Human pangenomics is moving beyond the single linear reference paradigm towards population-scale representations that better capture complex genomic variation. Many current human pangenomes include both global and regional initiatives, but their limited sample sizes constrain the representation of population diversity. Recently, the establishment of the 1000 Chinese Pangenome (1KCP) project represents a major milestone in large-scale regional pangenomics. By combining high-coverage de novo assemblies with pangenome-informed assembly of modest-coverage samples, 1KCP expanded the resource to 1,116 diploid genome assemblies while substantially reducing sequencing costs relative to uniformly high-coverage de novo assembly. This large-scale framework not only broadens the catalog of non-reference sequences and genetic variants, but also enables complex variants, including structural variants and tandem repeats, to be linked to gene regulation and human phenotypes, revealing classes of variation incompletely captured by conventional small-variant-centered analyses. Nevertheless, some challenges remain, including reduced assembly accuracy in repetitive and structurally complex genomic regions when using modest-coverage data. Broader and more balanced sampling will also be needed to better represent population diversity. Building on these insights, we propose a hierarchical framework for the next-generation global pangenome, where large-scale regional pangenomes guide diversity-informed selection of representative individuals for high-quality genome assembly, while global allele frequencies are integrated with the resulting pangenome graph.
Synapse specification and organisation rely on coordinated trans-synaptic interactions that couple molecular recognition to the assembly of pre- and postsynaptic compartments. While neurexins and cerebellin-mediated pathways have long been recognised as core determinants of synaptic identity, recent studies have identified latrophilins (LPHNs) as important organisers of defined excitatory pathways. In particular, the formation of teneurin-latrophilin-FLRT complexes has emerged as a key mechanism contributing to synaptic specificity in selected hippocampal and cortical circuits. Accumulating evidence further indicates that alternative splicing of LPHN3 configures intracellular signalling logic rather than merely modulating extracellular adhesion, thereby biasing the maturation of trans-synaptic contacts toward functional synapses. Here, we review recent advances that redefine latrophilin-dependent complexes as dynamic, signal-transducing synaptic modules linking molecular recognition to nanoscale synaptic organisation.
Pseudogenes, once regarded as genomic fossils or “junk DNA”, have emerged as important players in adaptive evolution of animals and regulation of human disease. In this review, we synthesize recent advances in understanding the evolutionary dynamics and functional implications of pseudogenes across vertebrates. We firstly focused on the adaptive evolution of pseudogenes in vertebrates, highlighting how pseudogenization-derived gene loss contributes to lineage-specific adaptations in diverse habitats, including immune, sensory, dietary changes, sex determination and metabolic traits. Convergent pseudogenization events have been documented across multiple species facing similar ecological challenges. We then summarized the functional roles of pseudogenes in human diseases, highlighting their dual capacity to act as either protective regulators or pathogenic drivers in cancer, hematopoiesis and metabolic disorders. These pseudogenes frequently act through non-coding networks, translation of truncated peptides, or cis-regulatory DNA elements. These advances demonstrate that pseudogenes are not passive relics but active regulators of gene expression networks. Finally, we propose that integrating long-read RNA-seq data and using CRISPR/Cas9 to test causal variants represent key future directions for dissecting pseudogene functions in evolution and disease.
Construction of microbial cell factories often requires extensive reconfiguration of metabolic networks, which frequently compromises cell growth. Here, we engineered E. coli to produce dencichine (β-ODAP), a plant-derived hemostatic agent. Knocking out serB blocks the competing L-serine pathway, causing L-serine auxotrophy and severely impairing cell growth. This growth defect was only partially restored by supplementation with L-serine or L-glycine, suggesting the presence of additional growth-limiting factors. Through adaptive laboratory evolution and reverse engineering, we further uncovered that overexpression of serA to enhance the supply of the precursor L-2,3-diaminopropionate led to accumulation of the toxic byproduct 2-hydroxyglutarate (2-HG) from α-ketoglutarate. To resolve these two growth constraints, we developed a growth-phase-dependent dual-dynamic regulation circuit. This circuit gradually activates serA expression and progressively represses serB expression as cells enter the stationary phase, thereby reducing 2-HG accumulation and alleviating L-serine auxotrophy. Combined with pathway balancing and cofactor optimization, the final engineered strain produced 13.46 g L-1 of β-ODAP with a yield of 0.32 g g-1 in 3-L bioreactors. This study reveals a toxicity mechanism in serine-pathway engineering and provides a dynamic regulation strategy applicable to the biosynthesis of serine-pathway-derived metabolites.
Halomonas bluephagenesis (H. bluephagenesis) was metabolically engineered to efficiently synthesize a biopolymer composed of three monomers—3-hydroxybutyrate (3HB), lactate (LA), and 3-hydroxyvalerate (3HV)—using glucose as the carbon source. In shake-flask cultures with glucose-sodium valerate as the carbon source, the recombinant strain produced 9.48 g L-1 of P(3HB-co-12.92 mol% LA-co-40.48 mol% 3HV). By knocking down 11 genes related to the β-oxidation cycle, the composition of the terpolymer was controllable. In a 7-L bioreactor, H. bluephagenesis CJN28 reached 61.65 g L-1 cell dry weight (CDW containing 85.64 wt% P(3HB-co-22.51 mol% LA-co-25.34 mol% 3HV). Both H. bluephagenesis CJN28 and its cytoskeletal protein MreB-knockdown mutant H. bluephagenesis CJN28△mreB (exhibiting significant cell enlargement) demonstrated better capability to synthesize P(3HB-co-LA-co-3HV) when cultured with glucose and gradient concentrations of sodium valerate. Thermal and mechanical studies revealed that the terpolymer exhibited higher ductility compared to P3HB and PLA. This study marks the first attempt of microbial production of P(3HB-co-LA-co-3HV) with enhanced efficiency for scale up.
