Base by Base

️ Episode 198: Mechanical Confinement and the Shape-Shifting Life of Melanoma Cells In this episode of PaperCast Base by Base, we explore how physical forces in the tumor microenvironment can push melanoma cells to switch from a pigment-producing, proliferative state into an invasive, drug-tolerant one, focusing on new work that links mechanical confinement, chromatin remodeling, and neuronal-like programs in cancer. Study Highlights:Using a zebrafish model of BRAFV600E-driven melanoma together with human tumor samples and single-cell transcriptomics, the authors identify a subpopulation of tumor cells at the tumor–microenvironment interface that displays elongated nuclei and a gene expression program resembling undifferentiated, neuron-like cells. In vitro confinement of human melanoma cells under a polydimethylsiloxane piston recapitulates this interface state, triggering assembly of a perinuclear cage of acetylated microtubules that protects the nucleus from mechanical stress. Mechanical confinement selectively upregulates the chromatin-bending protein HMGB2, whose increased residence time on chromatin opens neuronal and invasive gene loci and engages pathways such as Notch and BRN2 that drive a switch toward an invasive phenotype. Genetic disruption of HMGB2 in zebrafish melanomas and human melanoma cells shifts the balance back toward proliferation with larger but less invasive tumors, whereas HMGB2 overexpression enhances invasion and tolerance to BRAF and MEK inhibition in mouse xenografts. Conclusion:Mechanical confinement within the tumor microenvironment can rewire melanoma cells through HMGB2-dependent chromatin remodeling to favor an invasive, neuronal-like and drug-tolerant state over purely proliferative growth. Music:Enjoy the music based on this article at the end of the episode. Reference:Hunter MV, Joshi E, Bowker S, Montal E, Ma Y, Kim YH, Yang Z, Tuffery L, Li Z, Rosiek E, Browning A, Moncada R, Yanai I, Byrne H, Monetti M, de Stanchina E, Hamard P-J, Koche RP, White RM. Mechanical confinement governs phenotypic plasticity in melanoma. Nature. 2025;647:517–527. https://doi.org/10.1038/s41586-025-09445-6 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official websiteBase by Base – https://basebybase.com/ On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 163: Animal origins: looping back in time In this episode of PaperCast Base by Base, we explore how chromatin folding mechanisms emerged alongside animal evolution, focusing on a Spotlight article that synthesizes high-resolution 3D genome maps across unicellular relatives of animals and early-branching metazoans to probe when enhancer–promoter looping first appeared. Study Highlights:This Spotlight reviews evidence from micro-C datasets spanning ichthyosporeans, filastereans, choanoflagellates, sponges, ctenophores, placozoans, and cnidarians, showing that broad A/B-like chromatin compartments and, crucially, enhancer–promoter chromatin loops are features that arise within animals rather than in their unicellular relatives. It emphasizes that loops are readily detected in early metazoans such as ctenophores, placozoans, and cnidarians, while sponges show weaker or absent looping signals, hinting at lineage-specific trajectories or possible secondary loss. The article highlights unusual promoter hubs in placozoans, where hundreds of transcription start sites cluster, potentially coordinating housekeeping expression programs. Mechanistically, ctenophores appear to use abundant C2H2 zinc-finger proteins that bind unmethylated motifs at loop anchors, suggesting alternative loop-formation strategies distinct from the CTCF-driven loop extrusion and insulated TAD architecture characterized in vertebrates. Together, these observations argue that chromatin loops emerged with complex gene regulation in animals and diversified across lineages instead of following a single universal mechanism. Conclusion:Chromatin looping likely originated at the dawn of animal life and diversified across lineages, underpinning the rise of complex gene regulation before the canonical, CTCF-insulated TAD architecture seen in many bilaterians. Reference:Matar, O., & Marlétaz, F. (2025). Animal origins: looping back in time. Trends in Genetics. https://doi.org/10.1016/j.tig.2025.06.013 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Episode Slug: animal-origins-looping-back-in-time Keywords: chromatin loops; animal evolution; Micro-C; ctenophores; enhancer–promoter interactions

