Annual review of genetics最新文献

Genetic biocontrol aims to suppress or modify populations of species to protect public health, agriculture, and biodiversity. Advancements in genome engineering technologies have fueled a surge in research in this field, with one gene editing technology, CRISPR, leading the charge. This review focuses on the current state of CRISPR technologies for genetic biocontrol of pests and highlights the progress and ongoing challenges of using these approaches.

Recent advances in genomics have revealed a wide spectrum of genetic variants associated with neurodevelopmental disorders at an unprecedented scale. An increasing number of studies have consistently identified mutations-both inherited and de novo-impacting the function of specific brain circuits. This suggests that, during brain development, alterations in distinct neural circuits, cell types, or broad regulatory pathways ultimately shaping synapses might be a dysfunctional process underlying these disorders. Here, we review findings from human studies and animal model research to provide a comprehensive description of synaptic and circuit mechanisms implicated in neurodevelopmental disorders. We discuss how specific synaptic connections might be commonly disrupted in different disorders and the alterations in cognition and behaviors emerging from imbalances in neuronal circuits. Moreover, we review new approaches that have been shown to restore or mitigate dysfunctional processes during specific critical windows of brain development. Considering the heterogeneity of neurodevelopmental disorders, we also highlight the recent progress in developing improved clinical biomarkers and strategies that will help to identify novel therapeutic compounds and opportunities for early intervention.

Animal species present relatively high levels of gene conservation, and yet they display a great variety of cell type and tissue phenotypes. These diverse phenotypes are mainly specified through differential gene usage, which relies on several mechanisms. Two of the most relevant mechanisms are regulated gene transcription, usually referred to as gene expression (rGE), and regulated alternative splicing (rAS). Several works have addressed how either rGE or rAS contributes to phenotypic diversity throughout evolution, but a back-to-back comparison between the two molecular mechanisms, specifically highlighting both their common regulatory principles and unique properties, is still missing. In this review, we propose an innovative framework for the unified comparison between rGE and rAS from different perspectives: the three-dimensional (3D)-evo space. We use the 3D-evo space to comprehensively (a) review the molecular basis of rGE and rAS (i.e., the molecular axis), (b) depict the tissue-specific phenotypes they contribute to (i.e., the tissue axis), and (c) describe the determinants that drive the evolution of rGE and rAS programs (i.e., the evolution axis). Finally, we unify the perspectives emerging from the three axes by discussing general trends and specific examples of rGE and rAS tissue program evolution.

Over more than fifty years, I have studied how the logic that controls and integrates cell function is built into the dynamic architecture of living cells. I worked with a succession of exceptionally talented students and postdocs, and we discovered that the bacterial cell is controlled by an integrated genetic circuit in which transcriptional and translational controls are interwoven with the three-dimensional deployment of key regulatory and morphological proteins. Caulobacter's interconnected genetic regulatory network includes logic that regulates sets of genes expressed at specific times in the cell cycle and mechanisms that synchronize the advancement of the core cyclical circuit with chromosome replication and cytokinesis. Here, I have traced my journey from New York City art student to Stanford developmental biologist.

DNA polymerase θ (Pol θ) is a DNA repair enzyme widely conserved in animals and plants. Pol θ uses short DNA sequence homologies to initiate repair of double-strand breaks by theta-mediated end joining. The DNA polymerase domain of Pol θ is at the C terminus and is connected to an N-terminal DNA helicase-like domain by a central linker. Pol θ is crucial for maintenance of damaged genomes during development, protects DNA against extensive deletions, and limits loss of heterozygosity. The cost of using Pol θ for genome protection is that a few nucleotides are usually deleted or added at the repair site. Inactivation of Pol θ often enhances the sensitivity of cells to DNA strand-breaking chemicals and radiation. Since some homologous recombination-defective cancers depend on Pol θ for growth, inhibitors of Pol θ may be useful in treating such tumors.

