Viruses encode diverse regulatory elements, but their breadth and mechanisms remain poorly defined. To address this gap, we performed massively parallel reporter assays spanning ∼200,000 genomic segments from 297 vertebrate-infecting viral genera. We identified numerous viral elements that enhance RNA stability and translation through TENT4-mediated mixed tailing, distributed across 19 genera and grouped into six distinct subclasses, indicating extensive convergent evolution. We also found diverse TENT4-independent elements acting through alternative pathways. One such element, Pt1 from Potamipivirus, stabilizes linear mRNA to levels comparable to circular RNA, suggesting its potential for RNA therapeutics. Pt1 directly recruits canonical poly(A) polymerases (PAPγ/α)-previously thought to function exclusively in transcription-coupled nuclear pre-mRNA processing-to drive cytoplasmic polyadenylation. Together, these findings chart the rich landscape of viral regulation, extend the scope of poly(A)-tail biology, and establish the virome as a valuable source for uncovering host RNA regulatory mechanisms.

Deciphering which genes are most important to disease etiology is a central challenge in human genetics. While genome-wide association studies have cataloged thousands of variants, it's been proposed that most are indirect regulators of a limited, currently unidentified set of central disease-driving genes, defined here as disease-proximal genes (DPGs). Here, we introduce DANDELION, a mediation-inspired statistical framework that prioritizes DPGs by integrating trans-regulatory effects from disease-relevant tissues with gene-level burden from whole-exome sequencing. Applying DANDELION to asthma uncovers novel DPGs that escape detection by conventional methods. CRISPR screens in epithelial and T cells find that most DPGs regulate key asthma-related cellular phenotypes. We also demonstrate that loss of two DPGs, SLC27A3 and SCD, affects inflammation and airway remodeling in a mouse model of allergic asthma. Our study establishes DANDELION as a powerful framework for prioritizing novel, therapeutically actionable genes and pathways underlying disease pathogenesis.

Diverse organisms adjust metabolic gene expression during crowding as they encounter nutrient scarcity, oxidative stress, and waste accumulation. Apicomplexan parasites experience these stresses during intracellular growth within host cells yet lack known regulators of metabolic adaptation. We screened the apicomplexan parasite Toxoplasma gondii to identify genes that support parasite fitness during crowding. Nicotinamide adenine dinucleotide (NAD)(P)+ biosynthesis was required at high parasite density, along with several parasite-specific factors, including an RNA-binding protein we named "T. gondii parasite response to oxidation" (TgPRO). TgPRO loss elevated reactive oxygen species under ambient conditions, which was rescued by growth at low oxygen levels. TgPRO regulates the expression of transcripts involved in carbon metabolism and iron-sulfur cluster assembly. Regulation of the iron-sulfur cluster assembly protein ISCU relies on TgPRO binding to the transcript's 3' UTR. Through convergent evolution, TgPRO performs a role analogous to that of known metabolic regulators from other species, representing the first dedicated regulator of metabolic gene expression in apicomplexans.

Action understanding requires internal models that link visual input to motor goals. In monkeys, mirror neurons have been proposed to support this process through motor resonance during observation, yet single-unit evidence in humans remains scarce. We recorded neural activity from the motor cortex (MC) and the superior parietal lobule (SPL) in two tetraplegic participants implanted with Utah arrays while they intended or observed hand actions. MC strongly encoded intention but showed weak responses during observation, evident primarily at the population level. In contrast, SPL supported shared representations across intended and observed actions at both the single-unit and population levels. When incongruent instructed and observed actions occurred simultaneously, SPL encoded the observed actions only when they were behaviorally relevant, whereas MC remained intention dominant. Our results identify a context-dependent gating mechanism in SPL and suggest a hierarchical organization in which MC maintains intention-specific codes while SPL flexibly links observed actions with internal goals.

