Centromeres are essential chromosomal loci specified epigenetically by CENP-A chromatin, yet they undergo rapid sequence turnover, structural remodeling, and occasional repositioning. In this review, we integrate recent advances enabled by long-read genome assemblies and high-resolution chromatin mapping to synthesize current understanding of centromere organization across taxa. We examine how satellite repeats, transposable elements, molecular drive, and meiotic conflict generate extreme centromere diversity. We further explore how DNA methylation and H3K9me3 heterochromatin constrain CENP-A positioning, stabilize centromeric domains, and shape boundary dynamics during centromere drift, duplication, and de novo formation. Together, these perspectives show how centromeres accommodate evolutionary change while preserving the stringent requirements of faithful chromosome segregation.

The mitochondrial genome resides in a highly mutagenic environment and is typically maternally inherited with little recombination, features that should render mitochondrial DNA (mtDNA) prone to the accumulation of deleterious variants. Contrary to this expectation, mtDNA integrity is remarkably well-preserved over evolution. Purifying selection in the female germline that limits transmission of deleterious mtDNA mutations has been documented in various animal models and in humans. Here, we synthesize the literature, with an emphasis on insights from Drosophila, revealing that replication competition-the preferential propagation of healthy genomes over deleterious ones-is the main mechanism driving mtDNA purifying selection in the germline. We highlight developmentally orchestrated mitochondrial processes that couple genome function to replication, enabling selection based on the bioenergetic performance of individual genomes during oogenesis. Finally, we discuss how replication competition can generate genetic conflicts, particularly through the emergence of selfish mtDNA, and how such conflicts may have shaped mtDNA evolution and features of mitochondrial genetics, including maternal inheritance and the mitochondrial bottleneck.

Genomic imprinting is an epigenetic phenomenon in which chromosome behavior or gene expression depends on whether an allele was paternally or maternally inherited. Imprinting is commonly associated with a placenta or an analogous organ during embryo development; however, imprinting occurs in diverse species across animal and plant life, including those that lack a placenta. Common epigenetic modifications are associated with genome imprinting across these groups, although the exact mechanisms vary across taxa. There are also commonalities surrounding the evolutionary selection for imprinting. The most well-known hypothesis is parental conflict theory, which proposes that imprinting resolves conflict over the maternal allocation of resources to the developing embryo. Shared mechanisms and functions of imprinting across diverse groups suggest that parental epigenetic asymmetries may be an inherent characteristic of sexual reproduction in species where the sperm and egg differ in size and form.

Nonessential, supernumerary B chromosomes have been an intriguing anomaly known to researchers for over a century. B chromosomes were first identified in insects and have since been discovered in hundreds of species across many different taxa. Their prevalence has made it difficult to strictly define the nature of a B chromosome due to the variety of sizes, genetic compositions, and segregation behaviors; however, with modern molecular technologies, the impact, origin, and evolutionary trajectory of these B chromosomes are coming into focus. In this review, we consolidate what is currently known about B chromosomes, including their life cycle and evolutionary trajectory, the impact of B chromosomes on their host, and how B chromosomes are transmitted to the next generation. We highlight several prominent B chromosome model systems that have led to significant advances in B chromosome biology, serving as a prologue for the exciting future of the B chromosome field and its many unknowns.

Telomeres are sequences at chromosome ends that distinguish the natural end from a DNA break. Telomeres shorten at each round of cell division because the replisome cannot completely copy both DNA strands to the very end. This shortening is counterbalanced by telomerase, which adds telomeric sequences de novo onto telomeres. The balance of shortening and lengthening is regulated to establish an equilibrium distribution of telomere lengths. If the equilibrium is perturbed, short telomeres trigger a DNA damage response that leads to cellular senescence or cell death. In humans, short telomeres cause age-related degenerative disease, while long telomeres protect against senescence and allow the continued growth of cancer cells. To target the telomere in human disease, we need a more complete understanding of how telomere length is regulated. Here, we describe pathways that regulate telomere length with a focus on the fundamental mechanisms established over the last 40 years in the yeast Saccharomyces cerevisiae.

