Yi-Hsuan Pan

The end-Permian and end-Triassic mass extinctions, driven by massive catastrophic volcanism and prolonged hypoxia, fundamentally reshaped life on Earth. However, the genomic impacts of these two biodiversity crises on living organisms remain largely unknown. Here, we performed a genome-wide screening to identify accelerated evolved regions in the ancestral lineage of mammals that survived both extinction events. Nearly all (20/21) of these accelerated regions were located in protein-coding sequences, and 81% (17/21) were found to be associated with lung function. We further extended our analysis to three additional vertebrate lineages that experienced either one or both of the mass extinctions. Similar genomic signatures, involving accelerated evolution of lung-related genes, were also observed in these non-mammalian lineages. Collectively, these findings suggest that adaptation of lung-related genes to prolonged hypoxia may have occurred during the two mass extinction events, potentially driving a second evolutionary stage of the lung following the vertebrate transition to land.

Reconstructing ancient population size history is essential for understanding the evolutionary origin of Homo sapiens. We recently developed the fast infinitesimal time coalescent process (FitCoal) and detected a severe population bottleneck occurring approximately 930 thousand years ago. However, two recent studies compared FitCoal and mushi and concluded that the severe bottleneck is a statistical artifact. In this study, we compared the two methods against a benchmark of ten billion msprime coalescent simulations. We demonstrate that FitCoal achieves both superior speed and accuracy in expected site frequency spectrum (SFS) estimation. Analyses of simulated datasets confirmed that FitCoal reliably recovers the bottleneck, whereas mushi fails under identical conditions. Independent fossil and paleoclimate evidence is consistent with the timing and evolutionary impact of this bottleneck, including associations with hominin dispersals, speciation events, and a subsequent increase in brain size. These findings refine the demographic history of Homo during the Pleistocene and highlight the importance of high-precision SFS computation for revealing critical evolutionary transitions that shaped modern human ancestry.

Mammalian torpor imposes unique metabolic constraints, yet the mechanisms of nitrogen metabolism during this state remain unclear. In this study, we show that the urea cycle is selectively regulated rather than broadly suppressed in torpid bats. A significantly increased abundance of carbamoyl-phosphate synthase 1 (CPS1) maintained its functional capacity during torpor and arousal in Myotis ricketti. Proteomic analyses and confocal microscopy identified a specific association and co-localization between CPS1 and agmatinase (AGMAT), an ATP-independent enzyme involved in nitrogen metabolism. Co-localization of CPS1 and AGMAT was also observed in torpid Rhinolophus ferrumequinum, a phylogenetically distant species. Fluorescence resonance energy transfer (FRET) further supported an indirect CPS1-AGMAT interaction. Most urea cycle enzymes exhibited stable or only moderately reduced expression during bat torpor, and metabolic profiling demonstrated sustained nitrogen flux. Together, these findings reveal a conserved adaptive mechanism that maintains urea cycle function, potentially enhancing osmotic stability and energy efficiency during prolonged fasting and water scarcity.

