The centromere drive hypothesis invokes genetic conflict to explain the paradox that both centromere DNA sequences and centromere-binding proteins have evolved rapidly, despite highly conserved centromere function across eukaryotes. Genetic conflict at centromeres is grounded in the asymmetry inherent in female meiosis I (MI). In this reductionist cell division, one chromosome from each homologous pair remains in the egg and can be transmitted to the next generation, while the other is degraded in the polar body. Natural selection strongly favors any allele that can increase its chance of remaining in the egg, in violation of Mendel's First Law (Law of Segregation). Such biased chromosome segregation in meiosis does occur and is a form of meiotic drive. The first part of the centromere drive hypothesis is that rapid evolution of centromere DNA is driven by competition to orient towards the spindle pole that will remain in the egg. The model is that expansion of repetitive sequences at a centromere leads to formation of a larger kinetochore and preferential retention in the egg. The second part of the hypothesis explains the evolution of centromere proteins through conflict between individual centromeres, which expand to gain a reproductive advantage, and the reproductive fitness of the organism. If differences between centromeres of homologous chromosomes cause defects in male meiosis, this fertility cost provides selective pressure favoring alleles of centromere-binding proteins that equalize centromeres and suppress drive by binding independent of sequence. The centromere drive hypothesis has had a major impact on the centromere field because it provides a conceptual framework for understanding the evolution of centromere DNA and centromere proteins, but the underlying cell biological mechanisms are unknown. This proposal addresses three major gaps in our understanding of centromere drive. First, how does centromere DNA sequence influence centromere function? Centromeres are defined epigenetically in most organisms, and the contribution of sequence has long been unclear. Second, how is biased segregation in MI achieved? The mechanism by which one centromere preferentially remains in the egg is unknown. Third, is there a fertility cost in male meiosis? Direct evidence for this crucial component of the drive hypothesis is scant. If there is a cost, what is the mechanistic basis? To address these questions, we have established an experimental system in which we observe drive, using a hybrid mouse model created by crossing two strains with different centromeres. Genetic conflict has shaped many aspects of our genomes, and centromeres are a particularly fascinating case because of the implications for non-Mendelian inheritance. The outcomes of our experiments will provide the first mechanistic insight into the cell biology underlying centromere drive. With broad consequences for reproductive biology and chromosome evolution, this project represents a unique contribution to the field of evolutionary cell biology.
Proper regulation of cell division during the process of making a sperm or egg (termed meiosis) ensures that these crucial cells inherit the correct genetic material. Errors in this process lead to genetic abnormalities, pregnancy loss, and developmental defects. Furthermore, biased segregation of chromosomes in female meiosis increases the likelihood of inheriting common chromosomal abnormalities (Robertsonian fusions) so that they persist in families and in the population overall. The overall goal of this proposal is to understand the regulation of meiotic cell division, with a focus on mechanisms underlying biased segregation.
| Akera, Takashi; Chenoweth, David M; Lampson, Michael A (2018) Optogenetic Manipulation of Mouse Oocytes. Methods Mol Biol 1818:129-135 |
| Iwata-Otsubo, Aiko; Dawicki-McKenna, Jennine M; Akera, Takashi et al. (2017) Expanded Satellite Repeats Amplify a Discrete CENP-A Nucleosome Assembly Site on Chromosomes that Drive in Female Meiosis. Curr Biol 27:2365-2373.e8 |
| Akera, Takashi; Chmátal, Lukáš; Trimm, Emily et al. (2017) Spindle asymmetry drives non-Mendelian chromosome segregation. Science 358:668-672 |
| Lampson, Michael A; Black, Ben E (2017) Cellular and Molecular Mechanisms of Centromere Drive. Cold Spring Harb Symp Quant Biol 82:249-257 |