Tartary buckwheat is a nutritionally important crop of the Himalayas and is crucial for local economies and food security. However, key genes and superior alleles for high-altitude adaptability and yield remain poorly defined, constraining the breeding of high-altitude buckwheat varieties. Here, we generated a telomere-to-telomere reference genome and a 16-accession pangenome spanning Himalayan wild populations and globally distributed landraces. We identified 123,131 non-redundant structural variations in 16 accessions, including gene copy-number variations. The graph-based pangenome revealed FtRNH, a wild-specific gene that enhances high-altitude adaptability. We also identified a copy-number variation at the FtPLATZ locus and a 28-bp insertion in the FtPLATZ3 promoter that together contribute to seed-size variation across wild buckwheat and landraces. Leveraging these superior FtRNH and FtPLATZ alleles, we developed buckwheat lines with enhanced high-altitude adaptability and improved yields across sites. These findings establish a pangenome-guided strategy for recovering wild alleles and combining stress adaptation with yield improvement in crops.

Adult organs enlarge or regress in response to functional demands: changes commonly attributed to the dynamics of their resident stem cells. A striking example is the intestine, whose length varies with diet and reproductive status. We find that the size of the adult gut is extrinsically controlled by its surrounding muscles. In Drosophila, intestinal muscle differs in size and structure between sexes and grow in females during reproduction. By altering the sex or reproductive status of gut muscle cells, we establish that muscle-intrinsic sex determinants determine baseline sex differences in muscle myofibril width and organ size. Female muscles integrate hormonal and nutritional inputs during reproduction to elongate their sarcomeres; this reduces intestinal transit and further increases organ size. Such remodeling is adaptive and also occurs in mice. Our findings redefine the intestinal muscle as a responder to specific signals that adjust adult organ-level features and sustain reproductive demands.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the guanosine diphosphate (GDP)-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.

Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.

Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT2AR, lysergic acid diethylamide (LSD) enhances CD8+ T cell-mediated antitumor immunity and suppresses colorectal cancer (CRC) growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR. We show that IHCH-8110 inhibits CRC progression by activating 5-HT2AR on enteric glial cells, thereby inducing CXCL10 and interleukin (IL)-18 expression to promote CD8+ T cell recruitment and effector polarization within the tumor microenvironment. By converting immune-cold CRC into a more immunologically responsive state, IHCH-8110 enhances the efficacy of PD-1 blockade. Together, our findings identify enteric 5-HT2AR signaling as a regulator of antitumor immunity and support peripheral 5-HT2AR agonists as a therapeutic strategy for CRC immunotherapy.

Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. We observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.

Bird genomes are the smallest among amniotes; however, they remain challenging to assemble due to their structural complexity. This study presents a fully phased diploid telomere-to-telomere reference genome for the zebra finch (Taeniopygia guttata), a model organism for neuroscience and evolutionary genomics. Combining sequencing strategies allowed the closing of nearly all gaps, adding ∼90 Mbp of sequence (7.8%). The assembly contains gapless sequences for all microchromosomes, including the elusive dot chromosomes with their distinctive architecture. The genome was comprehensively annotated for genes, repeats, and structural variants. Complete centromeres were identified, along with candidate DNA-binding centromere protein B (CENP-B) homologs, suggesting that birds possess a kinetochore-associated CENP system similar to that of mammals. Relative to the previous reference generated by the Vertebrate Genomes Project, 2,710 (8.13%) previously unassembled or unannotated genes were identified. This complete genome of a songbird serves as a public reference and illuminates avian genome architecture and function.

We present T2T-MMU8v2.0, a near-perfect telomere-to-telomere assembly of the rhesus macaque (Macaca mulatta), representing high base-level accuracy reported in a primate genome. Our optimized assembly strategy exposes subtelomeric satellite-rich regions as the principal bottleneck in obtaining full assemblies, owing to long-read technological biases and limitations in hybrid assembly frameworks. By resolving ∼8 Mbp of SATR satellite arrays and discovering 268 previously unannotated repeat families, we define four distinct SATR genomic architectures, each with unique satellite composition, segmental duplication organization, and epigenetic signatures, which are distinct from the subtelomeric architectures observed in hominid genomes. These regions harbor 58 actively transcribed genes, suggesting gene innovation within these repetitive regions. Functionally, T2T-MMU8v2.0 improves alignment accuracy and chromatin accessibility detection, enabling a finer resolution in population variation and regulatory elements. Together, this work establishes a benchmark for primate genomics and illustrates the functional and evolutionary importance of previously inaccessible structures of the genome.