Background: Autism spectrum disorder (ASD) is biologically heterogeneous and has limited mechanism-informed interventions targeting core behavioral symptoms. Emerging evidence suggests that gut microbial metabolism shapes neurobehavioral outcomes, yet the specific metabolic pathways linking gut ecology to brain function remain incompletely understood. One candidate pathway is polyamine metabolism, which links microbial amino acid metabolism to host regulation and represents a plausible but underexplored contributor to ASD-related phenotypes. Notably, the psychobiotic Lactiplantibacillus plantarum PS128 has been reported to improve social behaviors in individuals with ASD, although the molecular basis for these effects is unclear. In this study, we used Fragile X mental retardation 1 knockout ( Fmr1 KO) mice, a well-established ASD model, to investigate microbiota-dependent metabolic mechanisms underlying autism-like behaviors. Results: We found that autism-like behaviors in Fmr1 KO mice were associated with gut dysbiosis, impaired intestinal barrier integrity, disruption of the arginine–ornithine–polyamine pathway, and elevated putrescine in the prefrontal cortex (PFC). Supplementation with PS128 remodeled the gut microbiota, reduced inflammation- and disease-associated taxa, improved intestinal structure and permeability, and restored polyamine homeostasis. Targeted metabolomics revealed an increased PFC-to-serum putrescine ratio in KO mice, which was normalized following PS128 intervention. This correction was accompanied by reduced expression of polyamine transporters in the PFC, including ATP13A family members. Causal experiments supported a functional role for putrescine, as peripheral elevation of putrescine induced autism-like behaviors in wild-type mice, whereas pharmacological inhibition of putrescine synthesis ameliorated behavioral deficits in Fmr1 KO mice. Conclusions: These findings identify putrescine metabolic dysregulation as a key contributor to autism-like phenotypes and support the existence of an ASD subtype defined by disruption of the arginine–ornithine–polyamine axis. Integrated multi-omics and causal perturbation analyses support a model in which microbiota-targeted intervention rebalances systemic polyamine regulation along the gut–brain axis, thereby improving ASD-relevant behaviors. Our work provides mechanistic evidence linking microbial metabolism to neurochemical homeostasis and highlights the translational potential of metabolic stratification in ASD. Graphical We identify dysregulated microbiota-driven polyamine homeostasis as a causal contributor to autism-like behaviors in Fmr1 knockout mice. A psychobiotic intervention restores gut–brain metabolic balance and rescues social and repetitive behavioral deficits through coordinated microbial and host transport regulation.

Mammalian torpor imposes unique metabolic constraints, yet the mechanisms of nitrogen metabolism during this state remain unclear. In this study, we show that the urea cycle is selectively regulated rather than broadly suppressed in torpid bats. A significantly increased abundance of carbamoyl-phosphate synthase 1 (CPS1) maintained its functional capacity during torpor and arousal in Myotis ricketti . Proteomic analyses and confocal microscopy identified a specific association and co-localization between CPS1 and agmatinase (AGMAT), an ATP-independent enzyme involved in nitrogen metabolism. Co-localization of CPS1 and AGMAT was also observed in torpid Rhinolophus ferrumequinum , a phylogenetically distant species. Fluorescence resonance energy transfer (FRET) further supported an indirect CPS1-AGMAT interaction. Most urea cycle enzymes exhibited stable or only moderately reduced expression during bat torpor, and metabolic profiling demonstrated sustained nitrogen flux. Together, these findings reveal a conserved adaptive mechanism that maintains urea cycle function, potentially enhancing osmotic stability and energy efficiency during prolonged fasting and water scarcity.

The molecular etiology of numerous risk genes for autism spectrum disorder (ASD), including Cadherin 11 (CDH11), remains elusive. We investigated the role of CDH11 in the development of ASD-related behaviors using gene-deficient mice. CDH11 is enriched at synapses in glutamatergic neurons of the anterior cingulate cortex (ACC), which project to the dorsal striatum, nucleus accumbens, and the basolateral amygdala. Developmental ablation of Cdh11 in these neurons led to increased self-grooming, reduced sociability, and decreased neuronal activity in the ACC. Chemogenetic inhibition of ACC glutamatergic neurons recapitulates the over-grooming phenotype, while activation of these neurons mitigates self-grooming in Cdh11-deficient mice. Moreover, targeted expression of CDH11 in the ACC of these mice significantly attenuated their over-grooming behaviors. Proteomics of ACC synaptosomes and CDH11 interactomes revealed that CDH11 participates in synaptic vesicle trafficking, as evidenced by a reduction in presynaptic vesicle density at excitatory synapses in Cdh11-deficient mice. These findings highlight an important role of CDH11 in the development of ASD-related brain circuits and provide insights into the molecular basis of repetitive behaviors in ASD.

