Evolvability refers to the capacity of biological systems to generate heritable and adaptive phenotypic variation. Theoretical work has identified general principles linking gene regulatory network (GRN) architecture, including modularity and connectivity, to the generation of such variation, whereas empirical studies have uncovered its molecular basis in specific systems. Despite these advances, the two approaches have largely developed in parallel, with direct tests of theoretically derived hypotheses remaining rare. Recent advances in single-cell omics techniques, GRN inference, and experimental perturbation methods now provide opportunities for a closer link between theory and empirical research on evolvability. Here, we synthesise the main advances on this topic and outline potentially fruitful avenues for investigating how network structure and developmental dynamics shape evolvability across systems.
As a foundational infrastructure of biomedical research, large-scale human population cohorts have undergone rapid progress over the past decades. Driven by advances in high-throughput omics technologies, widespread adoption of electronic health records, and the emergence of artificial intelligence, these cohorts now integrate deep molecular profiling with longitudinal real-world data at an unprecedented scale. This transformation has shifted cohort research from primarily descriptive association studies toward mechanistic discovery, refined risk stratification, and genetically informed therapeutic development. In parallel, cohort initiatives are expanding globally beyond Western populations, accompanied by increasingly diverse funding, governance, and data-sharing models. Here, we review the major transformative trends shaping large-scale human population cohorts and discuss how these resources are redefining disease biology, translational research, and the future of precision medicine.
In multicellular organisms, epigenetic inheritance is a process by which traits induced by life experiences or environmental factors in a parent are passed to offspring without involving changes in the DNA sequence, but rather in the epigenome. While epigenetic inheritance is evident in many species, from plants to rodents, it remains unproven in humans because of biological barriers, methodological complexity, and the difficulty of disentangling environmental from social and genetic factors. The unique human context of prolonged parental care, as well as cross-generational cultural and societal effects, compounds these difficulties and highlights the need for clear criteria to assess epigenetic inheritance claims. This article aims to help the field move from cataloging biological markers to conducting rigorous human research by clarifying key concepts and defining testable criteria as a guiding framework.
Cell-cell communication (CCC) is involved in regulating cellular behavior in tissues. Spatial transcriptomics adds local context to gene expression, enabling more biologically grounded CCC inference than single-cell RNA-seq alone. Rapid method development has yielded diverse CCC methods, each addressing distinct biological questions through varied analytical frameworks. We review 33 recent methods and organize them into three categories: inference of communication networks at cell-type or single-cell resolution, modeling of microenvironment-driven transcriptional variability and regulatory modules, and estimation of spatially informed signaling gene co-associations and higher-order interaction structures. We offer a structured guide for method selection aligned with researchers' analytical goals, highlighting strengths, limitations, and key technical features to support the informed application of CCC inference methods in spatial transcriptomic research.
Medical genetics can reveal how genetic variations shape human biology by addressing a critical question: how does a genetic lesion become a phenotype? Facioscapulohumeral muscular dystrophy (FSHD), exemplifies how a seemingly simple genetic lesion can affect multiple layers of cellular regulation, affecting 'everything, everywhere all at once'.
In addition to the essential set of chromosomes, individuals can carry supernumerary chromosomes that are not required for normal growth, development, or reproduction. Collectively, these extra chromosomes are called B chromosomes, and modern advances in genomic and cytological technology have accelerated our understanding of their fascinating biology. Here, we provide a brief history of B chromosome research, followed by an examination of their formation and dynamics. We conclude with an outlook on what the novel biology of B chromosomes can teach us and how it can be exploited as important tools for biotechnology, agriculture, and the advancement of human health.
Neoteny-a developmental slowdown that results in the retention of juvenile traits into adulthood-has long been viewed as central to human brain expansion. Olduvai domains are proposed here to function as a dosage-dependent metabolic 'brake' that slows development via mitochondrial downregulation. Their human-specific hyperamplification, paired with NOTCH2NL accelerators and new metabolic insights, may solve a century-old evolutionary puzzle.
