Chromosome Dynamics and Evolution

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

- Mechanisms of non-Mendelian segregation through female meiosis To understand how meiotic drive elements achieve non-Mendelian segregation, we currently focus on selfish centromeres in mice. Expanded centromeric satellite repeats can violate Mendel's law of segregation by preferentially segregating to the egg cell. In mice, these selfish centromeres enrich microtubule destabilizers (Aurora B kinase and kinesin-13 MCAK) at pericentromeres to detach from the spindle and flip toward the egg side of the meiotic spindle, thereby achieving preferential segregation. However, despite the consistent enrichment of destabilizers upon centromere expansion, such enrichment alone is insufficient to drive the preferential retention of expanded centromeres, suggesting a missing component in understanding their non-Mendelian segregation. This year, we reported that prolonged spindle checkpoint activation is crucial for expanded centromeres to cheat the segregation process by providing sufficient time for them to flip toward the egg side (Walton et al. Curr Biol. 2025). By experimentally manipulating kinetochore size in a species-specific manner, we found that assembling larger kinetochores triggers robust spindle checkpoint activation, leading to anaphase delay and preferential retention of expanded centromeres in the egg. Comparisons across multiple hybrid mouse models revealed that centromeric satellite asymmetry does not consistently lead to kinetochore asymmetry and anaphase delay, explaining why satellite asymmetry does not always result in the preferential retention of larger centromeres. Altogether, this work highlights the significance of checkpoint activation in exploiting the inherent asymmetry in female meiosis and the distinct responses of kinetochore proteins and microtubule destabilizers to centromere expansion. Meiotic drive is fundamental to sexual reproduction and has been recognized as a powerful force in genetics and evolutionary biology since first described in maize in 1942. The underlying mechanisms have long been mysterious to cell biologists. This project tackles this exciting problem, all the way from developing experimental systems to revealing how selfish elements challenge Mendel and affect fitness. Moreover, our work will lead to a deeper understanding of the interactions between chromosomes and spindle microtubules. These interactions are highly error-prone in humans and a major cause of infertility, which could be caused by selfish behaviors of meiotic drive elements. - Mechanisms of reproductive isolation through hybrid female sterility Reproductive isolation occurs when the genomes of two populations accumulate genetic incompatibilities that prevent inter-breeding. For example, hybrid incompatibility in the meiotic chromosome segregation process would lead to the formation of aneuploid gametes and fertility defects. Indeed, there are multiple studies, showing hybrid animals having reduced fertility, serving as a reproductive isolating barrier. However, the molecular basis causing reduced hybrid fertility is largely unknown especially in mammals. This year, we found that female hybrids between Mus musculus domesticus and Mus spicilegus mice are sterile due to the failure of homologous chromosome separation in oocyte meiosis I, producing aneuploid eggs (El Yakoubi et al. bioRxiv 2025). This non-separation phenotype was driven by the mis-localization of the cohesin protector, SGO2, along the chromosome arms instead of its typical centromeric enrichment, resulting in cohesin over-protection. The upstream kinase, BUB1, showed a significantly higher activity in hybrid oocytes, explaining SGO2 mis-targeting along the chromosome arm. Higher BUB1 activity was not observed in mitosis, consistent with viable hybrid mice. Cohesion defects were also evident in hybrid mice from another genus, Peromyscus, wherein cohesin protection is weakened. Defective cohesion in oocytes is a leading cause of reduced fertility especially with advanced maternal age. Our work provides evidence that a major cause of human infertility may play a positive role in promoting mammalian speciation. Overall, this project demonstrated that chromosome mis-regulations in oocytes can serve as a reproductive isolating barrier in mice. Since several chromosomal proteins are rapidly evolving in multiple taxa, including Drosophila and several mammalian clades, meiotic chromosome mis-regulation may represent a recurrent reproductive isolating barriers.