Pathogenic variants in MED13L cause MED13L syndrome, a well-defined neurodevelopmental disorder characterized by motor deficits, intellectual disability, and language delay, yet its underlying developmental and molecular mechanisms remain largely elusive. To address this gap, we generated a gene knockout mouse model of MED13L syndrome. While homozygous Med13l knockout exhibit neonatal lethality accompanied by reduced brain volume and cortical thickness, heterozygous mice are viable and display hallmarks of MED13L syndrome, including impaired learning and memory, reduced motor coordination, and heightened anxiety. Additionally, heterozygous mice show microcephaly with simplified neuronal morphology in the motor cortex. Single-cell transcriptomics and immunofluorescence reveal severe cortical neurogenesis deficits in Med13l knockout embryos, driven by impaired neural progenitor differentiation. Integrative multi-omics analyses reveal that MED13L orchestrates cortical neurogenesis by priming the transcriptional activation of key developmental genes, including Neurod2, Sox5, Auts2, and Nfib. This priming effect is mediated by MED13L binding to the core mediator complex, which facilitates the complex’s association with RNA Pol II and subsequent dissociation from MED13L. These findings uncover a pivotal role for MED13L in transcriptional regulation during brain development and highlight potential targets for restoring normal transcriptional programs in MED13L syndrome.

Reconstructing ancient population size history is essential for understanding the evolutionary origin of Homo sapiens . Using the fast infinitesimal time coalescent process (FitCoal), which precisely computes the expected site frequency spectrum (SFS), we revisited the debated population bottleneck that occurred approximately 930 thousand years ago. By benchmarking FitCoal against mushi and ten billion coalescent simulations, we demonstrate that FitCoal achieves both superior speed and accuracy in expected SFS estimation. Analyses of simulated datasets confirmed that FitCoal reliably recovered the bottleneck, whereas mushi failed under identical conditions. Independent fossil and paleoclimate evidence further corroborates the timing and evolutionary impact of this bottleneck, linking it to hominin dispersals, speciation events, and a subsequent increase in brain size. These findings refine the demographic history of Homo during the Pleistocene and highlight the importance of high-precision SFS computation for revealing critical evolutionary transitions that shaped modern human ancestry.

Developing cost-effective and disease-relevant animal models is essential for advancing biomedical research into human disorders. Here we investigate the feasibility of a pig model for autism spectrum disorder (ASD) using embryonic exposure to valproic acid (VPA), an antiepileptic drug known to increase ASD risk. We established experimental paradigms to assess the behavioral characteristics of these pig models. Administration of VPA to Bama miniature pigs (Sus scrofa domestica) during critical embryonic stages resulted in abnormal gait, increased anxiety levels, reduced learning capabilities and altered social patterns, while largely preserving social preference of treated piglets. Notably, we detected significant neuroanatomical changes in cortical regions associated with ASD in the VPA-treated pigs, including cortical malformation, increased neuronal soma size, decreased dendritic complexity and reduced dendritic spine maturation. Transcriptome analysis of the prefrontal cortex of VPA-treated pigs further revealed substantial alterations in the expression of genes linked to ASD, especially genes of the dopamine signaling pathway, highlighting the model’s relevance and potential for shedding light on ASD’s underlying neuropathological and molecular mechanisms. These findings suggest that pig models could serve as a promising alternative to traditional rodent models and provide a more ethical substitute for the use of primates in translational research on neurodevelopmental disorders.

The emergence of social structure and organization is essential for the evolution of amniotes, including human beings. Sociability and social hierarchy are two key features to form a social group. However, it remains unknown whether sociability and social hierarchy are genetically separable. In this study, we examined the social hierarchy, social and social novelty preference of PAS1 (placental-accelerated sequence 1) knock-out and knock-in mice. PAS1 is a social enhancer that modulates social hierarchy. We found that PAS1 knock-out mice lack social hierarchy while wallaby/chicken PAS1 knock-in mice establish stable social ranks. Moreover, social and social novelty preference was observed in all PAS1-mutated mice. PAS1 knock-in mice have stronger preference to interact with other mice than wild-type mice (C57BL/6). No aggressive alteration was found in PAS1-mutated mice. Overall, our results showed that PAS1 is an indispensable regulatory element in the formation of social hierarchy while PAS1 regulates one of pathways modulating sociability. Therefore, sociability is genetically separable from social hierarchy in amniotes, providing insights into how social structure and organization evolved. Highlights PAS1, a social enhancer, is indispensable for amniotes to establish social hierarchy. PAS1 modulates sociability in amniotes. Sociability and social hierarchy are regulated differently in amniotes. The frequency of PAS1 allele was not rare when social hierarchy first appeared.