Biology subjects

Akera, T.

Publications and source records attributed to Akera, T..

7 recordsLinked to original sources

bioRxiv2026

Discovery of a Genetic Toxin-Antidote System in Vertebrates

Toxin-antidote (TA) systems are selfish genetic elements that bias their own inheritance by coupling a toxin that kills offspring with an antidote that specifically rescues carriers. Although widespread across bacteria, archaea, fungi, plants, and invertebrates, TA systems have not been described in vertebrates. Here we report the first vertebrate TA system, which sabotages mammalian embryogenesis. We define HEX (Homogenously staining region-mediated Embryo eXecution) as a selfish element that biases its transmission through the female mouse germline. Crosses between HEX heterozygous females and wild-type males result in selective lethality of wild-type embryos, yielding preferential survival of HEX-bearing progeny. Using mouse genetics, embryo transfer, and zygote micromanipulation, we show that HEX operates through a canonical TA mechanism: the maternally deposited toxin SP100 induces genotoxic stress in embryos, while the linked antidote SP110 selectively rescues HEX-positive embryos. Both components are core factors of the interferon signaling pathway, revealing that HEX co-opts innate immune machinery to drive transmission bias. These findings establish a vertebrate TA system and demonstrate that selfish elements can repurpose fundamental cellular pathways to violate Mendelian inheritance, with profound consequences for female fertility.

genetics↗

bioRxiv2025

Hybrid female sterility due to cohesin protection errors in oocytes

Hybrid incompatibility can lead to lethality and sterility of F1 hybrids, contributing to speciation. Here 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. 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.

cell biology↗

bioRxiv2024

Meiosis-specific decoupling of the pericentromere from the kinetochore

The primary constriction site of the M-phase chromosome is an established marker for the kinetochore position, often used to determine the karyotype of each species. Underlying this observation is the concept that the kinetochore is spatially linked with the pericentromere where sister-chromatids are most tightly cohered. Here, we found an unconventional pericentromere specification with sister chromatids mainly cohered at a chromosome end, spatially separated from the kinetochore in Peromyscus mouse oocytes. This distal locus enriched cohesin protectors, such as the Chromosomal Passenger Complex (CPC) and PP2A, at a higher level compared to its centromere/kinetochore region, acting as the primary site for sister-chromatid cohesion. Chromosomes with the distal cohesion site exhibited enhanced cohesin protection at anaphase I compared to those without it, implying that these distal cohesion sites may have evolved to ensure sister-chromatid cohesion during meiosis. In contrast, mitotic cells enriched CPC only near the kinetochore and the distal locus was not cohered between sister chromatids, suggesting a meiosis-specific mechanism to protect cohesin at this distal locus. We found that this distal locus corresponds to an additional centromeric satellite block, located far apart from the centromeric satellite block that builds the kinetochore. Several Peromyscus species carry chromosomes with two such centromeric satellite blocks. Analyses on three Peromyscus species revealed that the internal satellite consistently assembles the kinetochore in both mitosis and meiosis, whereas the distal satellite selectively enriches cohesin protectors in meiosis to promote sister-chromatid cohesion at that site. Thus, our study demonstrates that pericentromere specification is remarkably flexible and can control chromosome segregation in a cell-type and context dependent manner.

cell biology↗

bioRxiv2024

An egg sabotaging mechanism drives non-Mendelian transmission in mice

During meiosis, homologous chromosomes segregate so that alleles are transmitted equally to haploid gametes, following Mendels Law of Segregation. However, some selfish genetic elements drive in meiosis to distort the transmission ratio and increase their representation in gametes. The established paradigms for drive are fundamentally different for female vs male meiosis. In male meiosis, selfish elements typically kill gametes that do not contain them. In female meiosis, killing is predetermined, and selfish elements bias their segregation to the single surviving gamete (i.e., the egg in animal meiosis). Here we show that a selfish element on mouse chromosome 2, R2d2, drives using a hybrid mechanism in female meiosis, incorporating elements of both male and female drivers. If R2d2 is destined for the polar body, it manipulates segregation to sabotage the egg by causing aneuploidy that is subsequently lethal in the embryo, so that surviving progeny preferentially contain R2d2. In heterozygous females, R2d2 orients randomly on the metaphase spindle but lags during anaphase and preferentially remains in the egg, regardless of its initial orientation. Thus, the egg genotype is either euploid with R2d2 or aneuploid with both homologs of chromosome 2, with only the former generating viable embryos. Consistent with this model, R2d2 heterozygous females produce eggs with increased aneuploidy for chromosome 2, increased embryonic lethality, and increased transmission of R2d2. In contrast to a male meiotic driver, which kills its sister gametes produced as daughter cells in the same meiosis, R2d2 eliminates "cousins" produced from meioses in which it should have been excluded from the egg.

genetics↗

bioRxiv2022

Condensin dysfunction is a reproductive isolating barrier in mice

Reproductive isolation occurs when the genomes of two populations accumulate genetic incompatibilities that prevent inter-breeding. Cell biological understanding of such hybrid incompatibility is limited, especially for hybrid female sterility. Here we find that species divergence in condensin regulation and centromere organization between two mouse species, Mus musculus and Mus spretus, drives chromosome de-condensation and mis-segregation in their F1 hybrid oocytes, reducing female fertility. The chromosome condensation defects in hybrid oocytes were especially prominent at Mus musculus centromeres due to their highly abundant major satellite DNA, leading to species-specific chromosome mis-segregation. This study provides the first mechanistic insights into hybrid incompatibility in female meiosis and demonstrates that condensin mis-regulation can be a reproductive isolating barrier in mammals.

cell biology↗

bioRxiv2018

Molecular and evolutionary strategies of meiotic cheating by selfish centromeres

Asymmetric division in female meiosis creates selective pressure favoring selfish centromeres that bias their transmission to the egg. This centromere drive can explain the paradoxical rapid evolution of both centromere DNA and centromere-binding proteins despite conserved centromere function. Here, we define a molecular pathway linking expanded centromeres to histone phosphorylation and recruient of microtubule destabilizing factors in an intraspecific hybrid, leading to detachment of selfish centromeres from spindle microtubules that would direct them to the polar body. We also introduce a second hybrid model, exploiting centromere divergence between species, and show that winning centromeres in one hybrid become losers in the other. Our results indicate that increasing destabilizing activity is a general strategy for drive, but centromeres have evolved distinct strategies to increase that activity. Furthermore, we show that drive depends on slowing meiotic progression, suggesting that a weakened meiotic spindle checkpoint evolved as a mechanism to suppress selfish centromeres.

cell biology↗

bioRxiv2017

Spindle asymmetry drives non-Mendelian chromosome segregation

Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through meiotic drive, in violation of Mendels Law of Segregation. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle, which implies some asymmetry between the two sides of the spindle, but molecular mechanisms underlying spindle asymmetry are unknown. Here we show that CDC42 signaling from the cell cortex regulates microtubule tyrosination to induce spindle asymmetry, and non-Mendelian segregation depends on this asymmetry. These signals depend on cortical polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.

cell biology↗