Strand LG et al., PNAS - In C. elegans germline, the deubiquitinase DUO-1 is required for assembly and active maintenance of the synaptonemal complex and REC-8 cohesin, preventing RAD-51 accumulation and ensuring diakinesis compaction. Study Highlights:Using C. elegans germline as a developmental timecourse model, the authors combined cytological analyses (immunofluorescence, FISH, RAD-51/MSH-5/COSA-1 staining), temporally controlled auxin-inducible degron (AID) depletion, and TurboID proximity labeling with LC–MS to probe DUO-1 function. Loss or acute depletion of DUO-1 impairs SC assembly, leads to progressive axis/SC instability, depletion of REC-8 cohesin from chromosomes, hyperaccumulation of RAD-51-marked early DSB repair intermediates, and premature sister-chromatid separation. TurboID identifies PARG-1 and cohesin/HORMAD components as proximal partners and DUO-1::GFP localizes to nucleoplasm and a subset of chromosome axes, most prominently in late pachytene/early diplotene. Temporal AID experiments show DUO-1 is required continuously for early SC assembly, late-pachytene SC maintenance, and rapid preservation of diakinesis chromosome compaction, implying an active maintenance role for DUO-1 in preserving chromosome architecture during meiotic prophase. Conclusion:DUO-1 is continuously required throughout meiotic prophase in C. elegans to promote assembly and maintain stability of chromosome axes and synaptonemal complexes, protect REC-8 cohesin distribution, limit accumulation of early DSB repair intermediates, and ensure late-prophase chromosome compaction. Music:Enjoy the music based on this article at the end of the episode. Reference:Strand LG, Choi CP, McCoy S, Nsamba ET, Silva N, Villeneuve AM. Active maintenance of meiosis-specific chromosome structures in Caenorhabditis elegans by the deubiquitinase DUO-1. Proc. Natl. Acad. Sci. U.S.A. 2026;123(12):e2532671123. https://doi.org/10.1073/pnas.2532671123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/duo-1-c-elegans-meiosis Chapters (00:00:00) - The architectural worksite of life(00:05:24) - The genetic disaster of Meotic mutants(00:10:49) - The Duplicity of Probes(00:16:29) - How does DNA repair become so fragile as we grow?

Lawrence et al., Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants. The American Journal of Human Genetics 113 - Using a cis-principal-component (pcQTL) approach in human GTEx tissues, the authors uncover novel multi-gene regulatory variants and 33% more GWAS colocalizations than single-gene eQTLs. Study Highlights:The study analyzes 13 human GTEx tissues and identifies clusters of co-expressed neighboring genes, then applies PCA to cluster expression and maps cis-principal-component QTLs (pcQTLs). pcQTL discovery and fine-mapping used SuSiE and TensorQTL permutation-based FDR to identify an average of ~1,396 pcQTLs per tissue, ~27% of which were not found by single-gene eQTL mapping. pcQTLs tend to represent smaller effects distributed across multiple genes in a cluster and often colocalize with GWAS hits missed by single-gene methods. Functionally, pcQTLs increased GWAS colocalizations by 33%, highlighting multi-gene regulatory proxitropy as a source of complex-trait-associated variation. Conclusion:Cis-multi-gene pcQTL mapping uncovers novel regulatory loci and increases GWAS colocalizations compared with single-gene analyses, demonstrating that multi-gene approaches improve detection and interpretation of complex-trait-associated variants. Music:Enjoy the music based on this article at the end of the episode. Reference:Lawrence, K.A., Gjorgjieva, T., Nachun, D., and Montgomery, S.B. (2026). Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants. The American Journal of Human Genetics 113, 1–10. https://doi.org/10.1016/j.ajhg.2026.02.022 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cis-pcqtl-allelic-proxitropy-gtex Chapters (00:00:00) - Deep Dive: The genome's interconnected networks(00:05:27) - The Shared Signal of Genomic Science(00:11:15) - Single gene mapping fails to explain complex traits(00:18:13) - Understanding the genetics of human diseases(00:20:39) - Beyond one gene

