Mechanism of meiotic drive in mammals

Meiotic drive is a phenomenon responsible for an unequal representation of alleles or whole chromosomes among gametes as a result of the mechanics of meiotic division (Sandler et Novitski 1957). When it drives segregation of Robertsonian translocations (Rb), a common chromosomal rearrangement in mammals, in oocytes these translocations are either preferentially maintained in the egg or preferentially expelled to the polar body during meiosis I (MI), thus being either transmitted or excluded from the next generation. Because Rb translocations are formed by fusion of two acrocentric chromosomes creating one metacentric chromosome, subsequent accumulation and fixation of these fusions over time leads to a change in karyotype (Castaglia 1982, Villena et Sapienza 2001). Despite the importance of this phenomenon for evolution and speciation, the underlying mechanisms of meiotic drive are unknown. We tested a model of meiotic drive based on three elements: (1) an asymmetric trivalent that forms in MI when a metacentric fusion pairs with the two homologous acrocentric chromosomes, (2) preferential orientation of the trivalent on an asymmetric spindle, and (3) orientation of the asymmetric spindle with one side preferentially facing the cortex. We find reduced levels of kinetochore proteins in fusion centromeres compared to the homologous acrocentric centromeres, suggesting that the trivalent asymmetry is based on differential centromere strength. We also find that stability of MI spindle microtubules is influenced by proximity to the cortex, leading to asymmetric spindles with more stable microtubules oriented towards the cortex. These MTs preferentially bind the fusion centromere, which orients the metacentric Rb fusion chromosome towards the cortex for eventual segregation to the polar body.Together, our data provide evidence for a model to explain the biased segregation of Rb translocations in mammalian oocytes.