The naked mole-rat (Heterocephalus glaber) defies mammalian norms with lifelong fertility and postnatal oogenesis. Unlike most mammals, which experience reproductive senescence due to depletion of a finite ovarian follicle pool, naked mole-rat queens maintain fertility for their entire 30+-year lifespan through multiple mechanisms, including postnatal oogenesis, an exceptionally large ovarian reserve, and maintenance of primordial germ cells into adulthood. This review explores the unique reproductive biology of naked mole-rats within the context of their eusocial lifestyle, examining how social suppression of reproduction in subordinates, the role of very-high-molecular-weight hyaluronan (vHMW-HA) in cancer resistance and tissue maintenance, and the maintenance of germline stem cell populations contribute to their extraordinary reproductive longevity. We discuss the evolutionary advantages of eusociality, mechanisms of reproductive suppression and activation, and the potential of naked mole-rats as a research model for understanding ovarian aging and developing fertility-preserving therapies in humans.

Decades of research into the noncoding transcriptome have unveiled a complex, multilayered web of molecular interactions that govern gene expression, protein synthesis, and cellular function, challenging the once-presumed linear simplicity of the flow of genetic information. In bacteria, highly diverse small RNAs (sRNAs) play a crucial role in gene expression, often acting at the heart of large regulatory networks to modulate cellular processes through direct base-pairing interactions with target messenger RNAs (mRNAs). The expression of most sRNAs is tightly controlled at the level of transcription, but RNA sponges have recently emerged as an additional layer of regulation restricting sRNA activity and abundance. By titrating sRNAs and influencing their interactions with target mRNAs and RNA-binding proteins, RNA sponges contribute to the fine-tuning of global gene expression networks. In addition, the integration of RNA sponges into functional loops promotes elegant crosstalk between major regulons at the posttranscriptional level.

The MAP3K dual-leucine zipper kinases are stress-sensing signaling molecules that have important roles in neuronal development and maintenance, traumatic injury, and neurodegeneration. These kinases activate signal transduction cascades and elicit distinct cellular phenotypes in response to a variety of physiological and pathological stimuli. Studies from animal and cellular models have supported their conserved functions and also highlight context and cell-type specificity. This review focuses on recent findings on the molecular landscape associated with these kinases and discusses key themes of the DLK function network in the mammalian nervous system.

Cochlear hair cells are epithelial cells that are not replaced when lost, leading to permanent hearing loss. The lack of spontaneous regeneration of hair cells is a rarity in epithelial tissues, including hair cell epithelia. Evolutionary considerations may explain why hair cell regenerative capacity of mammals was lost during the evolution of the cochlea. In parallel, at the molecular level, studies using transgenesis and developmental biology have revealed some of the key signaling molecular players that govern the development of hair cells and their neighboring supporting cells and provided candidates for manipulating the system to induce regeneration. Gene transfer technology using viruses showed proof of principle for the ability to induce the transdifferentiation of supporting cells to new hair cells, but the outcome is inconsistent and of low quantity and poor quality. Further use of modern sequencing technology should reveal additional details of gene expression and its regulation in the process of regenerating hair cell organs such as in fish, birds, and mammalian balance organs. Sequence data generated from supporting cells in mature ears with hair cell lesions, at the level of gene expression and its epigenetic regulation, will assist in designing these therapeutic interventions. Still, rebuilding a perfect new cochlea to provide normal hearing in profoundly deaf ears remains a formidable challenge.

Nucleus-forming jumbo bacteriophages display a surprisingly intricate replication cycle inside of bacterial host cells, challenging the long-standing paradigm of prokaryotic simplicity. The phage nucleus encloses phage DNA in a protein shell, strictly uncouples transcription from translation, and facilitates selective protein import and messenger RNA (mRNA) export, serving the same major functions as the eukaryotic nucleus. Infection of host cells by these phages begins with the formation of a transcriptionally active membrane-bound early phage infection vesicle, demonstrating that these phages are capable of constructing subcellular compartments composed of lipids and proteins. Here, we review the current body of literature revealing the complexities of nucleus-forming phages and the history of the major discoveries. Studies of these phages are revealing new insights into basic principles of subcellular organization, viral speciation, and intracellular viral competition.