Farnung J et al., The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation. Nature ( - Cryo-EM and biochemical reconstitution reveal how the ZSWIM8–CUL3 E3 ligase recognizes human AGO2–miRNA–trigger complexes to polyubiquitylate AGO and drive targeted microRNA degradation. Study Highlights:Using purified human proteins and cellular assays, the authors combined cryo-EM (3.1 Å), in vitro ubiquitylation, co-immunoprecipitation and sRNA-seq to dissect TDMD. Cryo-EM shows a dimeric ZSWIM8 that forms an asymmetric clamp around AGO2–miR-7–CYRANO, engaging the MID, N and PAZ domains and embracing trigger RNA flanks. Biochemical reconstitution demonstrates that ZSWIM8–CUL3 together with ARIH1 polyubiquitylates surface lysines of AGO only when the miRNA is paired to a trigger that vacates the PAZ pocket and imposes a specific RNA trajectory. Functionally, these multivalent RNA–RNA, RNA–protein and protein–protein interactions establish a two-RNA-factor authentication mechanism that explains TDMD selectivity and indicates ZSWIM8 can destabilize extensively trimmed miRNAs. Conclusion:ZSWIM8–CUL3 recognizes a trigger-induced AGO–miRNA conformation via multivalent interactions—including sensing a vacated PAZ pocket and flanking trigger RNA—to direct ARIH1-dependent polyubiquitylation of AGO and execute TDMD. Music:Enjoy the music based on this article at the end of the episode. Reference:Farnung J., Slobodyanyuk E., Wang P.Y., Blodgett L.W., Lin D.H., von Gronau S., Schulman B.A. & Bartel D.P. The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation. Nature (2026). https://doi.org/10.1038/s41586-026-10232-0 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/zswim8-cul3-tdmd-structure Chapters (00:00:12) - The Papercast(00:00:28) - A single molecular assassin(00:01:34) - The cell's ubiquitin murder(00:06:47) - How the CL3 box manipulates the ZS1 protein(00:11:36) - The ZSMATE hitman

Norgren J et al., JAMA Network Open - Population-based SNAC-K study finds higher meat consumption associated with slower cognitive decline and lower dementia risk in APOE ε3/ε4 and ε4/ε4 older adults. Study Highlights:Using the Swedish National Study on Aging and Care–Kungsholmen (SNAC-K) cohort of older adults and repeated validated food-frequency questionnaires, the authors applied panel data analyses with linear regression for cognitive trajectories and Fine and Gray models for dementia incidence. Higher total meat consumption (top vs bottom quintile) in APOE ε3/ε4 and ε4/ε4 participants was associated with better 10-year global cognitive trajectories (β = 0.32) and lower dementia risk (sHR = 0.45). The processed-to-total meat ratio was associated with higher dementia risk (sHR = 1.14) without APOE interaction. Post hoc vitamin B12 analyses suggested APOE-specific differences in nutrient uptake that could help explain the genotype-specific associations. Conclusion:Higher meat consumption was associated with slower cognitive decline and reduced dementia incidence among APOE ε3/ε4 and ε4/ε4 carriers, such that the expected excess risk in these genotypes was not observed at high intake levels. Music:Enjoy the music based on this article at the end of the episode. Reference:Norgren J, Carballo-Casla A, Grande G, et al. Meat Consumption and Cognitive Health by APOE Genotype. JAMA Network Open. 2026;9(3):e266489. https://doi.org/10.1001/jamanetworkopen.2026.6489 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/meat-apoe34-44-cognition Chapters (00:00:00) - A genetic flag for Alzheimer's disease?(00:05:33) - APOE4 genetic risk of dementia(00:11:30) - APOE4 Genotype and the Food Matrix

