The cellular mechanisms and consequences of centromere drive

Abstract

During female meiosis, only one of four meiotic products is retained in the egg. It was previously proposed that chromosomes might compete for inclusion in the egg via their centromere 'strength'. Recent findings have revealed the primary requirements for such 'centromere drive'. First, CDC42 signaling from the oocyte cortex renders the meiotic I spindle asymmetric. Second, 'stronger' centromeres preferentially detach from microtubules in cortical proximity, making them more likely to orient away from the cortex, and be included in the egg. Third, centromeric satellite DNA expansions result in greater recruitment of centromeric proteins. Despite these mechanistic insights, it is still unclear if centromere drive elicits rapid evolution of centromeric proteins, thereby driving cellular incompatibilities and wreaking havoc on centromere stability.

Figure 1. The three cellular requirements of centromere drive

In order for centromere drive to occur, three basic requirements must be met. First, the meiotic I spindle must be asymmetric (dark green vs light green microtubules). Second, there must be a preferred (winning) orientation that dictates which chromosomes will segregate to the egg instead of the polar body. In mouse oocytes, chromosomes positioned toward the center of the oocyte nucleus will end up in the egg while chromosomes positioned near the oocyte cortex will segregate to the polar body. Third, there must be centromeric heterozygosity (one homolog has large, orange, centromeres, while the other three have small black centromeres). Chromosomes drawn here are acrocentric (have their centromeres on one end) and are paired with one crossover each in late metaphase I. They segregate to opposite poles in anaphase I. DNA is in shades of grey.

Figure 2. Steps to spindle polarization in mouse oocyte meiosis I

(a) The meiotic I (MI) spindle is initially symmetric and is located in the center of the oocyte (i). The spindle migrates toward the cell cortex where a RAN-GTP gradient (light blue) emanates from the chromosomes and induces CDC42 signaling (dark blue), creating a polarized cortex (ii). CDC42 signaling from the polarized cortex induces tyrosination of α-tubulin (light green microtubules) on the side of the spindle closest to the cortex. The microtubules emanating from the spindle pole oriented toward the center of the oocyte remain primarily de-tyrosinated (dark green microtubules) (iii). (b) Global expression of a dominant negative CDC42 (grey diamonds) prevents cortex polarization and prevents the MI spindle from becoming asymmetrically tyrosinated (note: all microtubules are de-tyrosinated, dark green). (c) Optogenetic targeting of active CDC42 (dark blue) to one spindle pole induces asymmetric spindle tyrosination (dark vs. light green microtubules) even before spindle migration towards the cortex. (d) Global expression of a dominant negative RAN (grey circles) prevents cortex polarization and prevents the spindle from becoming asymmetrically tyrosinated.

Figure 3. How strong centromeres drive

(a) When a chromosome detaches from the meiotic I spindle (highlighted in yellow), it has equal likelihood of reattaching in the same orientation (b) or opposite orientation (b′) (equal weight arrows connect (a) to (b) and (a) to (b′). However, a driving centromere is more likely to detach from the cortical spindle (light green microtubules oriented toward polar body, thick arrow from (b) to (a) represents higher likelihood) than from the spindle oriented toward the egg (dark green microtubules, thin arrow from (b′) to (a) represents lower likelihood).

Figure 4. Competition between CenH3 orthologs induces aneuploidy in Arabidopsis

A CenH3 null mutant Arabidopsis thaliana plant can be fully rescued by an A. thaliana CenH3 transgene (black centromeres) (a) A self cross between pollen and ovules from an A. thaliana CenH3 transgene plant results in healthy seeds that develop into phenotypically wild-type, fertile plants. (b) A CenH3 null mutant A. thaliana plant can also be rescued by an orthologous CenH3 transgene from L. oleraceum (orange centromeres). A self cross between pollen and ovules from an L. oleraceum CenH3 transgene plant results in healthy seeds that develop into phenotypically wild-type, fertile plants. (c) However, when pollen from an A. thaliana CenH3 transgenic plant is crossed to ovules from a L. oleraceum CenH3 transgenic plant, the resulting progeny have high rates of aneuploidy which is entirely attributable to defects in the maternal, L. oleraceum-CenH3-packaged, genome. Note: all plants have an A. thaliana genetic background.