the embryo, usually arising during meiosis, the embryo is predisposed to segmental chromosomal imbalances (372) which arise during programmed DNA breakage and repair by homologous recombination during prophase I of meiosis (360). These rearrangements may lead to a failure to develop and implant, but also lead to phenotypic variability and hence ultimately genome evolution [for a detailed description of the origin of chromosomal rearrangement, see Voet et al (360)]. Hence, in IVF programs the majority of apparently morphologically normal embryos fail to implant as aneuploidy is such a frequent occurrence, occurring more frequently in an older woman, and a woman with a history of failed embryonic implantation (371).…”

Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

“…One interesting observation is that the rearranged alleles in both chromothripsis and chromoanasynthesis are preferentially of paternal origin; this was attributed to errors that result from the higher number of mitotic divisions in gametogenesis in males relative to females (Kloosterman and Cuppen 2013). In contrast, most human germline aneuploidies are maternally derived (Handyside et al 2012;Nagaoka et al 2012), and de novo chromosomal instability in early embryonic development does not show a preferred origin (Vanneste et al 2009;Voet et al 2011).…”