Annual review of genomics and human genetics最新文献

Nucleosomes wrap DNA and impede access for the machinery of transcription. The core histones that constitute nucleosomes are subject to a diversity of posttranslational modifications, or marks, that impact the transcription of genes. Their functions have sometimes been difficult to infer because the enzymes that write and read them are complex, multifunctional proteins. Here, we examine the evidence for the functions of marks and argue that the major marks perform a fairly small number of roles in either promoting transcription or preventing it. Acetylations and phosphorylations on the histone core disrupt histone-DNA contacts and/or destabilize nucleosomes to promote transcription. Ubiquitylations stimulate methylations that provide a scaffold for either the formation of silencing complexes or resistance to those complexes, and carry a memory of the transcriptional state. Tail phosphorylations deconstruct silencing complexes in particular contexts. We speculate that these fairly simple roles form the basis of transcriptional regulation by histone marks.

Nervous systems allow animals to acutely respond and behaviorally adapt to changes and recurring patterns in their environment at multiple timescales-from milliseconds to years. Behavior is further shaped at intergenerational timescales by genetic variation, drift, and selection. This sophistication and flexibility of behavior makes it challenging to measure behavior consistently in individual subjects and to compare it across individuals. In spite of these challenges, careful behavioral observations in nature and controlled measurements in the laboratory, combined with modern technologies and powerful genetic approaches, have led to important discoveries about the way genetic variation shapes behavior. A critical mass of genes whose variation is known to modulate behavior in nature is finally accumulating, allowing us to recognize emerging patterns. In this review, we first discuss genetic mapping approaches useful for studying behavior. We then survey how variation acts at different levels-in environmental sensation, in internal neuronal circuits, and outside the nervous system altogether-and then discuss the sources and types of molecular variation linked to behavior and the mechanisms that shape such variation. We end by discussing remaining questions in the field.

Concerns about genetic discrimination (GD) often surface when discussing research and innovation in genetics. Over recent decades, countries around the world have attempted to address GD using various policy measures. In this article, we survey these approaches and provide a critical commentary on their advantages and disadvantages. Our examination begins with regions featuring extensive policy-making activities (North America and Europe), followed by regions with moderate policy-making activities (Australia, Asia, and South America) and regions with minimal policy-making activities (the Middle East and Africa). Our analysis then turns to emerging issues regarding genetic testing and GD, including the expansion of multiomics sciences and direct-to-consumer genetic tests outside the health context. We additionally survey the shortcomings of current normative approaches addressing GD. Finally, we conclude by highlighting the evolving nature of GD and the need for more innovative policy-making in this area.

In recent years, our perspective on the cell nucleus has evolved from the view that it is a passive but permeable storage organelle housing the cell's genetic material to an understanding that it is in fact a highly organized, integrative, and dynamic regulatory hub. In particular, the subcompartment at the nuclear periphery, comprising the nuclear envelope and the underlying lamina, is now known to be a critical nexus in the regulation of chromatin organization, transcriptional output, biochemical and mechanosignaling pathways, and, more recently, cytoskeletal organization. We review the various functional roles of the nuclear periphery and their deregulation in diseases of the nuclear envelope, specifically the laminopathies, which, despite their rarity, provide insights into contemporary health-care issues.

When the Human Genome Project was completed in 2003, automated Sanger DNA sequencing with fluorescent dye labels was the dominant technology. Several nascent alternative methods based on older ideas that had not been fully developed were the focus of technical researchers and companies. Funding agencies recognized the dynamic nature of technology development and that, beyond the Human Genome Project, there were growing opportunities to deploy DNA sequencing in biological research. Consequently, the National Human Genome Research Institute of the National Institutes of Health created a program-widely known as the Advanced Sequencing Technology Program-that stimulated all stages of development of new DNA sequencing methods, from innovation to advanced manufacturing and production testing, with the goal of reducing the cost of sequencing a human genome first to $100,000 and then to $1,000. The events of this period provide a powerful example of how judicious funding of academic and commercial partners can rapidly advance core technology developments that lead to profound advances across the scientific landscape.

Many of the fundamental inventions of genome editing, including meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR, were first made at universities and patented to encourage commercial development. This gave rise to a diversity of technology transfer models but also conflicts among them. Against a broader historical and policy backdrop of university patenting and special challenges concerning research tools, we review the patent estates of genome editing and the diversity of technology transfer models employed to commercialize them, including deposit in the public domain, open access contracts, material transfer agreements, nonexclusive and exclusive licenses, surrogate licenses, and aggregated licenses. Advantages are found in this diversity, allowing experimentation and competition that we characterize as a federalism model of technology transfer. A notable feature of genome editing has been the rise and success of third-party licensing intermediaries. At the same time, the rapid pace of development of genome-editing technology is likely to erode the importance of patent estates and licensing regimes and may mitigate the effect of overly broad patents, giving rise to new substitutes to effectuate commercialization.

Citizen science encompasses activities with scientific objectives in which members of the public participate as more than passive research subjects from whom personal data or biospecimens are collected and analyzed by others. Citizen science is increasingly common in the biomedical sciences, including the fields of genetics and human genomics. Genomic citizen science initiatives are diverse and involve citizen scientists in collecting genetic data, solving genetic puzzles, and conducting experiments in community laboratories. At the same time that genomic citizen science is presenting new opportunities for individuals to participate in scientific discovery, it is also challenging norms regarding the manner in which scientific research outputs are managed. In this review, we present a typology of genomic citizen science initiatives, describe ethical and legal foundations for recognizing genomic citizen scientists' claims of credit for and control of research outputs, and detail how such claims are or might be addressed in practice across a variety of initiatives.

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants-causing loss-of-function or missense changes-have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants-both inherited and de novo-have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

RNA proximity ligation is a set of molecular biology techniques used to analyze the conformations and spatial proximity of RNA molecules within cells. A typical experiment starts with cross-linking of a biological sample using UV light or psoralen, followed by partial fragmentation of RNA, RNA-RNA ligation, library preparation, and high-throughput sequencing. In the past decade, proximity ligation has been used to study structures of individual RNAs, networks of interactions between small RNAs and their targets, and whole RNA-RNA interactomes, in models ranging from bacteria to animal tissues and whole animals. Here, we provide an overview of the field, highlight the main findings, review the recent experimental and computational developments, and provide troubleshooting advice for new users. In the final section, we draw parallels between DNA and RNA proximity ligation and speculate on possible future research directions.

Human survival is dependent upon the continuous delivery of O₂ to each cell in the body in sufficient amounts to meet metabolic requirements, primarily for ATP generation by oxidative phosphorylation. Hypoxia-inducible factors (HIFs) regulate the transcription of thousands of genes to balance O₂ supply and demand. The HIFs are negatively regulated by O₂-dependent hydrox-ylation and ubiquitination by prolyl hydroxylase domain (PHD) proteins and the von Hippel-Lindau (VHL) protein. Germline mutations in the genes encoding VHL, HIF-2α, and PHD2 cause hereditary erythrocytosis, which is characterized by polycythemia and pulmonary hypertension and is caused by increased HIF activity. Evolutionary adaptation to life at high altitude is associated with unique genetic variants in the genes encoding HIF-2α and PHD2 that blunt the erythropoietic and pulmonary vascular responses to hypoxia.