Granata J et al., PNAS - In mESCs and defined in vitro assays, EPOP and MTF2 stimulate PRC2 methyltransferase activity and promote de novo H3K27me3 deposition with GA- or GCN-rich DNA preference.

Study Highlights:
The study used mouse embryonic stem cells with an EED-rescue system and recombinant in vitro assays including HMT assays, EMSA, and ChIP-seq to probe EPOP and MTF2 function. Biochemical HMT assays on oligonucleosomes and dinucleosomes show both EPOP and MTF2 directly stimulate PRC2 catalytic activity, with MTF2 preferentially enhancing activity and binding on GCN-rich linkers and EPOP on GA-rich linkers. ChIP-seq during EED rescue demonstrated that EPOP is dispensable for initial PRC2 recruitment but its knockout reduces de novo H3K27me3 deposition by ~50% and cooperates with MTF2 and JARID2. Together these data indicate linker DNA sequence within nucleation sites guides subcomplex-specific PRC2 binding and catalytic output, influencing spatial establishment of H3K27me3 domains.

Conclusion:
EPOP and MTF2 define distinct PRC2 subcomplexes that stimulate PRC2 catalytic activity in a chromatin-dependent, DNA-sequence-specific manner to direct de novo H3K27me3 deposition.

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Reference:
Granata J., Liu S., Popoca L., Oksuz O., Reinberg D. EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2527303123. https://doi.org/10.1073/pnas.2527303123

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Larsen BB et al., PNAS - Deep mutational scanning of the Nipah virus fusion protein F using pseudoviruses maps ~8,500 single-residue effects, showing F is highly constrained and identifying antibody-escape mutations.

Study Highlights:
Using nonreplicative lentiviral pseudoviruses and deep mutational scanning, the authors measured the effects of 8,449 single amino-acid mutations to the Nipah virus F ectodomain on cell entry in CHO cells expressing bat ephrin-B3. Measurements were fit with global epistasis models and mapped onto prefusion and postfusion structures, revealing the fusion peptide, lateral surface patches, and hexameric-interface residues are highly constrained. The library was screened against six monoclonal antibodies, quantifying mutation-mediated decreases in neutralization and showing distinct resilience among antibodies; specific Hendra F residues (Q70K, R336K) explained loss or reduction of neutralization by 4H3 and 1A9. The data nominate candidate proline substitutions and other sites for prefusion stabilization and inform vaccine and therapeutic antibody selection.

Conclusion:
Nipah virus F is highly functionally constrained relative to RBP with specific surface-exposed and core residues critical for cell entry, and antibody neutralization varies by epitope, informing prefusion-stabilized immunogen and therapeutic antibody design.

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Reference:
Larsen BB, Harari S, Gen R, Stewart C, Veesler D, Bloom JD. Functional and antigenic constraints on the Nipah virus fusion protein. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2529505123. https://doi.org/10.1073/pnas.2529505123

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Berazategui MA et al., PNAS - ESBX (Tb927.3.1660) links RNA Pol I localization at the ESB to activation of the active BES and repression of inactive BESs in Trypanosoma brucei, supporting monoallelic VSG expression.

Study Highlights:
Using ESB1-guided proximity-dependent biotinylation proteomics, endogenous tagging and high-resolution fluorescence microscopy, RNAi knockdown, RNA-seq, and inducible overexpression in bloodstream-form Trypanosoma brucei, the authors identify Tb927.3.1660 (ESBX) as an ESB-specific protein. ESBX localizes adjacent to Pol I (RPA2) and ESB1 within the ESB with measured center separations of ~68–175 nm and contains predicted SUMO-interacting and BRCT domains. ESBX depletion causes loss of the extranucleolar Pol I ESB focus, reduced processive transcription from the active BES with larger decreases distal to the promoter, and derepression of inactive BESs with low-processivity transcripts, whereas ESBX overexpression weakly activates inactive BESs with processive transcription without forming extra ESBs. Together the data indicate ESBX integrates activation of the active BES with repression of inactive BESs, a mechanism that supports monoallelic VSG expression.

Conclusion:
Tb927.3.1660/ESBX is an ESB component required to integrate activation of the active BES with repression of inactive BESs, thereby supporting monoallelic VSG expression in bloodstream-form Trypanosoma brucei.