Steady-state RNA sequencing measures abundance-synthesis over decay-not activity, so abundance is an imperfect proxy for long noncoding RNA (lncRNA) function. A small, fast-decaying subpopulation can be filtered out. Reading turnover alongside abundance keeps it visible; whether the tail is enriched for regulators is a testable hypothesis.
When DNA double-strand breaks (DSBs) arise within actively transcribed loci, cells must tightly coordinate transcription with DNA repair to avoid detrimental interference between these processes. This coordination is initiated by signaling cascades that rapidly repress local transcription through chromatin remodeling, recruitment of repressive factors, and modifications of RNA polymerase II (RNAPII). However, the mechanisms that orchestrate and integrate these events remain incompletely understood. In this review, we discuss recent advances in the field and draw parallels with the pathways handling transcription-blocking lesions, such as those caused by UV irradiation or DNA-protein crosslinks. We further discuss the possibility that an altered transcription cycle, marked by slowed or stalled RNAPII, drives the production of distinct RNA species at DSB sites, thereby reconciling previously conflicting observations.
Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity, yet traditional scRNA-seq methods primarily capture transcript ends, limiting analyses to total gene expression. Advances in isoform-resolved scRNA-seq, including short-read technologies that span full-length transcripts and long-read technologies that directly sequence full-length transcripts end-to-end, have enabled the characterization of alternative splicing variation and transcript isoform diversity at single-cell resolution. These advances fill critical knowledge gaps about cell-type-specific transcript isoform usage and its regulation in single cells. Here, we review the evolution of isoform-resolved single-cell transcriptomics, highlighting experimental and computational innovations. We discuss its broad applications in characterizing transcriptome variation and RNA processing, and explore its emerging impact across new dimensions of single-cell biology.
Pre-mRNA undergoes extensive processing during transcription by RNA polymerase II, including splicing, folding, and 3'-end cleavage and polyadenylation. In this forum, we discuss recent studies that have devised powerful sequencing methods to detect coordination of RNA processing at the level of individual nascent transcripts.
The genetic code determines not only the amino acid sequences of proteins but also mRNA stability. How is this hidden message read? Hia and colleagues have now identified human DHX29 as a reader of the mRNA stability code carried by codons, providing new mechanistic insights into translation-coupled gene regulation.
Marsupials are a unique group of mammals widely used in clinical and evo-devo research for their unusual reproductive traits. The ability to edit marsupial genomes would vastly improve their utility as research models, as well as potentially alleviate the complex and pressing ecological challenges marsupials face. To date, however, genome editing has only been achieved for a single species (Monodelphis domestica), despite the recent influx of high-quality genomes, largely due to this species' similarity to rodent models. In this review, we outline the marsupial-specific challenges and opportunities of both zygote-based and germ cell transplantation approaches to genome editing and summarise current efforts to fill this critical gap in the marsupial research and conservation toolkit.
Most Mendelian diseases lack effective treatments, with current options often limited to symptomatic care rather than addressing the underlying genetic defect. In this opinion article, we argue that genetic suppressors, a specific class of modifier variants that can counteract the effects of disease-causing mutations, can identify promising new avenues for therapeutic intervention. We discuss the prevalence of potential suppressors across Mendelian diseases, describe approaches for their systematic identification, and consider their therapeutic relevance. As genome-wide screening technologies and machine learning methods continue to advance, we expect suppressor identification to accelerate in the near future. These suppressors present exciting opportunities for expanding our therapeutic arsenal and improving outcomes for individuals with inherited disorders.
Recent analyses challenge the long-standing view of small nuclear RNAs (snRNAs) as largely uniform and functionally interchangeable molecules. Their genes undergo lineage-specific expansions and losses, and in humans, individual loci display striking sequence constraints. Recurrent germline and somatic mutations cluster within defined structural domains of both major and minor spliceosomal snRNAs, revealing that single nucleotides can be subjected to changes affecting function. Even subtle alterations within conserved base-pairing regions can reshape recognition of cis-regulatory elements, while regulated abundance and RNA modifications further tune splicing outcomes. Rather than acting solely as structural scaffolds, snRNAs function as dynamic RNA components that participate directly in spliceosome assembly and catalytic-site formation. In this review, we distill the emerging principles and consider their implications for development, tissue homeostasis, and human disease.
