Biology subjects

Han, S.

Publications and source records attributed to Han, S..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

NEUROG2 regulates a human-specific neurodevelopmental gene regulatory program

Unique hallmarks of human neocortical development include slower rates of neurogenesis and the establishment of an extracellular matrix-rich, outer-subventricular zone that supports basal neural progenitor cell expansion. How gene regulatory networks have evolved to support these human-specific neurodevelopmental features is poorly understood. Mining single cell data from cerebral organoids and human fetal cortices, we found that NEUROG2 expression is enriched in basal neural progenitor cells. To identify and purify NEUROG2-expressing cells and trace their short-term lineage, we engineered two NEUROG2-mCherry knock-in human embryonic stem cell lines to produce cerebral organoids. Transcriptomic profiling of mCherry-high organoid cells revealed elevated expression of PPP1R17, associated with a fast-evolving human-accelerated regulatory region, oligodendrocyte precursor cell and extracellular matrix-associated gene transcripts. Conversely, only neurogenic gene transcripts were enriched in mCherry-high cortical cells from Neurog2:mCherry knock-in mice. Finally, we show that Neurog2 is sufficient to induce Ppp1r17, which slows human neural progenitor cell division, and Col13a1, an extracellular matrix gene, in P19 cells. NEUROG2 thus regulates a human neurodevelopmental gene regulatory program implicated in supporting a pro-proliferative basal progenitor cell niche and tempering the neurogenic pace. SUMMARY STATEMENTTranscriptomic analyses of NEUROG2-mCherry knock-in human embryonic stem cell-derived cerebral organoids reveal a link between NEUROG2 and extracellular matrix remodeling during human cortical development.

developmental biology↗

bioRxiv2023

Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement

Tau forms toxic fibrillar aggregates in a family of neurodegenerative diseases known as tauopathies. The faithful replication of tauopathy-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical segment of tau that forms a folding motif that is characteristic of a family of tauopathies and isolating it as a standalone peptide that form seeding-competent fibrils. The 19-residue jR2R3 peptide (295-313) spanning the R2/R3 splice junction of tau, in the presence of P301L, forms seeding-competent amyloid fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of every pathological tau fibril structure solved to-date and an intramolecular counter-strand that stabilizes the strand-loop-strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site that facilitates site-specific dewetting and in-register stacking of tau to form cross {beta}-sheets. We solve a 3 [A] cryo-EM structure of jR2R3-P301L fibrils with a pseudo 21 screw symmetry in which each half of the fibrils cross-section contains two jR2R3-P301L peptides. One chain adopts a SLS fold found in 4R tauopathies that is stabilized by a second chain wrapping around the SLS fold, reminiscent of the 3-fold and 4-fold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are able to template full length tau in a prion-like fashion. Significance StatementThis study presents a first step towards designing a tauopathy specific aggregation pathway by engineering a minimal tau prion building block, jR2R3, that can template and propagate distinct disease folds. We present the discovery that P301L--among the widest used mutations in cell and animal models of Alzheimers Disease--destabilizes an aggregation-prohibiting internal hairpin and enhances the local surface water structure that serves as an entropic hotspot to exert a hyper-localized effect in jR2R3. Our study suggests that P301L may be a more suitable mutation to include in modeling 4R tauopathies than for modelling Alzheimers Disease, and that mutations are powerful tools for the purpose of designing of tau prion models as therapeutic tools.

biophysics↗

bioRxiv2023

Somatic structural variants driving distinct modes of oncogenesis in melanoma

The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. Following our prior identification of double-stranded break repair deficiency in a subset of triple wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact. Statement of SignificanceThe diversity of SVs in melanoma, and how they directly or indirectly impact oncogenesis, are incompletely known. Here we present analysis of melanoma SVs that reveal distinct global genomic properties and molecular drivers, some of which point to opportunities for further biological and therapeutic investigation.

cancer biology↗

bioRxiv2023

Targeted Deletion of All Known Thyroid Hormone Receptors Causes Maturation Retardation and Early-onset Degeneration of Cochlear Outer Sulcus