Johnson MB et al., The American Journal of Human Genetics - Bi-allelic variants in snRNAs RNU6ATAC and RNU4ATAC cause infancy-onset autoimmune diabetes in humans, with RNA-seq showing U12 intron retention and impaired B cell development. Study Highlights:In human infants with early-onset diabetes and immune dysregulation, the authors used genome sequencing, RNA-seq, DNA methylation deconvolution, WGCNA, Sanger sequencing, and flow cytometry to define a genetic syndrome. They identified 19 individuals with bi-allelic RNU6ATAC or RNU4ATAC variants and RNA-seq revealed significant U12 intron retention in 274 genes, 94% of which are known U12-intron-containing genes. Multi-omic analyses and targeted immune profiling showed reduced naive B cells and abnormal B cell maturation. Half of tested individuals were GADA-positive, supporting an autoimmune mechanism for the diabetes in these snRNA spliceosome disorders. Conclusion:Bi-allelic pathogenic variants in RNU6ATAC cause early-onset autoimmune diabetes with immune dysregulation and bi-allelic RNU4ATAC variants extend RNU4ATAC-opathy to include infancy-onset autoimmune diabetes. Music:Enjoy the music based on this article at the end of the episode. Reference:Johnson MB, Russ-Silsby J, Blair PA, Govier M, Bonfield G, Domingo-Vila C, EXE-T1D consortium, ATAC clinical consortium, Wakeling MN, Oram RA, Flanagan SE, Tree TIM, Patel KA, Hattersley AT, De Franco E. Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes. The American Journal of Human Genetics. 2026 Apr 2;113:1–11. https://doi.org/10.1016/j.ajhg.2026.02.017 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/rnu6atac-rnu4atac-minor-spliceosome Chapters (00:00:11) - The dark matter of human genetics(00:06:06) - Common mutations in the RNU4ATAK gene cause diabetes(00:12:50) - The genetics of autoimmune diabetes

Koga T et al., et al. A complete set of canonical nucleobases in the carbonaceous asteroid (162173) Ryugu. Nature Astronomy ( - Ryugu asteroid samples analyzed by HPLC/ESI-HRMS reveal all five canonical nucleobases (adenine, guanine, cytosine, thymine, uracil) and distribution linked to ammonia. Study Highlights:The team analysed Ryugu aggregate samples A0480 and C0370 and the Orgueil meteorite using water and HCl extraction followed by HPLC/ESI-HRMS, CE-HRMS and nano-EA/IRMS. They identified all five canonical nucleobases and measured total nucleobase concentrations (C0370 = 1,577 pmol g−1) and purine-to-pyrimidine (Pu/Py) ratios of ~1.1–1.2 in Ryugu contrasted with 0.099 in Orgueil and 3.4 in Murchison. A strong negative correlation (R2=0.89) between Pu/Py ratios and ammonia across Ryugu, Bennu and Orgueil implies ammonia availability influenced nucleobase formation pathways. The results support widespread abiotic nucleobase synthesis in carbonaceous parent bodies and potential delivery of diverse prebiotic molecules to early Earth. Conclusion:All five canonical nucleobases are present in Ryugu samples and their purine-to-pyrimidine distributions, which correlate with ammonia, indicate shared but environment-dependent formation pathways on carbonaceous parent bodies. Music:Enjoy the music based on this article at the end of the episode. Reference:Koga T., Ogawa N. O., Ohkouchi N., Oba Y., Takano Y., Naraoka H., Sasaki K., Sato H., Yoshimura T. et al. A complete set of canonical nucleobases in the carbonaceous asteroid (162173) Ryugu. Nature Astronomy (2026). https://doi.org/10.1038/s41550-026-02791-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ryugu-nucleobases-ammonia-correlation Chapters (00:00:00) - Decoding the cosmic delivery of life(00:03:18) - The Ryugu Meteorite(00:08:52) - The Prebiotic grocery list of Earth(00:14:13) - The structure of DNA in the asteroid(00:15:38) - The Search for Life on Earth(00:21:26) - What Does This All Mean for Life?(00:26:39) - Falling Into You

