The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

Abstract

Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects is change in the relative dosage of products from genes located on the missegregated chromosomes. Abnormal expression of transcriptional regulators can also impact genes on the properly segregated chromosomes. The consequences of these perturbations in gene expression depend on the specific chromosomes affected and on the interplay of the aneuploid phenotype with the environment. Most often, these novel chromosome distributions are detrimental to the health and survival of the organism. However, in a changed environment, alterations in gene copy number may generate a more highly adapted phenotype. Chromosome segregation errors also have important implications in human health. They may promote drug resistance in pathogenic microorganisms. In cancer cells, they are a source for genetic and phenotypic variability that may select for populations with increased malignance and resistance to therapy. Lastly, chromosome segregation errors during gamete formation in meiosis are a primary cause of human birth defects and infertility. This review describes the consequences of mitotic and meiotic errors focusing on novel concepts and human health.

Keywords: aneuploidy; birth defects; cancer; centromere; chromosome instability; drug resistance; fertility; kinetochore; microtubule; polyploidy.

Figure 1

Mitotic defects have several potential outcomes. Failed alignment of chromosomes leads to mitotic arrest/delay enforced by the spindle checkpoint. If the failed alignment is not corrected, cells can follow several fates. They can undergo cell death directly from mitotic arrest. Cells may also suffer various kinds of abnormalities during mitotic exit, leading to the formation of aneuploid progeny. Alternatively, cells may exit mitosis without proper chromosome segregation and cytokinesis, resulting in a formation of a single tetraploid cell. Aneuploid or polyploid daughter cells may undergo cell death, cessation of proliferation and senescence, or continued proliferation. In most cases continued proliferation requires suppression or inactivation of the p53 tumor suppressor pathway.

Figure 2

Aneuploidy produces changes in mRNA dosage which lead to changes in protein dosage for genes on the gained or lost chromosome(s). Changed protein levels can have direct effects on biological processes in which they are involved, or change the stoichiometry of protein complexes of which they are components, causing changes in their function. Changes in gene dosage of regulatory proteins like transcription factors may also exert indirect effects on biological processes by altering expression of their target genes on other chromosomes. In most cases, alterations in protein levels are disadvantageous or detrimental for organisms adapted to their ordinary environment (left), where the euploid karyotype provides best fitness. However, under conditions of environmental change, rapid alterations in expression of many genes may provide adaptive potential and be selected (right).

Figure 3

Cell lines derived from cancers exhibit numerical and segmental aneuploidy. Spectral karyotype comparison of normal human mammary epithelial cells (HMEC) and two breast cancer cell lines (MCF-7 and SUM149PT) that exhibit extensive numerical and segmental aneuploidy. Image reproduced from [106].

Figure 4

Numerical and segmental aneuploidy as an outcome of cohesion fatigue and centromere fission. A cell at metaphase will normally undergo balanced chromosome segregation in normal anaphase (upper path). If metaphase is delayed (lower path), chromatids may begin to undergo cohesion fatigue and separate. When sister chromatids separate they may both move to one of the two spindle poles leading to numerical aneuploidy following anaphase and mitotic exit. In other cases the kinetochore of an individual chromatid may undergo merotelic attachment to microtubules from both spindle poles (exemplified by sequential stages for the pink chromatid and detailed in the green boxes). Under this circumstance, spindle forces or cytokinesis may sever the chromatid resulting in chromosome fragments that can attach to other chromosomes resulting in segmental deletions, duplications, translocations and the formation of micronuclei.

Figure 5

Micronuclei present in two daughter LLC-Pk cells, a cell line derived from porcine kidney. Micronuclei likely formed from lagging chromosomes that were partially trapped in the cytokinetic cleavage furrow. The midbody, the remnant of the cleavage furrow, bisects the region between the two micronuclei. (micrographs courtesy of Hem Sapkota.)

Figure 6

Meiotic errors lead to aneuploid gametes. (A) Normal meiosis consists of two chromosome segregation events without an intervening S phase. In Meiosis I, homologous chromosomes pair and undergo recombination, forming crossovers. In anaphase of Meiosis I, the homologous chromosomes segregate. In Meiosis II sister chromatids separate. The final product is four haploid (1N) cells; (B) Defects in meiosis result in aneuploidy. In the example shown, the chromatids of one chromosome separate prematurely and segregate to opposite poles resulting in an imbalance of chromatids in the two cells produced by Meiosis I. When these cells undergo Meiosis II, each produces one normal haploid (1N) gamete and one aneuploid (1N + 1 or 1N − 1) gamete. For simplicity, only two chromosome pairs are depicted.

Figure 7

Loss of cohesin and the cohesin protector, Sgo2, in older mammals may lead to increased premature chromatid separation in meiosis. In young mammals (left) paired homologous chromosomes have high levels of cohesin and Sgo2 in Meiosis I (MI). At anaphase of Meiosis I, the protease, Separase, clips Cohesin on the distal chromosome arms allowing the homologous chromosomes to separate. Sgo2 protects Cohesin near the centromeres until Meiosis II (MII) ensuring that sister chromatids will orient to opposite poles. In aged mammals (right) there are diminished amounts of Cohesin and Sgo2. During Meiosis 1 Separase cleaves the majority of cohesin, including that near the centromeres. This allows sister chromatids to separate during anaphase of Meiosis I. In Meiosis II the individual chromatids may separate randomly to the spindle poles leading to a high incidence of aneuploidy. (Adapted from [163].)

Figure 8

Failed cytokinesis can lead to multipolar spindle formation in the subsequent mitosis. (A) A field of control HeLa cells containing mitotic cells showing normal chromosome alignment at metaphase (arrows); (B) HeLa cells were treated for a short time with an actin polymerization inhibitor drug, which blocks cytokinesis and results in the formation of binucleate polyploid cells containing extra centrosomes. During the subsequent mitosis, polyploid cells form abnormal metaphase chromosome alignments (arrows) when the presence of extra centrosomes leads to assembly of multipolar mitotic spindles. When these cells then undergo anaphase and cytokinesis, chromosomes are segregated in a random, unequal manner, leading to the formation of daughter cells that are highly aneuploid. Chromosomes are depicted in green; cell surfaces are depicted in magenta.