Annual review of genomics and human genetics最新文献

Arthrogryposis multiplex congenita (AMC) is characterized by congenital joint contractures in two or more body areas resulting from reduced or absent fetal movements. AMC exhibits marked phenotypic and genetic heterogeneity, as it is a symptom rather than a disease and may be part of a large number of unrelated conditions. Despite advances in genomic approaches and the increasing number of newly identified genes, disease-gene identification was achieved in fewer than half of cases in several reports, including in a French cohort of 367 AMC patients. The most frequent cause of AMC in these reports was a primary involvement of skeletal muscle. In the French cohort, the most frequent mode of inheritance was autosomal recessive (68.3%); in autosomal dominant or X-linked form, a high proportion of de novo variants (24%) was observed, indicating that this mechanism plays a prominent part in this developmental condition. Accurate genetic diagnosis is critical for more tailored management of AMC and possibly other organ involvement.

Heteroplasmy is the mixture of mutant and wild-type mitochondrial DNA (mtDNA) within each of our cells. Heteroplasmy levels in cells, tissues, and organisms change over time, thus contributing to mitochondrial disease, aging, and evolution. Germline and pedigree studies first revealed heteroplasmy shifts between generations and have long offered a window into the dynamics of mtDNA inheritance through single oocytes. Single-cell technologies are now uncovering similar mechanisms that operate in somatic tissues throughout life. Stochastic processes (relaxed replication and vegetative segregation, enhanced through genetic bottlenecks) generate cell-to-cell variation, while selection mechanisms such as intercellular competition, mitophagy, and preferential replication allow or drive directional shifts. Single-cell sequencing, mtDNA imaging, and genetic screening, combined with mtDNA-editing technology and heteroplasmic model systems, have transformed our ability to dissect these processes, revealing heteroplasmy dynamics at molecular resolution. These approaches are uncovering quantifiable principles governing heteroplasmy across cell types and life stages, transforming our understanding from descriptive observations to predictive mechanistic models and novel therapeutic avenues.

Gene regulatory networks (GRNs) define the regulatory relationships among molecules such as transcription factors, chromatin remodelers, and target genes. GRNs play a critical role in diverse biological processes, including development, disease manifestation, and evolution. However, fully characterizing these networks across multiple cell types and states remains a significant challenge. Recent advances in single-cell omics have dramatically enhanced our ability to measure biological systems at unprecedented resolution. These technologies have opened new avenues for computational methods to infer GRNs, offering deeper insights into cell type-specific mechanisms, causality, and dynamic regulatory processes. This review summarizes the current state of GRN inference from single-cell omic datasets, with a particular focus on dynamics and perturbations, and outlines key open challenges that must be addressed to advance the field.

TDP-43 is an RNA-binding protein that regulates multiple aspects of RNA processing, and its mislocalization from the nucleus to the cytoplasm is a defining feature of amyotrophic lateral sclerosis (ALS). While both loss- and gain-of-function mechanisms contribute to disease, the discovery of cryptic splicing has shed light on the downstream consequences of TDP-43 nuclear clearance for neuronal health. Here, we highlight how loss of nuclear TDP-43 can drive a cascade of events that lead to the impairment of cellular proteostasis and result in a positive feedback loop that perpetuates neuronal dysfunction. This sustains the appearance of cryptic splicing events in genes that are involved in key pathways for the maintenance of axonal homeostasis and synaptic transmission. In contrast to their detrimental effects on neuronal health, cryptic splicing mechanisms may be harnessed to develop novel therapeutic strategies, unprecedentedly expanding the availability of therapeutic avenues for TDP-43 proteinopathies.

Organoids have reshaped biomedical research by providing stem cell-derived model systems that capture key aspects of tissue organization, homeostasis, and disease. Their physiological relevance and adaptability have made them indispensable tools for studying development, regeneration, and tumor biology under controlled experimental conditions. This is particularly powerful in the human setting, where organoids offer an experimentally accessible alternative to in vivo studies that are ethically and practically unfeasible. Central to their success is the ability to apply diverse perturbation strategies, ranging from targeted genetic edits and pharmacological interventions to microenvironmental and biomechanical manipulations, that reveal the molecular logic of cellular and tissue function. In this review, we discuss the current landscape of organoid perturbation studies, highlighting methodological advances, representative applications, and what these efforts have taught us about cellular behavior in complex systems. By outlining methodological innovations and conceptual insights, we aim to establish a framework for using organoids not only as descriptive models but as predictive systems for probing and engineering human tissue behavior.

Though individually rare, rare diseases collectively affect nearly 1 out of 30 individuals, highlighting the continued need for and importance of research on these disorders. We argue that the recent work in identifying and diagnosing previously undiagnosed diseases is only the beginning. To meet this need, animal models have played an important role in studying rare and undiagnosed diseases by providing functional and biological information to validate candidate disease genes. Specifically, nonmammalian models like nematode worms (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio) provide significant advantages to the scientific community and have, unsurprisingly, been essential in many advances in the rare disease field and beyond. Given this success, new priorities are emerging on how to use these animal models to drive therapeutic-focused research. In this review, we discuss how these common nonmammalian models have pointed to new therapeutic directions and are used to both test and create therapies. Through the characterization of genetic mechanisms and emerging protocols like drug repurposing, animal models have never been as important to the rare disease field as they are now. Ongoing mechanistic discoveries and therapeutic advances not only have the potential to improve our management of rare disease but may also have implications for more common disorders across multiple areas of medicine.

Founder populations have played a pivotal role in human genetics, enabling the discovery of causal variants for disease and providing insight into population history and dynamics. The rapid expansion of global genomic databases has revealed that founder populations are far more common than once recognized, as population-scale sequencing now allows for systematic detection of founder events and founder-like population structure across the world. Contemporary genomic methods facilitate the characterization of founder populations using genetic metrics such as identity by descent, runs of homozygosity, and haplotype-based clustering. As the field shifts from small, ascertained founder cohorts to biobank-scale datasets containing millions of participants, new opportunities and challenges have emerged, including analytical, interpretive, and ethical complexities in the study of founder populations. Here, we review the historical and ongoing contributions of founder populations to genetics, outline current approaches for biobanks, and highlight growing opportunities to integrate founder population research into genomic medicine.

The genomics era has yielded high-quality genome assemblies, comprehensive atlases of biochemical signatures of gene regulation, and genetic associations for thousands of common human diseases and traits. These dramatic advances in observational approaches have not been matched by perturbational genetic tools to facilitate direct and systematic hypothesis testing. Enabled by advances in DNA synthesis and assembly, genome engineering tools, and genomic readouts, synthetic regulatory genomics now promises access to a new scale of genomic manipulation to study the function of cohesive genomic units. Synthetic regulatory genomics is distinguished by the breadth of the genetic manipulations and their divergence from the reference sequence. These new tools enable an expanded focus to encompass sufficiency in addition to necessity and to enable a new era of perturbation analysis.

Richard Gibbs interviews James (Jim) Lupski about his training in New York and work in Houston to elucidate the role of complex genomic rearrangements in human genetic diseases. The challenges and excitement of developing human personalized genomics and the advantages of clinical translation of genome methods for both patients and researchers are discussed.

In this article, I recount and reflect on the US Department of Energy's contributions to sequence the human genome as part of the Human Genome Project.