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Reference:
Berazategui MA, Wheeler RJ, Tiengwe C, Lansink LIM, Rudenko G, Sunter JD, Goodwin I, Gull K, Faria JRC, et al. A factor integrating transcription and repression of surface antigen genes in African trypanosomes. Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2531377123. https://doi.org/10.1073/pnas.2531377123

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Solomon CU et al., Nat Commun ( - Integrative analysis in human VSMCs identifies pleiotropic genes including FES that regulate vascular remodeling; pooled CRISPR and mouse knockout show FES loss increases MMPs, atherosclerosis and blood pressure.

Study Highlights:
The study used a large human umbilical cord‑derived VSMC eQTL bank (n=1,486) combined with colocalization (eCAVIAR, SMR/HEIDI), ATAC‑seq, DNA methylation, H3K27ac HiChIP and pooled CRISPR‑Cas9 knockout screens to nominate likely causal genes for CAD, hypertension, stroke and AAA. Pooled CRISPR screens and siRNA validation in VSMCs highlighted BCAR1, CARF, SMARCA4 and FES as modulators of VSMC proliferation or migration, while FES knockdown increased MMP1/MMP3, reduced contractile markers and promoted migration by RNA‑seq and proteomics/phosphoproteomics. In vivo, Fes‑/-/Apoe‑/- mice had larger en face aortic lesion areas (8.34±2.54% vs 6.06±2.35%, P=0.013) and higher baseline systolic/diastolic blood pressure (104.4±6.7 vs 88.0±10.1 mmHg and 74.9±9.0 vs 58.8±8.9 mmHg, P=0.042). These results support FES as a pleiotropic, potentially druggable regulator of VSMC phenotype with functional effects on atherosclerosis and blood pressure.

Conclusion:
Integrative functional genomics implicates panels of likely causal and pleiotropic genes, including FES, that regulate VSMC behavior and whose loss promotes VSMC dedifferentiation, increased MMP production, larger atherosclerotic lesions and higher blood pressure.

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Reference:
Solomon CU, McVey DG, Andreadi C, Peng G, Turner L, Song DSS, Zhang H, Lee DP, Karamanavi E, Yang W, Chu J, Chen R, Haworth KE, Anene-Nzelu CG, Li H, Denniff MJ, Li PY, Zhang Y, Huang X, Morris GE, Greer PA, Stringer EJ, Yu H, Foo RSY, Douglas G, Samani NJ, Webb TR, Ye S. Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69273-8

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Ramírez Renta GM et al., The American Journal of Human Genetics - GALS survey of >4,000 US respondents (GenPop and SPARK) shows confidence in genetic knowledge predicts Familiarity, Knowledge, and Skills, explaining ~25% of variance.

Study Highlights:
Using the Genetic and Autism Literacy Survey (GALS) in two US samples (GenPop and SPARK; n>4,000), the authors measured three genetic literacy components: Familiarity, Knowledge, and Skills via subjective familiarity ratings, objective true/false items, and a comprehension task. They modeled associations between these subscales and identity/belief measures including perceived importance, confidence, religiosity, religious affiliation, and political belief using linear regression adjusted for education and population. Confidence in one’s genetic knowledge was the strongest predictor, accounting for roughly 25% of variance in Familiarity and Knowledge and substantially improving model R2; perceived importance had a positive but smaller effect while religious and political measures showed mixed associations. The finding implies improving individuals’ confidence in genetic knowledge, alongside tailored communication strategies, could support better comprehension and uptake of genetics and genomics services.

Conclusion:
Confidence in one’s genetic knowledge, after education, is the largest modifiable predictor of genetic literacy and should be a focus for interventions to improve comprehension and uptake of genetics services.

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Reference:
Ramírez Renta GM, Little ID, Koehly LM, et al. Interaction of identity and beliefs with genetic literacy. The American Journal of Human Genetics. 2026;113:16–28. https://doi.org/10.1016/j.ajhg.2025.11.014

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Episode link: https://basebybase.com/?episode=283-confidence-in-genetic-knowledge-drives-familiarity-knowl-17ljvj2

Liang Y et al., The American Journal of Human Genetics. 113 ( - TWAS using genetically predicted expression exhibit polygenicity-driven inflation that increases with GWAS sample size and heritability; a gene-specific variance-control correction yields calibrated p values.