Thyroid hormone (TH) and its receptors (TRs) are crucial for cochlear late-stage development and endocochlear potential (EP) maintenance. However, the mechanism underlying EP reduction in the absence of TH or TRs remains elusive. Cochlear outer sulcus root cells undergo significant morphological changes during late-stage cochlear development and are believed to play a role in maintaining endolymph homeostasis and EP. Yet, it is unknown whether TH and/or TRs are necessary for root cell differentiation and function. Here, we elucidate the essential role of TH or TRs in postnatal root cell development and survival in mice. TH deficiency significantly delayed root cell differentiation. Otocyst-selective deletion of both Thra and Thrb, but not Thrb alone, leads to a similar impairment, accompanied by early degeneration of root cells, with the stria vascularis remaining unaffected. Furthermore, a 22% reduction in mean EP magnitudes was observed in conditional TRs double knockout mice at 4 months of age, less pronounced than in global TRs knockout mice. Transcriptome analysis reveals that TH deficiency downregulates a significant portion of root cell-enriched genes. These findings underscore the redundant roles of TR and TR{beta} in promoting the late-stage differentiation and survival of root cells. Additionally, they suggest that the expression of TRs in cochlear epithelium is crucial for maintaining an optimal EP magnitude, while TRs expressed in areas outside cochlear epithelium, particularly in spiral ligament fibrocytes, may also significantly contribute to EP maintenance. This study advances our understanding of TH in cochlear outer sulcus development and EP maintenance.

developmental biology↗

bioRxiv2023

Pan-genome analysis of different morphotypes reveals genomic basis of Brassica oleracea domestication and differential organogenesis

The domestication of Brassica oleracea has resulted in diverse morphological types with distinct patterns of organ development. Here we report a graph-based pan-genome of B. oleracea constructed with high-quality genome assemblies of different morphotypes. The pan-genome harbors over 200 structural variant (SV) hotspot regions enriched with auxin and flowering-related genes. Population genomic analyses reveal that early domestication of B. oleracea focused on leaf or stem selection. Gene flows resulting from agricultural practices and variety improvement are detected among different morphotypes. Selective sweep analysis identifies an auxin-responsive SAUR gene and a CLE family gene as the crucial players in the leaf-stem differentiation during the early stage of B. oleracea domestication, and the BoKAN1 gene as instrumental in shaping the leafy heads of cabbage and Brussels sprouts. Our pan-genome and functional analyses further discover that variations in the BoFLC2 gene play key roles in the divergence of vernalization and flowering characteristics among different morphotypes, and variations in the first intron of BoFLC3 are involved in fine-tuning the flowering process in cauliflower. This study provides a comprehensive understanding of the pan-genome of B. oleracea and sheds light on the domestication and differential organ development of this globally important crop species.

plant biology↗

bioRxiv2023

Missing view completion for multi-timepoints omics data via representation disentanglement and temporal knowledge transfer

Longitudinal multi-view omics data offer unique insights into the temporal dynamics of individual-level physiology, which provides opportunities to advance personalized healthcare. However, the common occurrence of incomplete views makes extrapolation tasks difficult, and there is a lack of tailored methods for this critical issue. Here, we introduce LEOPARD, an innovative approach specifically designed to complete missing views in multi-timepoint omics data. By disentangling longitudinal omics data into content and temporal representations, LEOPARD transfers the temporal knowledge to the omics-specific content, thereby completing missing views. The effectiveness of LEOPARD is validated on three benchmark datasets constructed with data from the MGH COVID study and the KORA cohort, spanning periods from 3 days to 14 years. Compared to conventional imputation methods, such as missForest, PMM, GLMM, and cGAN, LEOPARD yields the most robust results across the benchmark datasets. LEOPARD-imputed data also achieve the highest agreement with observed data in our analyses for age-associated metabolites detection, estimated glomerular filtration rate-associated proteins identification, and chronic kidney disease prediction. Our work takes the first step toward a generalized treatment of missing views in longitudinal omics data, enabling comprehensive exploration of temporal dynamics and providing valuable insights into personalized healthcare.

bioinformatics↗

bioRxiv2023

A Small Tau Fragment Specifically Templates Four Repeat Tau Aggregates Through Multiple Generations

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau, folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high {beta}- sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting {beta}-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19- residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau--ten times the length of the peptide--and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions. Significance StatementA structural motif corresponding to a short junction sequence spanning R2 and R3 forms fibrils that adopt a fold characteristic of 4R tauopathy fibrils and induces misfolding of the larger tau protein with loss of microtubule binding and a prion-like specificity for 4R tau. Simulations, validated experimentally, pinpointed the specific amino acids in the peptide that can toggle its properties between aggregation competent and incompetent. The modifications suggest design principles for a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation in the 4R tauopathies.

molecular biology↗

bioRxiv2023

Proneural genes form a combinatorial code to diversify neocortical neural progenitor cells

