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. 2014 Oct 6;24(19):2295-300.
doi: 10.1016/j.cub.2014.08.017. Epub 2014 Sep 18.

Centromere strength provides the cell biological basis for meiotic drive and karyotype evolution in mice

Lukáš Chmátal  1 , Sofia I Gabriel  2 , George P Mitsainas  3 , Jessica Martínez-Vargas  4 , Jacint Ventura  4 , Jeremy B Searle  5 , Richard M Schultz  6 , Michael A Lampson  7
Affiliations

Centromere strength provides the cell biological basis for meiotic drive and karyotype evolution in mice

Lukáš Chmátal et al. Curr Biol. .

Abstract

Mammalian karyotypes (number and structure of chromosomes) can vary dramatically over short evolutionary time frames. There are examples of massive karyotype conversion, from mostly telocentric (centromere terminal) to mostly metacentric (centromere internal), in 10(2)-10(5) years. These changes typically reflect rapid fixation of Robertsonian (Rb) fusions, a common chromosomal rearrangement that joins two telocentric chromosomes at their centromeres to create one metacentric. Fixation of Rb fusions can be explained by meiotic drive: biased chromosome segregation during female meiosis in violation of Mendel's first law. However, there is no mechanistic explanation of why fusions would preferentially segregate to the egg in some populations, leading to fixation and karyotype change, while other populations preferentially eliminate the fusions and maintain a telocentric karyotype. Here we show, using both laboratory models and wild mice, that differences in centromere strength predict the direction of drive. Stronger centromeres, manifested by increased kinetochore protein levels and altered interactions with spindle microtubules, are preferentially retained in the egg. We find that fusions preferentially segregate to the polar body in laboratory mouse strains when the fusion centromeres are weaker than those of telocentrics. Conversely, fusion centromeres are stronger relative to telocentrics in natural house mouse populations that have changed karyotype by accumulating metacentric fusions. Our findings suggest that natural variation in centromere strength explains how the direction of drive can switch between populations. They also provide a cell biological basis of centromere drive and karyotype evolution.

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Figures

Figure 1
Figure 1. Metacentrics that preferentially segregate to the polar body have weak centromeres relative to telocentrics
(A) Two possible outcomes of balanced trivalent segregation when a metacentric pairs with its homologous telocentric chromosomes in MI: the metacentric segregates to the polar body and the telocentrics stay in the egg (i), or vice versa (ii). (B) DNA and centromere (CREST) staining in Rb(6.16) x CF-1 MII eggs treated with kinesin-5 inhibitor to disperse the chromosomes; insets: telocentric (left) or metacentric (right) chromosomes. The metacentric preferentially segregates to the polar body (60%, n=168, P=0.009). (C) HEC1 staining in Rb(6.16) x CF-1 MI oocytes (n=91) was quantified for the metacentric (inset, yellow asterisk) and homologous telocentrics in the trivalent, and for other telocentrics. (D) CENP-A staining, shown with synaptonemal complex protein SYCP2, was quantified for the metacentric (inset 1) and telocentrics (inset 2) in Rb(6.16) spermatocytes (n=305). Black asterisks: P<0.05; scale bars: 5 μm; AU: arbitrary units.
Figure 2
Figure 2. Differential centromere strength within telocentric bivalents affects their position at metaphase I
(A) HEC1 staining per centromere was quantified in CF-1 (n=28) and CHPO (n=15) MI oocytes, AU: arbitrary units, error bars: SEM. (B) HEC1 staining in CF-1 x CHPO oocytes (n=28). Graph shows the binned distribution of HEC1 intensity ratios (dimmer/brighter kinetochore) calculated for each telocentric bivalent in CF-1 x CHPO oocytes (green, n=28), CF-1 oocytes (red, n=32) or CHPO oocytes (blue, n=30). (C) Images show AURKA, HEC1, and DNA staining in CF-1 x CHPO oocytes (n=64) at metaphase I: a maximal intensity z-projection including all chromosomes (1) and optical sections showing each telocentric bivalent individually (2–7). Schematic shows bivalent positions as equidistant between the two poles (middle), or off-center towards the stronger kinetochore (upper panel) or weaker kinetochore (lower panel). The proportion of bivalents in each group is plotted. (D and E) Schematic shows bivalent position measured as distance (d) from the spindle midzone. Positions of CF-1 and CF-1 x CHPO bivalents at metaphase I are plotted. Each point represents one bivalent; mean shown as red bar. Insets: HEC1 in individual bivalents; scale bars: 5 μm; asterisks: P<0.001.
Figure 3
Figure 3. Metacentrics have stronger centromeres relative to telocentrics in mice that have accumulated multiple metacentrics
(A and B) Chromosome composition and HEC1 staining in CF-1 x CHPO MI oocytes (n=28). Staining was quantified at centromeres from CHPO telocentrics (identified as the dimmer kinetochores in bivalents, red asterisk) and from CHPO metacentrics in trivalents (yellow asterisk). (C) CENP-A staining in CHPO primary spermatocytes (n=67) was quantified for metacentrics (inset 1) and telocentrics (inset 2). Black asterisks: P<0.05; scale bars: 5 μm; AU: arbitrary units.
Figure 4
Figure 4. Relative centromere strength predicts meiotic drive in natural mouse populations with metacentrics
(A and B) HEC1 staining in MI oocytes from commercially available mouse species, subspecies and strains (A) and from natural metacentric populations in Barcelona and Greece and a telocentric population in Greece, together with a standard laboratory strain for comparison (B). (C) HEC1 staining was quantified relative to laboratory mouse strains and normalized to CF-1. Numbers of oocytes in each group are indicated; gray bars: telocentric populations, black bars: metacentric populations; asterisks: statistically different from lab strains (P<0.05). (D and E) CENP-A staining was quantified in spermatocytes from CHPO, Rb(6.16), and natural metacentric populations. A representative image of a metacentric karyotype (D) is shown (PSAN, 2n=22); insets: telocentric (1) and metacentric (2) chromosomes. The ratio of CENP-A staining in metacentrics/telocentrics was calculated for each group (E). Asterisks: metacentrics statistically different from telocentrics (P<0.05). Scale bars: 5 μm; AU: arbitrary units. (F) Listing of the karyotypes of the natural metacentric populations used in this study. (G) Model for meiotic drive of Rb fusions. In populations with strong centromeres, fusions that arise spontaneously (red chromosomes) tend to have weaker centromeres than the homologous telocentrics and therefore preferentially segregate to the polar body. In populations with weak centromeres, fusions tend to be relatively strong and are preferentially retained in the egg.
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