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As the number and variety of assembled genomes continue to grow, the number of annotated genomes is falling behind, particularly for eukaryotes. DNA-based mapping tools help to address this challenge, but they are only able to transfer annotation between closely related species. Here we introduce LiftOn, a homology-based software tool that integrates DNA and protein alignments to enhance the accuracy of genome-scale annotation and to allow mapping between relatively distant species. LiftOn's protein-centric algorithm considers both types of alignments, chooses optimal open reading frames, resolves overlapping gene loci, and finds additional gene copies when they exist. LiftOn can reliably transfer annotation between genomes representing members of the same species, as we demonstrate on human, mouse, honeybee, rice, and Arabidopsis thaliana It can further map annotation effectively across species pairs as far apart as mouse and rat or Drosophila melanogaster and Drosophila erecta ., (© 2025 Chao et al.; Published by Cold Spring Harbor Laboratory Press.)

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

As the number and variety of assembled genomes continues to grow, the number of annotated genomes is falling behind, particularly for eukaryotes. DNA-based mapping tools help to address this challenge, but they are only able to transfer annotation between closely-related species. Here we introduce LiftOn, a homology-based software tool that integrates DNA and protein alignments to enhance the accuracy of genome-scale annotation and to allow mapping between relatively distant species. LiftOn's protein-centric algorithm considers both types of alignments, chooses optimal open reading frames, resolves overlapping gene loci, and finds additional gene copies where they exist. LiftOn can reliably transfer annotation between genomes representing members of the same species, as we demonstrate on human, mouse, honey bee, rice, and Arabidopsis thaliana . It can further map annotation effectively across species pairs as far apart as mouse and rat or Drosophila melanogaster and D. erecta .

The rapid growth in the number of sequenced genomes makes it possible to search for the appearance of entirely new introns in the human lineage. In this study, we compared the genomic sequences for 19,120 human protein-coding genes to a collection of 3493 vertebrate genomes, mapping the patterns of intron alignments onto a phylogenetic tree. This mapping allowed us to trace many intron gain events to precise locations in the tree, corresponding to distinct points in evolutionary history. We discovered 584 intron gain events, all of them relatively recent, in 514 distinct human genes. Among these events, we explored the hypothesis that intronization was the mechanism responsible for intron gain. Intronization events were identified by locating instances where human introns correspond to exonic sequences in homologous vertebrate genes. Although apparently rare, we found three compelling cases of intronization, and for each of those we compared the human protein sequence and structure to homologous genes that lack the introns.

Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations. We identify 15,752 genes harboring a significant xQTL and map 3,739 eQTLs to a specific cellular context. We observe a striking drop in gene expression and splicing heritability as the human brain develops. Isoform-level regulation, particularly in the second trimester, mediates the greatest proportion of heritability across multiple psychiatric GWAS, compared with eQTLs. Via colocalization and TWAS, we prioritize biological mechanisms for ~60% of GWAS loci across five neuropsychiatric disorders, nearly two-fold that observed in the adult brain. Finally, we build a comprehensive set of developmentally regulated gene and isoform co-expression networks capturing unique genetic enrichments across disorders. Together, this work provides a comprehensive view of genetic regulation across human brain development as well as the stage-and cell type-informed mechanistic underpinnings of neuropsychiatric disorders., Competing Interests: M.J.G. and D.H.G. receive grant funding from Mitsubishi Tanabe Pharma America.

Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive deficits persist. Determining biological mechanism(s) underlying abnormalities is critical to minimize the long-term impact of HIV. Positron emission tomography (PET) studies reveal that PLWH exhibit elevated neuroinflammation, potentially contributing to these problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV entry into a cell contributing to HIV-related neurotoxicity. In vivo evidence for mice overexpressing gp120 (transgenic) mice exhibiting neuroinflammation remains unclear. Here, we conducted microPET imaging in gp120 transgenic and wildtype mice, using the radiotracer [(18)F]FEPPA (binds to the translocator protein expressed by activated microglial serving as a neuroinflammatory marker). Imaging was performed at baseline and 24 h after lipopolysaccharide (LPS; 5 mg/kg) treatment (endotoxin that triggers an immune response). Gp120 transgenic mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus. Gp120 transgenic mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or sensitive to any treatments., (Copyright © 2022 Elsevier B.V. All rights reserved.)