Amour C et al., Human Genetics and Genomics Advances, Journal Pre-proof - Sex-stratified cQTL mapping in Tanzanian and Dutch adults identifies sex-specific regulators such as TOX-linked IFN-γ in males and EGFR-linked IL-10 in females, revealing multiple genome-wide cQTLs. Study Highlights:The study analyzed cytokine production after ex vivo stimulation in two human cohorts (Tanzania 300TZFG and Dutch 500FG) using sex-stratified cytokine QTL mapping with linear models adjusted for cell counts and covariates. Genotyping, imputation, ELISA cytokine assays, colocalization (coloc) and SNP×sex interaction tests were applied to test sex-specific genetic effects. The authors report twelve genome-wide significant cQTLs in the Tanzanian cohort (seven male-specific, five female-specific) and twelve in the Dutch cohort with multiple sex-specific loci, highlighting TOX-associated IFN-γ regulation in males and EGFR-linked IL-10 regulation in females. These sex-specific autosomal effects altered which associations were detectable in pooled analyses, implying implications for sex-aware precision approaches to immune-related diseases. Conclusion:Sex-stratified autosomal analyses identify distinct genetic regulators of cytokine production, demonstrating that many cQTLs act in a sex-specific manner across Tanzanian and Dutch cohorts and can be missed by pooled analyses. Music:Enjoy the music based on this article at the end of the episode. Reference:Amour C, Cetatean R, Ponce IR, Keur N, Temba GS, Kullaya VI, Mmbaga BT, Kavishe R, Joosten LAB, Netea MG, de Mast Q, Boahen CK, Kumar V, Sex-stratified genetic regulators of cytokine production in the Dutch and Tanzanian populations, Human Genetics and Genomics Advances (2026), doi: https://doi.org/10.1016/j.xhgg.2026.100593. License:Not specified in the provided text. Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/sex-stratified-cytokine-qtl

Fortuno C et al., Human Genetics and Genomics Advances - TP53 germline variant analysis using functional assays finds reduced-penetrance variants have intermediate activity, higher frequency, later onset, and 106 predicted candidates. Study Highlights:Using ClinVar curation and comparison to benign and pathogenic reference sets, the authors analyzed TP53 germline variants with multiple functional assays, bioinformatic predictors, immune-fitness scores, and gnomAD frequencies. Reduced-penetrance variants tended to show intermediate activity across Kato, Giacomelli, Kotler, and Funk assays and intermediate BayesDel/AlphaMissense/aGVGD scores, with higher allele frequencies than pathogenic variants. A random forest model trained on these features prioritized 106 additional ClinVar missense variants as potential reduced-penetrance candidates. Clinically, carriers of reduced-penetrance variants exhibited later average age at first cancer and weaker enrichment for core Li-Fraumeni phenotypes, supporting consideration of attenuated surveillance criteria. Conclusion:Reported reduced-penetrance TP53 variants display intermediate functional and bioinformatic signatures, higher population frequency, and later cancer onset, and a combined-feature predictive model identifies additional candidate reduced-penetrance variants for follow-up. Music:Enjoy the music based on this article at the end of the episode. Reference:Fortuno C, Richardson ME, Pesaran T, McGoldrick K, James PA, Spurdle AB. Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53. Human Genetics and Genomics Advances. 2025;6:100484. https://doi.org/10.1016/j.xhgg.2025.100484 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/tp53-reduced-penetrance-prediction

Mendez R et al., Human Genetics and Genomics Advances, Journal Pre-proof - Biallelic RNU6ATAC variants disrupt the U6atac minor spliceosomal snRNA, causing transcriptome-wide minor intron retention and short stature with variable multisystem manifestations. Study Highlights:This study analyzed three unrelated human individuals using RNA-seq on whole-blood and fibroblasts and applied a FRASER-based minor intron retention (MIR) outlier pipeline alongside whole-genome sequencing. The integrated approach identified biallelic RNU6ATAC variants that map to U4atac–U6atac Stem I/II and the central stem-loop of U6atac. Affected individuals show transcriptome-wide excess MIR (for example A1 exhibited 254 MIR outliers in whole blood and B1 exhibited 16 MIR outliers in fibroblasts), indicating impaired minor spliceosome function. The molecular defect correlates with impaired growth and variable multisystem phenotypes including immunodeficiency and neurodevelopmental involvement. Conclusion:Biallelic RNU6ATAC variants cause a multisystem minor spliceopathy defined by transcriptome-wide minor intron retention and variable short stature, immunologic, and neurodevelopmental manifestations. Music:Enjoy the music based on this article at the end of the episode. Reference:Mendez R, Arriaga TM, Ma J, Bonner DE, Emami S, Levy RJ, Alsagheir A, Alhaddad B, Bakur K, Ungar RA, Matalon DR, Miller AM, Nguyen J, Smith KS, Scott SA, Liao L, Ng Z, Marwaha S, Ward A, Undiagnosed Diseases Network, Genomics Research to Elucidate the Genetics of Rare Diseases Consortium, Novacic D, Alkuraya FS, Bernstein JA, Ganesh VS, O’Donnell-Luria A, Montgomery SB, Wheeler MT, Biallelic Variants in RNU6ATAC Result in a Minor Spliceopathy Characterized by Transcriptome-Wide Minor Intron Retention Events and Short Stature with Variable Multisystem Manifestations, Human Genetics and Genomics Advances (2026), doi: https://doi.org/10.1016/j.xhgg.2026.100588 License:Not specified in the provided text. Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/rnu6atac-minor-spliceopathy