Neocortical neural progenitor cells (NPCs) are molecularly heterogeneous, yet the genes that confer distinct neuronal morphologies and connectivities during development are poorly understood. Here, we determined that a proneural gene combinatorial code diversifies cortical NPCs. By mining scRNA-seq data from murine embryonic and early postnatal cortices and generating trajectory inference models, we found that Neurog2 is predominant, and is transiently co-expressed with Ascl1 and/or Neurog1 during an apical-to-basal NPC transition state in NPCs with early pseudotime identities. To assess whether proneural gene pairs confer distinct properties, we first used Neurog2/Ascl1 reporter mice expressing unique reporters, revealing that NPCs have distinct cell division modes and cell cycle dynamics dependent on their proneural gene profile. To assess Neurog2/Neurog1 interactions, we used double knock-out mice and novel split-Cre transgenics crossed to a Rosa-diptheria-toxin-A line to delete double+ cells, showing Neurog1/Neurog2 are specifically required to generate early-born neurons and to maintain NPCs. Finally, in silico mutation of a cortical Neurog2-gene regulatory network and validation using Neurog1/Neurog2 mutant and deleter mice, identified Bclllb and Nhlh2, expressed in early-born neurons, as dependent on Neurog1/Neurog2. Our data explains how proneural genes act combinatorically to diversify gene regulatory networks, thereby lineage restricting NPCs and creating cortical neuronal diversity.

developmental biology↗

bioRxiv2023

CBD and PSP cell-passaged Tau Seeds Generate Heterogeneous Fibrils with A Subpopulation Adopting Disease Folds

The recent discovery by cryo-electron microscopy (cryo-EM) that the neuropathological hallmarks of different tauopathies, including Alzheimers disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are caused by unique misfolded conformations of the protein tau is among the most profound developments in neurodegenerative disease research. To capitalize on these discoveries for therapeutic development, one must achieve in vitro replication of tau fibrils that adopt the representative tauopathy disease folds, which represents a grand challenge for the field. An widely used approach is seeded propagation using pathological tau fibrils derived from post-mortem patients in biosensor cells that expresses a fragment of the tau protein, known as K18 or Tau4RD, containing mainly the microtubule-binding repeat domain of tau as the substrate. The new insight from cryo-EM raised the question whether the Tau4RD fragment is capable of adopting the specific tau folds found in CBD and PSP patient fibrils, and whether cell-passaged and amplified tau fibrils can be used as seeds to achieve cell-free assembly of recombinant 4R tau into fibrils without the addition of any cofactors. Using Double Electron Electron Resonance (DEER) spectroscopy, we discovered that cell-passaged pathological seeds generate heterogeneous fibrils that are distinct between the CBD and PSP lysate-seeded fibrils. These fibrils are also distinct from heparin-induced tau fibril populations. Moreover, the lysate-seeded fibrils contain a characteristic sub-population that resembles the disease fold corresponding to the respective starting patient sample. These findings indicate that templated propagation using CBD and PSP patient-derived fibrils is possible with a tau fragment that does not contain the entire pathological fibril core, and that additional mechanisms must be tuned to converge to a homogeneous fibril population.

biophysics↗

bioRxiv2023

DrugGPT: A GPT-based Strategy for Designing Potential Ligands Targeting Specific Proteins

DrugGPT presents a ligand design strategy based on the autoregressive model, GPT, focusing on chemical space exploration and the discovery of ligands for specific proteins. Deep learning language models have shown significant potential in various domains including protein design and biomedical text analysis, providing strong support for the proposition of DrugGPT. In this study, we employ the DrugGPT model to learn a substantial amount of protein-ligand binding data, aiming to discover novel molecules that can bind with specific proteins. This strategy not only significantly improves the efficiency of ligand design but also offers a swift and effective avenue for the drug development process, bringing new possibilities to the pharmaceutical domain. In our research, we particularly optimized and trained the GPT-2 model to better adapt to the requirements of drug design. Given the characteristics of proteins and ligands, we redesigned the tokenizer using the BPE algorithm, abandoned the original tokenizer, and trained the GPT-2 model from scratch. This improvement enables DrugGPT to more accurately capture and understand the structural information and chemical rules of drug molecules. It also enhances its comprehension of binding information between proteins and ligands, thereby generating potentially active drug candidate molecules. Theoretically, DrugGPT has significant advantages. During the model training process, DrugGPT aims to maximize the conditional probability and employs the back-propagation algorithm for training, making the training process more stable and avoiding the Mode Collapse problem that may occur in Generative Adversarial Networks in drug design. Furthermore, the design philosophy of DrugGPT endows it with strong generalization capabilities, giving it the potential to adapt to different tasks. In conclusion, DrugGPT provides a forward-thinking and practical new approach to ligand design. By optimizing the tokenizer and retraining the GPT-2 model, the ligand design process becomes more direct and efficient. This not only reflects the theoretical advantages of DrugGPT but also reveals its potential applications in the drug development process, thereby opening new perspectives and possibilities in the pharmaceutical field.

