Preimplantation chromosomal mosaics, chimaeras and confined placental mosaicism

Abstract

Some human preimplantation embryos are chromosomally mosaic. For technical reasons, estimates of the overall frequency vary widely from <15 to >90% and the true frequency remains unknown. Aneuploid/diploid and aneuploid/aneuploid mosaics typically arise during early cleavage stages before the embryonic genome is fully activated and when cell cycle checkpoints are not operating normally. Other mosaics include chaotic aneuploid mosaics and mixoploids, some of which arise by abnormal chromosome segregation at the first cleavage division. Chimaeras are similar to mosaics, in having two genetically distinct cell populations, but they arise from more than one zygote and occur less often. After implantation, the frequency of mosaic embryos declines to about 2% and most are trisomic/diploid mosaics, with trisomic cells confined to the placenta. Thus, few babies are born with chromosomal mosaicism. This review discusses the origin of different types of chromosomal mosaics and chimaeras; their fate and the relationship between preimplantation chromosomal mosaicism and confined placental mosaicism in human conceptuses and animal models. Abnormal cells in mosaic embryos may be depleted by cell death, other types of cell selection or cell correction but the most severely affected mosaic embryos probably die. Trisomic cells could become restricted to placental lineages if cell selection or correction is less effective in placental lineages and/or they are preferentially allocated to a placental lineage. However, the relationship between preimplantation mosaicism and confined placental mosaicism may be complex because the specific chromosome(s) involved will influence whether chromosomally abnormal cells survive predominately in the placental trophoblast and/or placental mesenchyme.

Lay summary: Human cells normally have 23 pairs of chromosomes, which carry the genes. During the first few days of development, some human embryos are chromosomal mosaics. These mosaic embryos have both normal cells and cells with an abnormal number of chromosomes, which arise from the same fertilised egg. (More rarely, the different cell populations arise from more than one fertilised egg and these embryos are called chimaeras.) If chromosomally abnormal cells survive to term, they could cause birth defects. However, few abnormal cells survive and those that do are usually confined to the placenta, where they are less likely to cause harm. It is not yet understood how this restriction occurs but the type of chromosomal abnormality influences which placental tissues are affected. This review discusses the origin of different types of chromosomally abnormal cells, their fate and how they might become confined to the placenta in humans and animal models.

Keywords: aneuploidy; chimaera; chromosomal mosaic; confined placental mosaicism; mixoploidy.

Figure 1

Preimplantation development, mosaicism and mixoploidy. (A) After fertilisation, the preimplantation embryo undergoes three cleavage divisions to the eight-cell stage (cleavage divisions are mitotic divisions that increase cell number but not embryo size and cells produced by cleavage division are called blastomeres). The embryo then compacts to form a morula, which cavitates to form a blastocyst, with an outer layer of trophectoderm cells surrounding the inner cell mass (ICM) and the blastocyst cavity. By the late blastocyst stage, the ICM forms the epiblast and primitive endoderm (hypoblast). (B) A normal diploid embryo may produce (i) monosomic/diploid, (ii) monosomic/trisomic/diploid, (iii) trisomic/diploid (origin may be indirect – see text) and (iv) tetraploid/diploid mosaics. (C) Non-disjunction, at the first mitotic division, would produce (i) monosomic/trisomic mosaics or (ii) other types of mosaics, including monosomic/trisomic/diploid mosaics, if further changes, such as trisomic rescue, occurred. (D) Normal bipronuclear zygotes sometimes form tripolar spindles and (i) individual chromosomes may segregate abnormally to produce a chaotic mosaic or (ii) entire haploid sets of chromosomes may segregate to form a haploid/diploid mixoploid. (E) A trisomic zygote could produce (i) trisomic/diploid or (ii) various types of trisomic/aneuploid mosaics. (F) A haploid zygote often produces some diploid cells by endoreplication, so forming a haploid/diploid mosaic. (G) A tripronuclear zygote may (i) produce a non-mosaic, triploid embryo; (ii) form a tripolar spindle and produce a chaotic mosaic which may continue to be unstable, (iii) extrude a small haploid cell which may fuse with a diploid cell to produce a triploid/diploid mixoploid, (iv) undergo atypical early cytokinesis so the pronuclei segregate passively to the two blastomeres or (v) form a tripolar spindle and segregate entire haploid sets of chromosomes to initially form a haploid/triploid/diploid mixoploid. See Fig. 2 for other details.

