Biology subjects

Skinner, M.

Publications and source records attributed to Skinner, M..

4 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

Context-dependent effects of microbial inoculation on sagebrush seedlings during drought stress

The leaf microbiome interacts with its plant host and can have critical positive and negative effects on plant health. However, the interactions between leaf microbiomes and host plants remain understudied, particularly in reference to context-dependency, e.g., during drought conditions. Plants naturally exist in environments with ever-changing weather and epiphytic foliar microbes are often exposed to extreme conditions. Little is known about how different environmental contexts can alter the effects of phyllosphere microbes on their plant hosts. In this study, we measured the response of seedlings to microbial inoculations and drought conditions. We used Artemisia tridentata subsp. tridentata (hereafter, sagebrush), a foundation species in the vast and critically threatened sagebrush steppe ecosystem. We grew sagebrush plants in growth chambers from sterile seed and after 6 months the seedlings were inoculated in one of four inoculation treatments: (1) no inoculant, (2) sterile water, (3) the microbes washed from the surface of the leaves (a whole natural community), and (4) the single species, Bacillus amyloliquefaciens. We then exposed the seedlings to two environmental treatments: regular watering and a tapered drought. We found context-dependent effects of inoculation on seedling health for both of our inoculation microbial treatments. For example, both inoculants had a negative effect on host plant photosynthesis, which was lessened drought conditions. Furthermore, seedlings inoculated with B. amyloliquefaciens had increased leaf nitrogen levels, and the highest survival under drought conditions. Our study shows that seedling health and survival can be influenced by leaf-associated microbes, and is dependent on environmental context.

plant 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↗

bioRxiv2021

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA-approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

animal behavior and cognition↗