bioinformatics↗

bioRxiv2023

Guanine-containing ssDNA and RNA induce dimeric and tetrameric SAMHD1 in cryo-EM and binding studies

The dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNA, and telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with [~]20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.

biochemistry↗

bioRxiv2023

A mutation-mediated host shift drives Avian paramyxovirus type 1 evolution

PPMV-1, an antigenic variant of APMV-1, associated with specific pigeon host species. However, its evolutionary strategy and underlying drivers of host specificity remain unknown. In this study, we collect the outbreak data on a global scale to investigate its evolutionary dynamics, and provide an evidence-supported analysis the host shift of PPMV-1 from chickens to pigeons, and this shift is driven by the P protein. Our data indicated that the viruses in the United States and China have undergone convergent evolution. We find that three mutations of P protein, especially R163G, can significantly affect the adaptation of APMV-1 in pigeons. Mechanistically, sensor LSm14A inhibits the replication APMV-1 in DF-1 cells, and R163G substitutionon P protein increase LSm14A degradation. We propose the host shift drive the evolution of PPMV-1 and the underlying mechanism, offering new insights into the adaptive evolutionary process of the virus.

microbiology↗

bioRxiv2023

Mutations in tau protein promote aggregation by favoring extended conformations

Amyloid aggregation of the intrinsically disordered protein (IDP) tau is involved in several diseases, called tauopathies. Mutations in the gene encoding tau are responsible for a class of inherited tauopathies called frontotemporal dementia and parkinsonism linked to chromosome 17Q (FTDP-17). These mutations are thought to trigger FTDP-17 by favoring the formation of tau amyloid fibrils. This work aims at deciphering the mechanisms through which the diseases-associated single point mutations promote amyloid formation. We combined biochemical characterization and small angle X-ray scattering (SAXS) to study six different FTDP-17 derived mutations. We found that the mutations promote aggregation to different degrees and can modulate tau conformational ensembles, intermolecular interactions and liquid-liquid phase separation propensity. In particular, we found a good correlation between the aggregation lag time of the mutants and their radius of gyration. We show that mutations disfavor intramolecular protein interactions which in turn favor extended conformations and promote amyloid aggregation. This work proposes a new connection between the structural features of tau monomers and their propensity to aggregate, providing a novel assay to evaluate aggregation propensity of tau variants.

biophysics↗

bioRxiv2023

MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation

Correlative evidence has suggested that DNA methylation promotes the formation of transcriptionally silent heterochromatin. Accordingly, the methyl-CpG binding domain protein MeCP2 is often portrayed as a constituent of heterochromatin. This interpretation has been reinforced by the use of mouse cells as an experimental system for studying the mammalian epigenome, as heterochromatin, DNA methylation and MeCP2 colocalise in prominent foci. The findings presented here revise this view. We show that focal localisation of MeCP2 in mice is independent of heterochromatin, as DNA methylation-dependent MeCP2 foci persist even when the signature heterochromatin histone mark H3K9me3 is absent and heterochromatin protein HP1 is diffuse. Contrary to the proposal that MeCP2 forms condensates at mouse heterochromatic foci via liquid-liquid phase transition, the short methyl-CpG binding domain, which lacks the disordered domains thought to be required for condensation, is sufficient to target foci in mouse cells. Importantly, we find that the formation of MeCP2 foci in mice is highly atypical, as they are indetectable in 14 out of 16 other mammalian species, including humans. Notably, MeCP2 foci are absent in Mus spretus which can interbreed with Mus musculus but lacks its highly methylated pericentric satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form nuclear condensates and its localisation is independent of heterochromatin formation. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns and is typically euchromatic.