The common marmoset is a New World monkey widely used to study primate evolution and human disease. We present a telomere-to-telomere (T2T) reference assembly for the species, plus three near-T2T haplotypes. These resolve previously inaccessible regions, including the centromeres, sex chromosomes, subterminal satellites, acrocentric chromosomes, and the major histocompatibility complex (MHC). We find marmoset centromeres carry dimeric alpha satellites with chromosomal specificity, flanked by inactive layers interpreted as ancestral centromere remnants. We assemble gene-poor, satellite-rich short arms of the acrocentrics and find that most can harbor rDNA and all share pseudo-homolog regions (PHRs). PHR-sharing chromosomes also share closely related centromeric satellites, consistent with a model of ongoing rDNA-facilitated recombinational exchange between heterologous chromosomes. We further identify over 500 marmoset-lineage-specific transcribed genes with previously unknown transcript models or expansions. These resources, along with a preliminary pangenome, improve the utility of the marmoset as a model organism and address gaps in primate genome evolution.

Highly repetitive short arms of human acrocentric chromosomes have remained largely inaccessible to studies of meiotic recombination and de novo mutation. Integrating long-read and complementary sequencing approaches, we created 156 phased short arms and assessed 107 transmissions from 23 samples in a four-generation human pedigree. We observed a significant depletion of p-arm allelic recombination, although one ectopic recombination was identified between chromosomes 13 and 21, mediated by a large segmental duplication near the SST1 array. In contrast, 18 maternal-biased q-arm allelic recombination events were significantly enriched near the centromere. Relative to autosomal euchromatin, acrocentric short arms showed a 10-fold higher single-nucleotide variant rate, with a distinct mutation spectrum marked by reduced C>T but increased C>G and A>C mutations. These findings suggest that acrocentric sequence composition biases and limited allelic recombination contribute to an elevated mutation rate and promote distinct mutational processes linked to mismatch repair defects and oxidative DNA damage.

Human genome sequencing typically relies on mapping reads to a reference genome to call variants, but this approach introduces technical biases, excluding duplicated and structurally polymorphic regions of the genome. To overcome this, we present a telomere-to-telomere genome benchmark with near-perfect accuracy across 99.4% of the diploid HG002 genome. This benchmark adds 701.4 Mb of autosomal sequence and both sex chromosomes (216.8 Mb), which were absent from prior benchmarks. We annotated genes and repeats on both haplotypes, including 19,956 protein-coding genes on the maternal haplotype and 19,190 on the paternal haplotype, and developed new methods to measure the accuracy of reads, phased variant call sets, and assemblies against a diploid reference. Genome-wide analyses show that de novo assembly resolves 2%-7% more sequence and outperforms variant calling accuracy by an order of magnitude, expanding the reach of genomic medicine to the entire genome and enabling a new era of personalized genomics.

Classical evolutionary theories of aging, including antagonistic pleiotropy (AP) and the disposable soma theory (DST), explain why aging exists but are often applied without considering how sex-specific reproductive strategies shape the forces of natural selection on survival. They do not explain why females consistently outlive males across taxa, despite their greater reproductive investment, or why in some contexts, such as eusocial queens, extraordinary fecundity is coupled with exceptional longevity. To explain these patterns, we propose the reproductive resilience hypothesis (RRH), which posits that when reproductive success depends on prolonged survival and caregiving, natural selection favors coupling reproduction with enhanced somatic maintenance rather than trading it off. We suggest that reproductive events, including age at sexual maturity, pregnancy, lactation, and menopause, are pivotal life-history transitions and must be explicitly integrated into studies of sex differences that drive aging and susceptibility to age-related diseases. We further propose that loss of reproductive resilience is a sex-specific hallmark of aging that coordinates the emergence of multiple downstream hallmarks, helping explain the acceleration of systemic aging and age-related disease following reproductive decline. We propose that, for these reasons, studying females should be prioritized, as it has unique implications for discovering pathways to slow aging and prevent age-related diseases, ultimately benefiting both women and men.

In this issue of Cell, Wang et al. reveal the mechanism of a bacterial antiphage system that contains two reverse transcriptases. Through an unprecedented process, the enzymes synthesize double-stranded DNA; one uses a noncoding RNA template and the other uses its amino acid residues to template and prime DNA synthesis.