ABSTRACTRecent discoveries of transposable element (TE) activity in the octopus genome suggest, to some, that these “jumping genes” facilitated the evolution of cephalopod brains and possibly contribute to cognitive flexibility in these animals. In contrast, TEs are often regarded as genomic parasites with net deleterious effects on host fitness. The octopus genome provides an opportunity to compare these proposals to a genome‐ecological alternative. We review evidence of TE accumulation and somatic activity, showing compatibility with both organism‐beneficial and selfish‐DNA interpretations. To resolve this, we apply ecological thinking within the genome to generate novel predictions. If TEs are adapted to a “requirement niche” typically found in germline cells, then TE‐population growth rates (replication rates) should be nonnegative under similar “environmental” conditions (e.g., similar gene expression patterns to testes). This invites a comparison of expression levels across tissues. It is reasonable to infer some organism‐beneficial function only when TE expression levels deviate from those predicted by the degree of niche‐overlap with germline cells.

ABSTRACTRecapitulation of the nuclear auxin response pathway in yeast led to the hypothesis that corepressors prime loci for rapid bursts of transcription. Specifically, the TPL corepressor, which inhibits transcription in the absence of auxin, interfaces with Mediator and core components of the transcription pre‐initiation complex (PIC). Once auxin is perceived, RNA Pol‐II is likely to essentially displace TPL, allowing for rapid transcription initiation (and likely re‐firing). Here, we present the current evidence supporting the role of TPL‐type corepressors in multiple levels of transcriptional control, including modulation of regulatory transcription factor activity, interactions between cis‐elements and the core promoter, and in organizing multiple loci within the nucleoplasm. We also highlight critical areas for future investigations.

ABSTRACTLaplane et al. recently provided a valuable framework for understanding cancer evolution through multilevel selection (MLS), distinguishing between MLS1, where groups differ in persistence based on the traits of their constituent cells but do not reproduce or evolve group‐level adaptations, and MLS2, where groups themselves reproduce and possess emergent fitness distinct from that of individual cells. However, as the authors themselves acknowledge, applying MLS2 to metastasis is challenging for several reasons. We argue that, rather than behaving as isolated evolutionary units, tumor sites function as components of a distributed system. This perspective suggests that metastasis may be better understood through the lens of selection for function, a framework that explains how traits contributing to system‐level persistence can be maintained without requiring group‐level reproduction. This approach complements MLS theory and helps account for the resilience of the metastatic system as a whole, namely, the persistence and coordination of multiple tumor sites functioning as a collective rather than as isolated tumors, beyond classical Darwinian models. It also aligns with the view that metastasis may reflect the reactivation of ancient cellular programs in a novel, nonreproductive context.

ABSTRACTMost vertebrate genes are split up into exons and introns, with exons being spliced together to make mRNA. Many of the proteins involved in splicing, called splicing factors, exert concentration‐dependent effects on gene expression through post‐transcriptional modification of mRNAs. These include the serine/arginine‐enriched (SR) proteins that have essential roles in normal development and physiology. All SR proteins (and many other splicing factors) regulate their own expression levels, often using negative feedback pathways involving alternative splicing of “poison exons” (PEs), which lead to mRNA degradation. The PEs within SR protein genes are encoded by ultra‐conserved genome sequences, suggesting they have been under extreme selective pressure despite not encoding protein sequences. Here, we discuss the hypothesis that PEs enable rapid switches in SR protein concentrations, yet prevent these splicing regulators from increasing to toxic levels that cause cell death or interfere with cell function. This hypothesis is based on analysis of an ultra‐conserved PE in the TRA2B gene during male meiosis. Distinct roles for this TRA2B PE in different tissues further predict cell type‐specific effects on development and physiology that will need to be experimentally detected using animal models.

ABSTRACTThe allosteric mechanism of G‐protein‐coupled receptors (GPCRs) involves a population shift from inactive to active receptor conformations in response to the binding of ligand agonists. Two possible kinetic mechanisms for this population shift are induced fit and conformational selection. In the induced‐fit mechanism, ligands bind to inactive receptor conformations prior to the conformational transition of the receptor. In the conformational‐selection mechanism, ligands bind to active conformations after the conformational transition. For the peptide‐activated neurotensin receptor 1, stopped‐flow mixing experiments that probe the chemical relaxation into binding equilibrium and conformational transition rates measured with NMR experiments indicate an induced‐fit mechanism. For the small‐molecule‐activated β2‐adrenergic receptor, an induced‐fit mechanism has been inferred from a decrease of ligand association rates after stabilization of the active receptor conformation. A structural explanation for the induced‐fit mechanism of the β2‐adrenergic receptor is a closed lid over the binding site that blocks ligand entry in the active conformation. Since constriction and closing of the ligand‐binding site in the active conformation is rather common for small‐molecule‐activated and peptide‐activated GPCRs, induced fit is likely shared as allosteric mechanism by these GPCRs.

ABSTRACTVertebrate gonadal function is regulated by pituitary gonadotropins, follicle‐stimulating hormone (FSH) and luteinizing hormone (LH). These hormones are considered to be regulated by hypothalamic factor(s). Since the discovery of gonadotropin‐releasing hormone (GnRH) in mammals, which stimulates the secretion of both FSH and LH, GnRH had been believed to be the sole gonadotropin‐releasing hormone in vertebrates for more than 5 decades. However, recent studies have identified an alternative primary regulator of FSH in teleosts, leading to the hypothesis that FSH and LH are regulated by different factors in teleosts (dual GnRH model). This contrasts with the situation in mammals, where a single GnRH regulates both hormones (solo GnRH model). Importantly, although underlying mechanisms likely differ, both teleosts and mammals reproduce efficiently and have convergently evolved similar phenomena, including steroid feedback regulation. In this review, by comparing these taxa, we summarize mechanistic differences and propose an evolutionary scenario based on current experimental evidence.

ABSTRACTRecent advances in genomics uncovered a large number of microproteins, which are peptides of less than 100 amino‐acids encoded by small open reading frames. In contrast to their identification, the validation of the functions of microproteins remains challenging. Especially, what are their biological functions in the cell and how this relates to disease conditions are still largely unknown. Although microproteins ensure a plethora of cellular functions, recent evidence demonstrate that they may disproportionately affect cellular metabolism. In this review, we will address the roles of mitochondrial‐targeted microproteins, and especially how this class of protein regulates neuronal metabolism in neurodevelopment and neurodegeneration, and may contribute to axonal and dendritic metabolic disorders.