Figure 2

Segregation of complete haploid sets of parental chromosomes. (A, B, C and D) Three pronuclei form after dispermy and may segregate in different ways. (A) One male pronucleus is extruded in a small androgenetic haploid cell and the other two form two normal blastomeres. Later the extruded haploid cell may fuse with one blastomere and both blastomeres divide to form a triploid/diploid mixoploid embryo. (B) The zygote undergoes an atypical early cytokinesis and intact pronuclei are distributed between the two blastomeres. After the next division, there are two biparental diploid cells and two androgenetic haploid cells. In this example (from Supplementary Fig. 4A in Destouni et al. 2016) one diploid and one haploid cell fuse to produce a diandric triploid cell line and other cells divide but various fates are possible. Later the haploid cells may undergo endoreplication, fuse with other cells or die. (C) Entire haploid sets of chromosomes segregate on a tripolar spindle to form a mixoploid embryo with a biparental diploid, diandric triploid and an androgenetic haploid cell. Subsequently, haploid cells may die, fuse or endoreplicate to form androgenetic diploid cells or fuse with other cells. Only two of various possible fates are illustrated. (D) Entire haploid sets of chromosomes segregate on a tripolar spindle to form a chimaera with two biparental diploid cells with different paternal genomes and a diandric diploid cell with two different paternal sets of chromosomes. (E) Two pronuclei form after monospermic fertilisation but, occasionally, entire haploid sets of chromosomes may segregate on a tripolar spindle to form a chimaera with a biparental diploid cell, a gynogenetic haploid and an androgenetic haploid cell. Subsequently, haploid cells may die, endoreplicate to form diploid cells or fuse with other cells. Only two of various possible fates are illustrated.

Figure 3

Different types of chimaeras. (A) Two cleavage stage embryos may lose their zonae pellucidae and aggregate to form an aggregation chimaera. (B) Fertilisation of both the egg and the second polar body, which may be enlarged. (C) Parthenogenetic activation of an oocyte produces a two-cell embryo with two haploid nuclei that are then both fertilised by different spermatozoa to produce a chimaera with identical maternal contributions in both cell lines.

Figure 4

Simplified lineage diagram showing the origin of human extraembryonic tissues. The diagram shows the relationship between the embryonic lineage and the two lineages that produce the chorionic villi (trophectoderm and extraembryonic mesoderm). The three germ layers (ectoderm, mesoderm and endoderm) that form the embryo are produced from the epiblast and the embryonic mesoderm and embryonic endoderm emerge from the primitive streak (labelled ‘PS’) during gastrulation. Both the cytotrophoblast and syncytiotrophoblast are produced from the trophectoderm layer of the blastocyst. Evidence suggests that the human extraembryonic mesoderm is produced first by the primitive endoderm (labelled ‘1’) and later from epiblast via the primitive streak (labelled ‘2’). See text for references. For simplicity, both sources of cells are shown feeding into a common pool of extraembryonic mesoderm but they may colonise different tissues.

Figure 5

Events in preimplantation embryos that could cause or initiate CPM-I. By the late-blastocyst stage, there are three primary lineages, namely the epiblast, primitive endoderm (or hypoblast) and the trophectoderm, which produces all the placental trophoblast cells (Fig. 4). The outer morula cells form the trophectoderm layer and the inner cells form the ICM of the blastocyst. At least in the mouse, some outer morula cells produce additional inner cells by asymmetrical division and the epiblast and primitive endoderm (hypoblast) precursor cells are initially intermixed in the ICM but they assume their final positions in the late blastocyst (Saiz & Plusa 2013). In reality, restriction of abnormal cells to the trophectoderm/trophoblast lineage in CPM-I is likely to occur gradually and not be completed until after implantation. However, for simplicity, the figure illustrates how complete restriction of abnormal cells to the trophectoderm lineage could occur by the late blastocyst stage. (A) The chromosomally abnormal cell population (shaded blue) could arise exclusively in the trophectoderm at any time after it has separated from the ICM. (B) The abnormal cell population might arise at an early stage but be exclusively or predominantly allocated to the trophectoderm lineage. (C) The abnormal cell population could arise at an early stage and initially be present in both the ICM and trophectoderm but only survive in the trophectoderm lineage. Ab, chromosomally abnormal cell (shaded blue); 2n, normal diploid cell (shaded grey).