Saferali A et al., Human Genetics and Genomics Advances - RNA-seq in human lung (LTRC) and blood (COPDGene) reveals COPD-associated variants colocalize with splicing QTLs, implicating FBXO38 cryptic exon NMD and BTC exon4 isoform shifts. Study Highlights:The study analyzed RNA-seq from COPDGene whole blood (n≈3,743) and LTRC lung tissue (n=1,241) using LeafCutter for splicing and tensorQTL for cis associations, followed by Moloc colocalization and targeted Oxford Nanopore long-read sequencing. Authors identified 58,258 lung splice sites and widespread eQTLs/sQTLs, and found 38 genomic windows (corresponding to 33 GWAS loci) with strong colocalization between QTLs and COPD GWAS signals. Top colocalizations in lung sQTLs included NPNT, FBXO38, HHIP, NTN4, and BTC, and long-read data resolved isoform changes for FBXO38 and BTC. Functionally, FBXO38 cryptic exon inclusion is associated with predicted nonsense-mediated decay and decreased expression, and BTC exon 4 inclusion alters isoform ratios that affect the EGF-like domain. Conclusion:Multiple COPD GWAS associations colocalize with sQTLs and eQTLs in lung and blood, identifying candidate genes such as FBXO38 and BTC and implicating splicing-mediated mechanisms in COPD risk. Music:Enjoy the music based on this article at the end of the episode. Reference:Saferali A., Kim W., Chase R.P., NHLBI TransOmics in Precision Medicine (TOPMed), Vollmers C., Silverman E.K., Cho M.H., Castaldi P.J., Hersh C.P. Overlap between COPD genetic association results and transcriptional quantitative trait loci. Human Genetics and Genomics Advances. 2026 Jan 15;7:100493. https://doi.org/10.1016/j.xhgg.2025.100493. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/copd-sqtl-fbxo38-btc

Pimplaskar A et al., The American Journal of Human Genetics - In UCLA ATLAS EHR-linked biobank analyses, random forest-derived enrollment probabilities and inverse-probability weighting increased replication of known GWAS variants and altered PGS associations. Study Highlights:Using the UCLA ATLAS EHR-linked biobank, the authors trained random forest classifiers on demographics, healthcare utilization, and ICD-10 features to distinguish enrolled from background patients. They converted predicted enrollment probabilities into inverse-probability weights and applied these to GWAS replication tests and PGS-PheWAS scans. The classifier achieved AUROC≈0.85 and weighting increased replication of known GWAS variants by 54% while changing phenome-wide PGS association patterns. These results indicate that enrollment-driven inclusion bias can materially affect variant discovery and downstream PGS-based phenotypic associations in health-system biobanks. Conclusion:Inclusion bias in EHR-linked biobanks like UCLA ATLAS measurably affects common-variant discovery and PGS associations, and enrollment-aware inverse-probability weighting can improve replication while reducing effective sample size. Music:Enjoy the music based on this article at the end of the episode. Reference:Pimplaskar A, Qiu J, Lapinska S, Tozzo V, Chiang JN, Pasaniuc B, Olde Loohuis LM. Inclusion bias affects common variant discovery and replication in a health-system linked biobank. The American Journal of Human Genetics. 2026;113:1–13. https://doi.org/10.1016/j.ajhg.2026.02.011 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/inclusion-bias-ucla-atlas

