Mitotic Antipairing of Homologous Chromosomes

Abstract

Chromosome organization is highly dynamic and plays an essential role during cell function. It was recently found that pairs of the homologous chromosomes are continuously separated at mitosis and display a haploid (1n) chromosome set, or "antipairing," organization in human cells. Here, we provide an introduction to the current knowledge of homologous antipairing in humans and its implications in human disease.

Keywords: Antipairing; Homologous chromosomes; Mitosis; Nuclear organization.

Figure 1:. Current models for nonrandom chromosome organization.

Different models of global chromosome organization have been proposed for the human interphase cell. Studies have argued against a random model as in A) (Cornforth et al, 2002; Lesko et all, 1995). B) In the parental origin model, maternal and paternal chromosomes are spatially segregated (Reichmann et al, 2018, Gondos et al, 1970; Odartchenko and Keneklis, 1973; Brandriff et al, 1991; Brandriff et al, 1992; Mayer et al, 2000; De La Fuente et al, 2015; Payne et al, 2021; Schneider et al, 2021). C) Size-dependent organization proposes larger chromosomes are positioned along the nuclear periphery, close to the nuclear envelope, and smaller ones in the nuclear interior. (Cremer et al, 2001; Sun et al, 2000; Bolzer et al, 2005; Emmerich et al, 1989; Popp et al, 1990; Fritz et al, 2014) D) Although similar in size, chromosomes 18 and 19 have been shown to distribute based on gene-density. (Boyle et al, 2001; Bridger et al, 2000) E) Chromosome positions have been proposed to change under various physiological conditions that include differentiation and cell type identity. (Bolzer et al, 2005; Cremer et al, 2001; Boyle et al, 2001; Parada et al, 2004; Marella et al, 2009; Mayer et al, 2005; Zeitz et al, 2009; Foster et al, 2005; Alcobia et al, 2000). F) It has been shown that chromosomes positions are more similar in cells with a common progenitor suggesting differentiation may be important for nuclear organization (Cremer et al, 2003).

Figure 2:. Model of the haploid (1n) chromosome set organization in human endothelial cells at mitosis.

A) We have recently shown that a pair of homologous and sex chromosomes segregate to individual nuclear hemispheres forming a haploid (1n) chromosome set (Hua & Mikawa, 2018). A 3D coordinate axis was defined as following: the x-axis is a line crossing both centrosomes (line of nuclear division); the z-axis is along the laser line of the microscope; and the y-axis is perpendicular to both x- and z-axes. B) Top view of a tetraploid mouse C2C12 mouse myoblasts at prometaphase stained for Chromosomes 6 (red), Chromosome 1 (green), Chromosome 3 (magenta), and TO-PRO3 for DNA (blue) from confocal optical sections. Individual homologous chromosomes are spatially segregated from one another.

Figure 3:. Schematic representation of a loss of heterozygosity (LOH) because of mitotic recombination that contributed to abnormal somatic pairing.

Heterozygous parent cells carry a wild type (wt, yellow), and mutant (mt, red) allele on two different homologous chromosomes. During mitosis, if there is a loss of antipairing and an abnormal pairing event, mitotic recombination can occur between the homologous chromosomes (Inset). During prophase and up to metaphase, there could be a regional exchange between homologous chromosomes, and resulting daughter cells could have different allelic composition. Mitotic recombination generates genetically different daughter cells than the parental cell. Both daughter cells would be homozygous for the alleles. One daughter cell would have two wt alleles and the other daughter cell would have two mutant alleles which demonstrate a loss of heterozygosity (LOH) event. In retinoblastoma, there is a loss of both alleles that promote tumorigenesis.