cell biology↗

bioRxiv2023

An inverse agonist of orphan receptor GPR61 reveals a novel allosteric mechanism

GPR61 is a biogenic amine receptor-related orphan GPCR associated with phenotypes relating to appetite and thus, is of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study its structure and function. Here, we report the first ever structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its unprecedented allosteric site and mode of action. These findings offer key mechanistic insights into an orphan GPCR, while providing both a new structural framework and tool compound to support further studies of GPR61 function and modulation.

biophysics↗

bioRxiv2023

Selective effects of estradiol on human corneal endothelial cells

Fuchs endothelial corneal dystrophy (FECD) results from genetic and environmental factors triggering mitochondrial and oxidative stress in corneal endothelial cells (CEnCs) leading to CEnC death and corneal opacification. FECD is more common in women than men, but the basis for this observation is unknown. Because FECD is commonly diagnosed around the time of the menopausal transition in women when estrogen levels decrease precipitously, we studied the effects of the potent estrogen,17-{beta} estradiol (E2) on growth, oxidative stress, and metabolism in primary cultures of human CEnCs (HCEnCs) under conditions of physiologic 2.5% O2 ([O2]2.5) and under hyperoxic stress ([O2]A: room air + 5% CO2). We hypothesized that E2 would counter the stresses of the hyperoxic environment in HCEnCs. HCEnCs were treated {+/-} 10 nM E2 for 7-10 days at [O2]2.5 and [O2]A followed by measurements of cell density, viability, reactive oxygen species (ROS), mitochondrial morphology, oxidative DNA damage, ATP levels, mitochondrial respiration (O2 consumption rate [OCR]), and glycolysis (extracellular acidification rate [ECAR]). There were no significant changes in HCEnC density, viability, ROS levels, oxidative DNA damage, OCR, and ECAR in response to E2 under either O2 condition. We found that E2 disrupted mitochondrial morphology in HCEnCs from female donors but not male donors at the [O2]A condition. ATP levels were significantly higher at [O2]2.5 compared to [O2]A in HCEnCs from female donors only, but were not affected by E2. Our findings demonstrate the overall resilience of primary HCEnCs against hyperoxic stress. The selective detrimental effects of hyperoxia and estradiol on HCEnCs from female but not male donors suggests mechanisms of toxicity based upon cell-sex in addition to hormonal environment.

cell biology↗

bioRxiv2023

Behavior-relevant top-down cross-modal predictions in mouse neocortex

Animals rely on predicting their environment and the consequences of their actions to adapt to a constantly changing world. The predictive coding hypothesis proposes that the brain generates predictions and continuously compares them with bottom-up sensory inputs to guide behavior. However, how the brain reconciles conflicting top-down predictions and bottom-up sensory information during behavior remains unclear. To address this question, we simultaneously imaged neuronal populations in the mouse somatosensory cortex and the posterior parietal cortex during an auditory-cued texture discrimination task. After mice learnt the task with fixed tone-texture matching, mismatched pairing caused conflicting tone-based texture predictions and actual texture inputs. When top-down interaction was dominant, texture representations in both areas were modified and mice decided based on the predicted rather than actual texture, whereas dominant bottom-up interaction corrected the representations as well as behavioral choice. Our findings provide evidence for hierarchical predictive coding in the mouse neocortex and open new avenues for understanding higher cognitive functions.

neuroscience↗

bioRxiv2023

Genetic and environmental contributions to ancestry differences in gene expression in the human brain

Ancestral differences in genomic variation are determining factors in gene regulation; however, most gene expression studies have been limited to European ancestry samples or adjusted for ancestry to identify ancestry-independent associations. We instead examined the impact of genetic ancestry on gene expression and DNA methylation (DNAm) in admixed African/Black American neurotypical individuals to untangle effects of genetic and environmental factors. Ancestry-associated differentially expressed genes (DEGs), transcripts, and gene networks, while notably not implicating neurons, are enriched for genes related to immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinsons disease, and 30% of heritability for Alzhemiers disease. Ancestry-associated DEGs also show general enrichment for heritability of diverse immune-related traits but depletion for psychiatric-related traits. The cell-type enrichments and direction of effects vary by brain region. These DEGs are less evolutionarily constrained and are largely explained by genetic variations; roughly 15% are predicted by DNAm variation implicating environmental exposures. We also compared Black and White Americans, confirming most of these ancestry-associated DEGs. Our results highlight how environment and genetic background affect genetic ancestry differences in gene expression in the human brain and affect risk for brain illness. SummaryWe examine the impact of genetic ancestry on gene expression and DNA methylation of admixed African/Black Americans, highlighting how genetic and environmental background affect risk for brain illness.

genetics↗