Mathur Y et al., E., Monir M. M., Islam M. T., Sultana M., Ahmed T., Alam M. & Seed K. D. Capturing dynamic phage–pathogen coevolution by clinical surveillance. Nature ( - Clinical surveillance in Bangladesh shows Vibrio cholerae acquired PLE11 encoding Rta that restricts ICP1 tail assembly, driving a selective sweep of phage-resistant strains. Study Highlights:This study analysed clinical Vibrio cholerae and ICP1 isolates from stool in Bangladesh using genomic surveillance, plaque assays, qPCR, experimental phage evolution, TEM and mass spectrometry. The authors identify a newly acquired mobile element, PLE11, whose small protein Rta disrupts ICP1 tail assembly by targeting the phage tape measure protein (TMP), producing genome-filled tailless capsids. PLE11 also encodes a TMP and other tail factors enabling assembly of chimeric virions that incorporate PLE-encoded TMP and BhuB, preserving satellite transmission. Continued surveillance documented natural ICP1 counteradaptation via CRISPR–Cas acquisition and convergent TMP substitutions that restore infectivity. Conclusion:Acquisition of PLE11 encoding the tail-targeting protein Rta drove selection of phage-resistant Vibrio cholerae in Bangladesh and prompted convergent ICP1 counteradaptations that restore phage propagation. Music:Enjoy the music based on this article at the end of the episode. Reference:Mathur Y., Boyd C. M., Farnham J. E., Monir M. M., Islam M. T., Sultana M., Ahmed T., Alam M. & Seed K. D. Capturing dynamic phage–pathogen coevolution by clinical surveillance. Nature (2026). https://doi.org/10.1038/s41586-026-10136-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ple11-rta-icp1-tail-assembly

Rockowitz S et al., Scaling genomic reanalysis to unlock diagnoses and transform rare disease care. Human Genetics and Genomics Advances - Boston Children's Hospital used VS-NN, HPO NLP, and DRAGEN reprocessing in a proactive genomic reanalysis to identify candidate diagnoses in 2% of pediatric ES/GS cases. Study Highlights:The study deployed a centralized Proactive Genomic Reanalysis (PGR) workflow on a Boston Children’s Hospital pediatric ES/GS cohort integrated into the CRDC infrastructure. Key methods combined DRAGEN reprocessing, automated HPO extraction from EHR notes, CFA filtering on the GeneDx research platform and a VS-NN variant-scoring neural network followed by two-pass manual review. Applied to 2,144 previously unsolved cases, the pipeline flagged 310 variants, manual review prioritized 45 variants in 42 patients, and clinicians judged 33 variants to have high suspicion of disease causality, yielding ~2% candidate diagnostic rate. The work shows that institution-led, semi-automated reanalysis can produce clinically actionable findings while reducing reliance on clinician-initiated lab reanalysis, though it requires infrastructure for data transfer, confirmation and patient recontact. Conclusion:A centralized, semi-automated, clinically integrated Proactive Genomic Reanalysis workflow at Boston Children’s Hospital is feasible and identified candidate diagnostic variants in 2% of reviewed pediatric ES/GS cases, demonstrating a scalable model that can increase diagnoses while requiring institutional resources for confirmation and recontact. Music:Enjoy the music based on this article at the end of the episode. Reference:Rockowitz S, Shao W, French C, Truong TK, Hagen J, McGonigle R, et al.; and Wendy K. Chung. Scaling genomic reanalysis to unlock diagnoses and transform rare disease care. Human Genetics and Genomics Advances. 2026;7:100582. https://doi.org/10.1016/j.xhgg.2026.100582. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/proactive-genomic-reanalysis-bch

Cromer SJ et al., The American Journal of Human Genetics - This paper reviews polygenic risk scores (PRS) and social determinants of health (SDoH) and outlines best practices for integrating PRS and SDoH across diverse populations to improve prediction and equity. Study Highlights:This review focuses on human populations and uses conceptual frameworks, hypothetical population examples, and synthesis of methodological studies to evaluate PRS and SDoH integration. It summarizes methods for PRS construction and transferability, SDoH measurement at individual and area levels, and analytic approaches including interaction, mediation, and calibration. Quantitatively, the authors note substantial declines in PRS predictive accuracy when applied to genetically distinct populations (for example, African-ancestry performance often ~20–40% of European-derived PRS). The review highlights harmonization, population-specific calibration, and interdisciplinary teams as functional steps to improve predictive validity and reduce inequitable impacts. Conclusion:Integrating PRSs with carefully measured and harmonized SDoH across diverse populations requires population-aware conceptual frameworks, calibrated analytic methods, diverse datasets, and ethical safeguards to improve predictive validity and equity. Music:Enjoy the music based on this article at the end of the episode. Reference:Cromer SJ, Cobran EK, Iyer HS, Hysong MR, Vargas LB, Smith JL, Konigsberg IR, Bogumil D, Glover L, King G, PRIMED Consortium SDoH Working Group, Lange LA, Patel A, Wojcik G, Raffield L, Conti DV, et al. Incorporating polygenic risk scores and social determinants of health across populations: Considerations and best practices in research. The American Journal of Human Genetics. 2026;113:1–25. https://doi.org/10.1016/j.ajhg.2026.02.007 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/polygenic-risk-sdoh-harmonization