Study Highlights:
The authors evaluated TWAS and related xWAS using simulated polygenic null traits and UK Biobank genotypes with predicted mediators including gene expression, metabolites, and brain features. They combined large-scale simulations, theoretical derivations, and empirical regression of mean Z2 on N*h2δ to estimate a gene-specific inflation slope Φ and applied corrections with S‑PrediXcan/PrediXcan across 110 GWAS traits. They show analytically and empirically that Var(Z) ≈ 1 + N*h2δ*Φ, observe a cohort-level slope around 4.2×10^-5, and demonstrate that dividing Z by sqrt(1+N*h2δ*Φ) restores calibration. Applying the variance-control correction yields well-calibrated p values, reduces false positives for highly polygenic traits, and improves precision with minimal loss of power.

Conclusion:
A gene-specific variance-control correction based on an empirically estimated inflation slope Φ corrects polygenicity-driven inflation in TWAS/xWAS and yields calibrated false-positive rates in simulations and real GWAS analyses.

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Reference:
Liang Y, Nyasimi F, Im HK. A gene-specific variance-control approach corrects polygenicity-driven inflation observed in transcriptome-wide association studies. The American Journal of Human Genetics. 113 (2026) 276-290. https://doi.org/10.1016/j.ajhg.2025.12.014

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Di Donato N et al., The American Journal of Human Genetics. 113:324-341 ( - Analysis of 290 individuals with ACTB and ACTG1 variants defines eight distinct non-muscle actinopathies and links BWCFF-causing variants to altered actin polymerization dynamics.

Study Highlights:
The study assembled a clinical-genomic cohort of 290 individuals with P/LP ACTB or ACTG1 variants and used expert phenotyping plus GestaltMatcher facial analysis to delineate eight distinct non-muscle actinopathies. Complementary methods included patient-derived fibroblast transcriptomics, recombinant actin production, differential scanning fluorimetry, and pyrene-based polymerization/depolymerization assays. BWCFF-associated missense variants (e.g., ACTB:R196H, ACTG1:T203M) produced decreased polymerization rates and faster depolymerization, whereas selected ACTB missense or in-frame variants impaired folding or thermal stability consistent with loss-of-function. These mechanistic stratifications support improved diagnostic classification, prognostication, and selection of functional assays for variant interpretation.

Conclusion:
Variant-level analysis of 290 individuals delineates eight distinct non-muscle actinopathies and shows that BWCFF-linked missense variants disrupt actin polymerization while select ACTB variants cause protein instability consistent with loss-of-function.

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Reference:
Di Donato N, NMA Consortium, et al. Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies. The American Journal of Human Genetics. 113:324-341 (2026). https://doi.org/10.1016/j.ajhg.2025.12.007

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Yan X et al., The American Journal of Human Genetics, Corrected proof - In 569 TwinsUK subcutaneous adipose biopsies, twin models and GWAS identify SCD, FADS and 3p25.2 (PPARG) loci regulating fatty acid levels and conversions.

Study Highlights:
System and sample: 569 female TwinsUK subcutaneous adipose biopsies with matched serum, RNA-seq and 450K methylation data were analyzed. Key methods: gas chromatography fatty acid profiling, ACE twin heritability models, GWAS of 18 fatty acids and 15 product-to-precursor ratios, colocalization with adipose eQTLs and meQTLs, and polygenic score analysis. Main quantitative results: heritability of individual fatty acids ranged from 5%–59% while 15 fatty acid ratios were heritable and GWAS identified 10 genome-wide significant loci including SCD and FADS with the SCD lead variant explaining ~7–11% of variance and ratios showing heritability up to ~54%. Functional implication: colocalizations with adipose-specific eQTLs and meQTLs and associations between metabolic polygenic scores and fatty acid levels link local genetic regulation in adipose tissue to renal and cardio-metabolic phenotypes.

Conclusion:
Local genetic variation in adipose tissue, including SCD, FADS and a 3p25.2 locus near PPARG, regulates fatty acid composition and conversion and is connected to renal and cardio-metabolic traits.

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Reference:
Yan X., Roberts A.L., El-Sayed Moustafa J.S., Villicaña S., Al-Hilal M., Tomlinson M., Menni C., Sanders T.A.B., Freidin M.B., Bell J.T., Small K.S., Genetic regulation of fatty acid content in adipose tissue. The American Journal of Human Genetics 113, 1–18, February 5, 2026. https://doi.org/10.1016/j.ajhg.2025.12.008

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