Annual review of genetics最新文献

Parasitoid wasps are a large and diverse group of species that infect a wide variety of insect hosts. In response, hosts have evolved numerous defensive strategies to protect against infection. Here, we review the immune and behavioral defense responses of the fruit fly Drosophila melanogaster against parasitoid wasps, the best-characterized dipteran system for host-parasitoid interactions. The melanotic encapsulation of parasitoid eggs is a highly conserved immune response that defends hosts against both coevolving and novel parasitoid species while simultaneously protecting against self-inflicted immune damage. Behavioral defense mechanisms include parental behaviors to protect offspring from infection and adaptive alterations in infected juveniles. We discuss the genetic basis and conserved mechanisms of these responses and identify exciting questions for future research.

Bone morphogenetic protein (BMP) signaling functions in a vast range of biological contexts. The basic signaling mechanism of this pathway is well-defined, with BMP ligand dimers recruiting tetrameric receptor complexes that phosphorylate Smads to regulate gene expression. Research has found that the mechanism of BMP signal activation may not be as simple as this linear relay, specifically in considering signal activation by ligand homodi-mers versus heterodimers. Focusing largely on in vivo vertebrate contexts, we discuss how BMP heterodimers exhibit enhanced or exclusive signaling over homodimers, demonstrating that not all signal inputs are functionally equivalent. Challenging the notion that ligand-receptor binding affinity is the primary driver of signal activation, we highlight evidence that some receptors do not signal even when high-affinity ligands are present. Further, not all receptors in the signaling complex are equal, with the kinase activity of some being dispensable while others are obligatory. These observations shift the focus of BMP signal activation to mechanisms by which heterodimeric ligands with specific receptor combinations facilitate signal outcomes in different contexts.

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.

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.

Cardiovascular disease is the leading cause of global morbidity and mortality, despite advances in pharmacological and surgical interventions. The emergence of CRISPR-Cas9 genome editing technology offers promising approaches for correcting genetic causes of hereditary cardiovascular disorders and modulating pathogenic signaling pathways implicated in various heart diseases. However, several challenges with respect to in vivo delivery of gene editing components, as well as important safety considerations, remain to be addressed in the path toward possible clinical application. We review current gene editing strategies, their potential therapeutic applications in the context of a variety of cardiovascular disorders, and their respective merits, limitations, and regulatory considerations. The rapid advances in this field combined with the many opportunities for deploying gene editing therapies for cardiovascular disorders augur well for the future of this transformative technology.

The faithful transmission of genomic DNA over succeeding generations is an essential prerequisite for species maintenance. The germplasm theory by August Weismann has been foundational for the current understanding of heredity; it proposed that genetic inheritance is exclusively mediated by germ cells while they are protecting heritable germline genomes from the phylogenetic influences of an individual's life history. However, recent studies on the inheritance of epigenetic variation have challenged the traditional dogma of heredity and opened new perspectives on molecular mechanisms of inheritance. This review highlights the current knowledge about heritable memories of the ancestral lifestyle and discusses emerging frontiers in soma-germline circuits with a focus on the control of the integrity of heritable genomes as well as their implications for somatic and reproductive aging.

Type 2 diabetes (T2D) is a complex genetic disease with substantial environmental inputs leading to glucose homeostasis defects. Insulin production is central to proper glucose control, and islet cell dysfunction and death lie at the nexus of T2D genetics and pathophysiology. Comprehensive identification of genes and pathways contributing to these processes is essential for mechanistic understanding and therapeutic targeting. Here, we summarize the latest human and mouse T2D genetic and genomic studies and assess how these parallel variant-to-function efforts and associated data contribute convergent or complementary insights and new opportunities to dissect T2D islet (dys)function. We distill mechanistic and phenotypic studies of candidate T2D effector genes into prevailing themes by which these T2D risk genes likely contribute to islet dysfunction. We assess how recent molecular and metabolic studies in genetically diverse mice (i.e., Collabo-rative Cross, Diversity Outbred) help to nominate new putative T2D effector genes and processes for future exploration and provide examples where these studies illuminate potential limitations of studies using inbred mice. Finally, we discuss opportunities to address knowledge gaps and modeling challenges to translate T2D genetic associations into molecular and pathophysiologic understanding.

Cell death, compensatory proliferation, and cell competition are fundamental interconnected processes that shape how tissues develop, maintain homeostasis, and regenerate. In this review, I highlight how cell death (apoptosis) not only eliminates excess and damaged cells but can also initiate compensatory proliferation, an adaptive response that occurs following cell loss. I examine cell competition, a quality-control mechanism that removes less fit loser cells in favor of healthier winner neighbors. Cell competition is intricately linked to cell death and compensatory proliferation. I present the history of these processes, discuss the most important examples, and reveal the key molecular mechanisms that underlie them. I incorporate findings from Caenorhabditis elegans, Drosophila melanogaster, vertebrates, and other models to underscore the conservation of the key molecular signaling events. I also discuss how misregulation of these processes can contribute to pathological conditions, including cancer.

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.

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.