In bacteria, transcription and translation take place in the same cellular compartment. Therefore, a messenger RNA can be translated as it is being transcribed, a process known as transcription-translation coupling. This process was already recognized at the dawn of molecular biology, yet the interplay between the two key players, the RNA polymerase and ribosome, remains elusive. Genetic data indicate that an RNA sequence can be translated shortly after it has been transcribed. The closer both processes are in time, the less accessible the RNA sequence is between the RNA polymerase and ribosome. This temporal coupling has important consequences for gene regulation. Biochemical and structural studies have detailed several complexes between the RNA polymerase and ribosome. The in vivo relevance of this physical coupling has not been formally demonstrated. We discuss how both temporal and physical coupling may mesh to produce the phenomenon we know as transcription-translation coupling.

Spermatogenesis is a complex differentiation process coordinated spatiotemporally across and along seminiferous tubules. Cellular heterogeneity has made it challenging to obtain stage-specific molecular profiles of germ and somatic cells using bulk transcriptomic analyses. This has limited our ability to understand regulation of spermatogenesis and to integrate knowledge from model organisms to humans. The recent advancement of single-cell RNA-sequencing (scRNA-seq) technologies provides insights into the cell type diversity and molecular signatures in the testis. Fine-grained cell atlases of the testis contain both known and novel cell types and define the functional states along the germ cell developmental trajectory in many species. These atlases provide a reference system for integrated interspecies comparisons to discover mechanistic parallels and to enable future studies. Despite recent advances, we currently lack high-resolution data to probe germ cell-somatic cell interactions in the tissue environment, but the use of highly multiplexed spatial analysis technologies has begun to resolve this problem. Taken together, recent single-cell studies provide an improvedunderstanding of gametogenesis to examine underlying causes of infertility and enable the development of new therapeutic interventions.

Though cell size varies between different cells and across species, the nuclear-to-cytoplasmic (N/C) ratio is largely maintained across species and within cell types. A cell maintains a relatively constant N/C ratio by coupling DNA content, nuclear size, and cell size. We explore how cells couple cell division and growth to DNA content. In some cases, cells use DNA as a molecular yardstick to control the availability of cell cycle regulators. In other cases, DNA sets a limit for biosynthetic capacity. Developmentally programmed variations in the N/C ratio for a given cell type suggest that a specific N/C ratio is required to respond to given physiological demands. Recent observations connecting decreased N/C ratios with cellular senescence indicate that maintaining the proper N/C ratio is essential for proper cellular functioning. Together, these findings suggest a causative, not simply correlative, role for the N/C ratio in regulating cell growth and cell cycle progression.

Kinetochores are molecular machines that power chromosome segregation during the mitotic and meiotic cell divisions of all eukaryotes. Aristotle explains how we think we have knowledge of a thing only when we have grasped its cause. In our case, to gain understanding of the kinetochore, the four causes correspond to questions that we must ask: (a) What are the constituent parts, (b) how does it assemble, (c) what is the structure and arrangement, and (d) what is the function? Here we outline the current blueprint for the assembly of a kinetochore, how functions are mapped onto this architecture, and how this is shaped by the underlying pericentromeric chromatin. The view of the kinetochore that we present is possible because an almost complete parts list of the kinetochore is now available alongside recent advances using in vitro reconstitution, structural biology, and genomics. In many organisms, each kinetochore binds to multiple microtubules, and we propose a model for how this ensemble-level architecture is organized, drawing on key insights from the simple one microtubule-one kinetochore setup in budding yeast and innovations that enable meiotic chromosome segregation.

Meiosis, a key process in the creation of haploid gametes, is a complex cellular division incorporating unique timing and intricate chromosome dynamics. Abnormalities in this elaborate dance can lead to the production of aneuploid gametes, i.e., eggs containing an incorrect number of chromosomes, many of which cannot generate a viable pregnancy. For many decades, research has been attempting to address why this process is notoriously error prone in humans compared to many other organisms. Rapidly developing technologies, access to new clinical material, and a mounting public infertility crisis have kept the field both active and quickly evolving. In this review, we discuss the history of aneuploidy in humans with a focus on its origins in maternal meiosis. We also gather current working mechanistic hypotheses, as well as up-and-coming areas of interest that point to future scientific avenues and their potential clinical applications.