The chromosomal challenge of human embryos: Mechanisms and fundamentals

Abstract

Chromosomal abnormalities in human pre-implantation embryos, originating from either meiotic or mitotic errors, present a significant challenge in reproductive biology. Complete aneuploidy is primarily linked to errors during the resumption of meiosis in oocyte maturation, which increase with maternal age, while mosaic aneuploidies result from mitotic errors after fertilization. The biological causes of these abnormalities are increasingly becoming a topic of interest for research groups and clinical specialists. This review explores the intricate processes of meiotic and early mitotic divisions in embryos, shedding light on the mechanisms that lead to changes in chromosome number in daughter cells. Key factors in meiotic division include difficulties in spindle assembly without centrosomes, kinetochore (KT) orientation disturbances, and inefficient cell-cycle checkpoints. The weakening of cohesion molecules that bind chromosomes, exacerbated by maternal aging, further complicates chromosomal segregation. Mitotic errors in early development are influenced by defects in sperm centrosomes, KT misalignment, and the gradual depletion of maternal regulatory factors. Coupled with the inactive or partially active embryonic genome, this depletion increases the likelihood of chromosomal aberrations. While various theoretical mechanisms for these abnormalities exist, current data remain insufficient to determine their exact contributions. Continued research is essential to unravel these complex processes and improve outcomes in assisted reproductive technologies.

Keywords: aneuploidy; cell-cycle checkpoints; chromosomal mosaicism; chromosome segregation errors; kinetochore orientation; meiotic errors; mitotic errors.

Figure 1

Options for normal and abnormal chromosome segregation in oocyte meiosis, and their consequences (using the example of chromosome nondisjunction mechanism) A chromosome segregation error can occur during MI or, less often, during MII. The error that occurred in MI can be subsequently corrected in MII; however, in the vast majority of cases, errors in chromosome segregation in both MI and MII lead to embryonic aneuploidy (trisomy or monosomy) of maternal meiotic origin. Aneuploidy in spermatozoa is rare; therefore, this figure does not contain the consequences of fertilization of the oocyte by aneuploid sperm. Red, maternal chromosomes; blue, paternal chromosomes; green, cells with a normal chromosome set; red, cells with an aneuploid chromosome set. Created with BioRender.com.

Figure 2

Options for chromosome segregation in the first two cleavage divisions (with chromosome nondisjunction used as an example of mitotic error) Nondisjunction in the first mitosis would lead to aneuploid/aneuploid mosaicism, clinically regarded as aneuploidy. The possible variants of euploid/aneuploid mosaicism due to an error in the second division, are marked with letters: (A) blastocysts with mosaic inner cell mass (ICM) and mosaic trophectoderm (TE); (B) blastocysts with euploid (B1) or aneuploid (B2) ICM and mosaic TE; (C) mosaicism manifested in ICM, whereas TE is aneuploid (C1) or euploid (C2); and (D) embryos in which TE is completely aneuploid and ICM is completely euploid (D1) and vice versa (D2). Importantly, these options should have considerably different rates (see more in the text). Blue, paternal chromosomes; red, maternal chromosomes; green, cells with a normal chromosome set; red, cells with an aneuploid chromosome set. Created with BioRender.com.

Figure 3

Types of KT orientation In mitosis (A), as well as in MII, the proper KT orientation is monotelic, or biorientation, when sister KTs are attached to microtubules from opposite spindle poles. In contrast, the correct orientation in MI (B) is syntelic when both KTs of one chromosome are connected to microtubules from one pole, and both KTs from the second chromosome are connected to the opposite pole. All other attachment variants are incorrect and lead to chromosomal errors. Incorrectly oriented KTs are shown in red, while correctly oriented KTs are shown in green. Created with BioRender.com.

Figure 4

SAC and its regulation in mitosis Proper chromosome segregation relies on the SAC, which delays anaphase until all KTs are correctly attached to spindle microtubules. During prometaphase, SAC assembles the MCC. The MCC complex inhibits the APC/C until all KT-microtubule attachments are formed. Correct chromatid biorientation suppresses the SAC signal, this allows APC/C activation through released Cdc20, leading to Sec and cyclin B degradation, separase activation, and sister chromatids cohesin cleavage, finally separating sister chromatids and initiating mitotic exit. Adapted from Barbosa et al. Created with BioRender.com.

Figure 5

Patterns of cell division errors leading to whole-chromosomal aberrations in daughter cells Anaphase lag and chromosome breakage lead to the chromosomal loss and the formation of monosomal cells. Nondisjunction and non-bipolar spindle formation cause an uneven distribution of chromosomes between daughter cells, which results in reciprocal aneuploidy (in the case of nondisjunction) or chaotic aneuploidy, including both monosomies and trisomies (in the case of a non-bipolar spindle). Chromosome endoreplication and premature cell division without replication are opposite processes, and lead to the formation of tetraploid and haploid cells, respectively. Errors in cytokinesis and fusion of blastomere cells can lead to the formation of binucleated cells, and even to the formation of multinucleated cells in the case of multiple fusion of blastomeres. Created with BioRender.com.