Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis

Abstract

Aneuploidy is a hallmark of cancer and a major cause of miscarriages in humans. It is caused by chromosome segregation errors during cell divisions. Evidence is mounting that the probability of specific chromosomes undergoing a segregation error is non-random. In other words, some chromosomes have a higher chance of contributing to aneuploid karyotypes than others. This could have important implications for the origins of recurrent aneuploidy patterns in cancer and developing embryos. Here, we review recent progress in understanding the prevalence and causes of non-random chromosome segregation errors in mammalian mitosis and meiosis. We evaluate its potential impact on cancer and human reproduction and discuss possible research avenues.

Keywords: aneuploidy; cancer; chromosomal instability; development; embryo; meiosis; mitosis; non-random segregation errors.

Figure 1

Chromosomes differ in many ways. The graph shows the length of chromosome arms and the location of centromeres, the relative radial distances of chromosomes towards the center of the nucleus [37], and the gene densities, as calculated from Ensembl (GRCh38.p13). Grey areas on chromosomes indicate the presence of large heterochromatin blocks. Chromosomes can be metacentric (centromere is near the middle of the chromosome), submetacentric (centromere is more towards one side of the chromosome), or acrocentric (centromere is near the end of a chromosome).

Figure 2

Cartoon illustrating different phases of mitosis (top) and meiosis (bottom). During mitosis, all the DNA is supposed to evenly split, creating two genetically identical daughter cells. Chromosomes (blue) are brought to the metaphase plate with the help of microtubules (orange) or motor proteins (light blue). During this phase, sister kinetochores (green) could be: (1) unattached, leading to the activation of the spindle assembly checkpoint (SAC); (2) erroneously attached, which is resolved by the error-correction machinery; (3) laterally attached, which allows for transport towards the metaphase plate; (4) end-on attached, which favors proper segregation. Only when all sister kinetochores are bioriented is the SAC silenced, causing the removal of centromeric cohesin (white) and the movement of sisters to opposite poles. Meiosis follows many of the same principles as mitosis, but differs as well. Instead of creating two genetically identical diploid daughter cells, meiosis generates four genetically different haploid cells. Furthermore, homologous chromosomes are not only affected by cohesin, but also by chiasmata (red), which are physical links created during genetic recombination. During meiosis, the homologous chromosomes are separated first followed by separation of the sisters. Zoom-ins in the figure highlight some of the mechanisms responsible for proper chromosome segregation; 4C, 2C, and 1C refer to DNA content.

Figure 3

Hypothesized consequences of non-random segregation errors. (a) Frequently missegregating chromosomes gives rise to the recurrent aneuploidy pattern seen in cancer. Graphs depicting influence of non-random segregation errors on the speed by which a tumor grows (b), it reaches metastatic potential (c) or is able to grow out after therapy (d). (e) Graph showing the relationship between age and oocyte aneuploidy rate [62] or the aneuploidy syndrome live-birth rate [126].