The natural world is full of valuable lessons about genetic adaptation as organisms respond to changing conditions around them. Deciphering these changes is a major goal of evolutionary genetics. Advances have been made through phylogenomic approaches using the wealth of closely related genome sequences in mammals. These studies bring us lessons about the adaptive capacity allowed by the evolutionary process as well as the underlying genetic mechanisms controlling important traits. Diverse methods are now routinely used to identify the genetic basis of these adaptations. These reveal new functions of genes and regulatory regions that have responded to changes in lifestyle, such as aquatic life and flight, as well as major life history axes, such as lifespan. Phylogenomic studies have been equally revealing of specific traits that evolve in response to different selective pressures, such as hair formation and vocal learning. These approaches continue to develop to overcome challenges inherent in information-poor regulatory regions to find changes to gene regulatory networks as well. The development of these approaches is expected to accelerate as new tools, such as machine learning models, are incorporated and deployed on ever denser phylogenies containing new interesting traits.

The brain has a remarkable ability to adapt its function in response to both environmental and internal cues. The cellular composition of the brain is largely static after birth; thus, persistent experience-dependent changes in brain function depend on altered programs of gene expression that result in the plasticity of circuit connectivity and network function. High-throughput sequencing studies have comprehensively cataloged stimulus-dependent programs of gene expression in the brain. The current challenge is to integrate this information in the context of specific cells and circuits to understand the mechanisms by which transcriptional regulation coordinates adaptive plasticity of the brain and behavior. Here, I review molecular genetics studies that reveal how neuronal activity-regulated gene products orchestrate intricate cellular and intercellular adaptations in response to changes in patterns of brain activity. I also discuss examples of genetic mutations that impair experience-dependent transcriptional plasticity in the context of neurodevelopmental disorders.

The adult human brain, under resting conditions, consumes approximately 20% of total body glucose, a demand that is even higher during the first decade of life. The brain metabolic landscape is intricately regulated throughout development, and each cell type exhibits distinct metabolic signatures at each specific stage. This picture becomes even more intricate when considering that metabolism is dynamically modulated to sustain critical biological processes, such as cell proliferation and differentiation and synaptic activity-dependent processes. The orchestration between metabolic regulation and the aforementioned physiological processes often relies on metabolism-dependent changes in the epigenetic landscape, which shape gene expression patterns to trigger selected downstream biological responses. Perturbations of brain metabolic pathways are frequently the cause of severe neurodevelopmental disorders. This review explores the latest insights into the regulation of brain metabolism in health and disease.

Species such as planarians expand our horizons of imagination and fuel innovation. The ability to regenerate any tissues lost to injury has fascinated many generations of biologists studying regenerative biology. Recent experimental data have shown that regeneration in older planarians can reverse age-associated physiological decline, effectively rejuvenating the animals and making them biologically younger. The remarkable biology manifested by planarians, encompassing whole-body regeneration and rejuvenation, intersects with some of the most critical topics of twenty-first-century research, including stem cell function, lifespan regulation, and healthspan improvement, despite being viewed by some as an evolutionary oddity. Here, we discuss how advances in next-generation sequencing technologies and the advent of genomic approaches over the past two decades have revolutionized planarian research. The results of these studies have transformed our understanding of regeneration, tissue patterning, germ cell development, chromosome evolution, aging, and age reversal (rejuvenation). We anticipate that genetic and genomic tools will drive groundbreaking discoveries in the fundamental mechanisms of regeneration, aging, and rejuvenation in the coming decades.

Studies of globin gene clusters have established many paradigms of gene regulation. This review focuses on the α- and β-globin gene clusters of humans and mice, summarizing important insights from high-throughput biochemical assays and directed genetic dissections and emphasizing similarities across the types of gene clusters and between species. The overall arrangements and architectures are similar, with each gene cluster being localized within a topologically constrained unit of chromatin containing a multicomponent enhancer (i.e., a locus control region) and other regulatory elements bound by a similar set of transcription factors and coactivators. Differential expression of the globin genes within each cluster during ontogeny is associated with changes in contacts with the locus control region and involves the action of gene-specific repressors. Detailed study of the fetal β-like HBG1 and HBG2 globin genes has revealed a remarkable diversity of regulatory pathways that provide candidates for therapeutic approaches to reactivate these genes for β-hemoglobinopathies.