The sequencing of the Neanderthal genome revealed that interbreeding with early modern humans left a genetic legacy of approximately 1–2% in non-African populations. This introgression provides a natural experimental pathway for exploring the complex functional consequences of archaic ancestry and the evolutionary forces shaping the modern human genome. This review outlines the spatiotemporal dynamics of admixture, suggesting multiple waves of gene flow, and examines the evolutionary fates of introgressed sequences—from purifying selection removing deleterious alleles to adaptive introgression aiding human adaptation to Eurasian environments. Neanderthal-derived alleles have been linked to variation in immune responses, skin barrier, metabolism, and susceptibility to neurological and psychiatric disorders. These effects are complex and context-dependent, including potential antagonistic pleiotropy, where alleles that were once adaptive may now increase disease risk. We highlight future directions, including integrating ancient DNA with multi-omics data, expanding studies to diverse populations, and using functional genomics to identify causal mechanisms.
The evolutionary ecology of prokaryotes within oceanic trenches remains largely unexplored. Here, we analyzed 19,194 medium-quality prokaryotic metagenomic assembled genomes (MAGs) from sediments of the Diamantina, Kermadec, Yap and Mariana trenches. Hadal zones hosted relatively ancient phylogenetic lineages across most prokaryotic phyla compared to non-hadal zones. A linear correlation between depth differences and the pairwise patristic distances was observed inter/intra trenches, indicating a depth-dependent evolutionary boundary. This pattern was further reflected by a clear vertical shift of genomic features, including carbon/nitrogen atoms per amino-acid-residue side chain (C/N-ARSC), pseudogene density and non-synonymous to synonymous mutation ratio (pN/pS). Close phylogenomic relationships for MAGs among different trenches suggested a rapidly and continuously exchange, which was very likely facilitated by deep-sea currents. Molecular dating of hadal Nitrososphaeria and Alphaproteobacteria revealed a divergence of respective 2.2 and 1.8 billion years ago, earlier than the emergence of contemporary trenches, emphasized the hadal zone sediments as a crucial ecological reservoir for prokaryotic evolution.
The gut microbiota forms a highly dynamic and multilayered ecological system that plays a pivotal role in maintaining mucosal immune homeostasis. When the “microbiota-immune regulatory” axis is perturbed in genetically susceptible individuals, antigen recognition and effector responses at the mucosal surface may be reshaped, thereby driving the onset and persistent progression of IBD. This review highlights the distinct patterns of microbe-immune interactions under physiological and pathological conditions, with particular focus on the key immunoregulatory events at different disease stages. In the early phase of IBD, adhesive and invasive bacterial strains and microbial dysbiosis can disrupt epithelial barriers, trigger aberrant innate immune activation, and induce chronic local inflammation. As the disease advances, T-cell polarization, tissue remodeling, and extraintestinal manifestations collectively sustain the inflammatory network and promote systemic damage. We further summarize emerging microbiota-based immunotherapeutic strategies-such as fecal microbiota transplantation, probiotics/prebiotics, targeted manipulation of specific bacterial taxa, bacteriophage therapy, and engineered probiotics-and their potential value and remaining clinical challenges in IBD management. Future work should integrate gut microbiota-immune crosstalk to identify clinically actionable targets and validate their biological and therapeutic significance through well-designed prospective studies.
Dementia constitutes a significant public health crisis, accounting for one-third of deaths among the elderly and exceeding the combined mortality of breast and prostate cancers. Alzheimer's disease (AD), the predominant form of dementia (60–70%), primarily manifests as late-onset AD (LOAD), which constitutes over 95% of all AD cases. The risk of developing LOAD escalates dramatically with age, affecting approximately half of individuals over 85 years of age, thus positioning LOAD as a critical age-related medical challenge. The present study proposes a novel conceptual framework for understanding LOAD, positing it not merely as a discrete disease but rather as a maladaptive trajectory of brain aging, in which physiological aging processes progressively evolve into pathological states. This transition is driven by synergistic interactions between genetic susceptibility, environmental exposures, and aging-related mechanisms, with epigenetic alterations serving as a central dynamic mediator. This analysis demonstrates that genetic factors, aging, and environmental influences collectively regulate LOAD susceptibility through a multidimensional interplay: while genes directly drive pathological pathways, their expression is dynamically modulated by age and environmental context via epigenetic mechanisms. Deciphering these complex interactions provides crucial insights into LOAD pathogenesis. This reconceptualisation necessitates a paradigm shift in therapeutic strategy. Rather than focusing exclusively on amyloid-centric approaches, we advocate targeting core aging mechanisms to enhance brain resilience. The most promising interventions aim to counteract maladaptive cognitive decline by improving proteostasis, modulating epigenetic drivers, and suppressing chronic neuroinflammation. This would reposition healthy brain aging as the cornerstone of LOAD prevention and treatment.
Cytokines and receptors of the IL-1 family are generally known for their role in inducing and modulating the inflammatory responses upon infectious challenges and, in particular, for their pathological role in chronic inflammatory, degenerative and autoimmune diseases. On the other hand, increasing evidence supports the notion that these molecules have a physiological role in promoting and maintaining tissue homeostasis in normal healthy conditions. The physiological importance of IL-1 family cytokines and receptors in the human brain is of particular interest, since several of these molecules are preferentially or specifically expressed in the brain and absent in other body compartments. Here, we critically examine the evidence pointing at the homeostatic functions of IL-1 family members in the human healthy brain, and highlight the existence of multiple/alternative mechanisms of brain cell regulation initiated by these molecules, including neurogenesis and neurodevelopment, neuroplasticity, neuroendocrine and neurometabolic functions.
