Annual review of genomics and human genetics最新文献

Molecular profiling of DNA and RNA from pediatric cancers by next-generation sequencing has been demonstrated to improve diagnosis and prognosis and to identify somatic alterations indicating vulnerability to targeted therapies. Hence, much like in the treatment of adult cancers, molecular profiling is now routinely utilized in clinical workflows for pediatric cancers as a companion to conventional pathology diagnosis. Many variants of unknown significance identified through DNA profiling are being characterized by saturation genome editing, enabled by CRISPR editing technology and clever functional assays. Newer technologies and analytics are revealing additional structural complexity around cancer drivers and gene fusions in pediatric cancer DNA. Similarly, computational methods such as rare variant association studies and polygenic risk scoring are being used to identify novel cancer susceptibility. Together, these advances are expanding our understanding of pediatric cancer's complexity and fueling the development of emerging methods such as liquid biopsy-based monitoring.

Over the last decade, a set of very short (3-51 nt) and highly conserved microexons have been found to crucially influence a set of diverse protein functions and interactions. Advancements in RNA sequencing and analysis pipelines have revealed an enrichment for the alternative splicing of microexons in a subset of tissues and cell types, especially across the central nervous system. Microexons are thought to fine-tune important developmental processes such as synaptogenesis by preserving the protein's reading frame upon inclusion. Dysregulation of microexon splicing has been linked to several neurological conditions, including autism spectrum disorder and schizophrenia, as well as metabolic disorders like diabetes and various cancer types. This review discusses the expanding body of literature on the molecular and organismal consequences of microexon inclusion, emphasizing their evolutionary conservation, tissue specificity, and functional diversity. It also explores the potential for therapeutic interventions, including pharmacological modulation, on microexon splicing and splicing regulators like SRRM3 and SRRM4, offering perspectives on targeting diseases related to microexon misregulation. More research is needed to better understand similarities and differences between microexon functions across tissues, pathologies, and species.

In this short memoir, I recount the series of improbable interactions and events that led me from medical school to a leadership role in the Human Genome Project.

Aging is the primary risk factor for many diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. The rapid advancement of single-cell sequencing technologies has opened promising avenues for investigating aging-associated cellular changes that contribute to disrupted system homeostasis and increased vulnerability to age-related diseases. Despite the abundance of data generated over the past decade, a systematic understanding of how aging affects cell type-specific populations across the entire mammalian organism remains lacking-a critical gap for elucidating the cellular foundations of aging-related system dysfunction. In this review, we address this knowledge gap by summarizing recent single-cell studies examining the impact of aging on cell type-specific population changes across mammalian organs. We also review the impact of gender and anti-aging interventions on cell population dynamics in aged mammals. This work provides a comprehensive catalog of cellular states susceptible to aging, highlighting potential therapeutic targets for aging and age-related diseases.

Genetic counselors have a complex relationship with disability communities due to both the legacy of eugenics and their ongoing role counseling families about prenatal testing. Drawing on a social model of disability and highlighting mistaken assumptions about quality of life for people with disabilities, scholars and activists have raised concerns about genetic technologies that strive to eliminate disability. We review the disability rights critique of prenatal screening and emphasize its ongoing relevance to genetic counseling. We then consider disability perspectives on prognostication in genetics and highlight disability-informed critiques of gene therapies. We close by reviewing efforts by, and opportunities within, the genetic counseling profession to center the perspectives of people with disabilities in genetic counseling practice and education.

Social and behavioral scientists increasingly work with geneticists or adapt the methods of genetic research to investigate genomic variation in a wide variety of behavioral and social phenotypes. Using genome-wide association studies, these social and behavioral genomics (SBG) researchers generate polygenic indexes (PGIs)-weighted sums of the estimated effects of each genetic variant on an individual's phenotype. This review examines the ethical, conceptual, and social issues in SBG research and its downstream applications. In particular, it focuses on PGIs for ethically sensitive SBG phenotypes-those that (a) can be viewed as consequential to social status (e.g., obesity and substance-use disorders), (b) are contributing or have historically contributed to harmful stereotypes about minoritized groups and threaten to reify the biologization of social identities (e.g., financial prowess and athleticism), and/or (c) are central to a minoritized group's identity (e.g., sexual orientation and sexual behavior).

2025 marks the twenty-fifth anniversary of the completion of a working draft of the 3-Gb human genome sequence and its availability in public databases to promote research into human health and disease for the benefit of all. The sequence was produced by the International Human Genome Sequencing Consortium, which comprised sequencing centers from six countries who together undertook the largest collaborative biological project to date. Under the leadership of Sir John Sulston, the United Kingdom played a significant role in the project through the Sanger Centre (now the Wellcome Sanger Institute), which was founded in 1992 with support from the Wellcome Trust, a charitable foundation funding medical research. The Sanger Centre contributed approximately one-third of the final human genome sequence generated by the Human Genome Project and, along with the European Bioinformatics Institute, developed Ensembl, one of the major databases providing free access to genomic data and annotation for biomedical research. As a result of a chance meeting, I came to work at the Sanger Centre (and later the Wellcome Sanger Institute) from 1992 to 2007, initially as a scientific administrator and later as the Human Genome Project manager and head of sequencing. Over that period, the Sanger Centre became one of the largest genome sequencing centers in the world and began its transition to become a world-leading center in genomics research to advance biology and health.

The growing field of human synthetic biology has rapidly accelerated the development of programmable genetic systems that can control cellular phenotypes and function. As the scale of synthetic systems has increased, researchers have focused on identifying modular regulators that act at the levels of DNA, RNA, and protein to create synthetic control points at each level of gene expression. Expanding these assays to multiple cellular contexts has made it possible to both manipulate endogenous gene programs and create synthetic gene circuits that yield designer cell outputs. Here, we review recent advances in high-throughput human synthetic biology that have led to the development of multilevel tools for gene expression control. We highlight the development of synthetic gene programs that can both provide information on and manipulate cellular behavior and discuss the application of programmable genetic tools in therapeutic contexts to illuminate the power of these new biological approaches.

Understanding the drivers of human brain specialization, and how specialized properties are codified during development and evolution, seems to be within reach for the first time. Improved cell-based experimental models of the human brain have empowered the field to address some of the most fundamental questions about our brains, including mechanisms of neurodevelopment, the etiology of neurological disease, and the underpinnings of human-to-human variation in brain function and response. The emergence of scalable in vitro systems has enabled investigation of interindividual variation within large human cohorts in both normal development and disease processes, which is fundamental to developing effective and personalized treatments. This review explores recent advancements in organoid technology, highlighting future directions that employ interdisciplinary approaches to enhance the physiological relevance of these models. This work promises to bring us ever closer to understanding not only what makes a brain human but also how each of our brains is human in unique ways.

As the field of genomics and human genetics continues to push our understanding of disease and biodiversity through an ever-increasing pool of genomic data, it is critical to consider the social, ethical, and legal implications of using such data. This is particularly true for genomic data pertaining to Indigenous Peoples, much of which has been collected and (re)used in research without the informed consent of Indigenous communities or without the return of benefits of research discoveries to these communities. Indigenous data sovereignty (IDSov) provides a framework through which Indigenous Peoples can assert their right to control data on or about their communities and lands. Here, we provide a review of IDSov and recommendations for how researchers can integrate it into their genomic research with Indigenous Peoples. Inclusion of IDSov in genomic research design supports meaningful partnerships between researchers and Indigenous communities, ensuring the maximization of benefits and minimization of harms for improved community health and prosperity.