Molecular 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 recruitment of microtubule destabilizing factors, leading to detachment of selfish centromeres from spindle microtubules that would direct them to the polar body. Exploiting centromere divergence between species, we show that selfish centromeres in two hybrid mouse models use the same molecular pathway but modulate it differently to enrich destabilizing factors. Our results indicate that increasing microtubule destabilizing activity is a general strategy for drive in both models, but centromeres have evolved distinct mechanisms to increase that activity. Furthermore, we show that drive depends on slowing meiotic progression, suggesting that selfish centromeres can be suppressed by regulating meiotic timing.

Dach1 Extends Artery Networks and Protects Against Cardiac Injury.

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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 Mendel's 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.

Vascular endothelial cell development and diversity.

Vascular endothelial cells form the inner layer of blood vessels where they have a key role in the development and maintenance of the functional circulatory system and provide paracrine support to surrounding non-vascular cells. Technical advances in the past 5 years in single-cell genomics and in in vivo genetic labelling have facilitated greater insights into endothelial cell development, plasticity and heterogeneity. These advances have also contributed to a new understanding of the timing of endothelial cell subtype differentiation and its relationship to the cell cycle. Identification of novel tissue-specific gene expression patterns in endothelial cells has led to the discovery of crucial signalling pathways and new interactions with other cell types that have key roles in both tissue maintenance and disease pathology. In this Review, we describe the latest findings in vascular endothelial cell development and diversity, which are often supported by large-scale, single-cell studies, and discuss the implications of these findings for vascular medicine. In addition, we highlight how techniques such as single-cell multimodal omics, which have become increasingly sophisticated over the past 2 years, are being utilized to study normal vascular physiology as well as functional perturbations in disease.

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 a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on 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.