Wong BHH et al., PNAS - Mouse and human studies show the LPC transporter Mfsd2a enables plasma-derived LPC uptake into keratinocytes, preserving linoleate-rich phosphatidylcholine pools and promoting epidermal differentiation. Study Highlights:Using epidermis-specific (2aEpKO) and conventional (2aKO) Mfsd2a-deficient mice, lineage tracing, untargeted shotgun lipidomics, LightOx-LPC uptake assays, and primary human keratinocyte cultures, the authors mapped Mfsd2a expression to suprabasal/granular keratinocytes and demonstrated Mfsd2a-dependent uptake of plasma-derived LPC in vivo. Lipidomic quantification showed reductions in linoleate-containing phospholipids (PL-18:2 decreased ~15% in 2aEpKO and ~13% in 2aKO) and a marked loss of TAG-18:2 (−79% in 2aEpKO). Inducible epidermal Mfsd2a loss produced transient dermatitis, defective desquamation, retained lamellar bodies, and keratinocyte activation, while MFSD2A knockdown in human keratinocytes reduced LPC-driven differentiation. Functional rescue experiments in vitro revealed that LPC-18:1 and LPC-18:2 promote keratinocyte differentiation in an MFSD2A-dependent manner, linking plasma LPC uptake to epidermal lipid homeostasis and differentiation. Conclusion:Mfsd2a mediates uptake of plasma-derived LPC (notably LPC-18:2) into suprabasal keratinocytes to maintain linoleate-containing phospholipid pools and support keratinocyte differentiation and normal desquamation. Music:Enjoy the music based on this article at the end of the episode. Reference:Wong BHH, Behmoaras J, Chua AWC, Galam DLA, Tan BC, Torta F, Chin CF, Mishra K, Ding M, Silver DL. Mfsd2a is important for maintaining epidermal homeostasis. Proc. Natl. Acad. Sci. U.S.A. 2026 Feb 19;123(8):e2531159123. https://doi.org/10.1073/pnas.2531159123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/mfsd2a-lpc-epidermal-homeostasis

Herpe L et al., PNAS - CRISPR knockout of Drosophila mtG3PDH (GPO1) reduces ATP production by ~60% and O2 consumption by ~33%, lowering mitochondrial efficiency and ROS emission. Study Highlights:Using CRISPR/Cas9-generated GPO1 mutant Drosophila and isolated thoracic mitochondria, the authors combined enzymatic assays, ATP production and oxygen consumption measurements, and H2O2 emission assays to probe mtG3PDH function. Loss of mtG3PDH markedly reduced mtG3PDH enzymatic activity and drove a ~60% decrease in ATP production and ~33% decrease in O2 consumption, producing a pronounced drop in mitochondrial efficiency (ATP/O). mtG3PDH-linked ROS emission was also strongly reduced (~70%), reflecting diminished direct and reverse electron-transfer ROS generation. Functionally, GPO1 flies showed sharply reduced survival and severe climbing impairment, linking the bioenergetic defects to organismal outcomes. Conclusion:mtG3PDH is essential for mitochondrial bioenergetics and redox homeostasis in Drosophila, with GPO1 loss causing major decreases in ATP production, O2 consumption, mitochondrial efficiency, and mtG3PDH-linked ROS that correlate with reduced survival and locomotion. Music:Enjoy the music based on this article at the end of the episode. Reference:Herpe L, Aminot M, Pichaud N. When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 2026;123(9):e2535701123. https://doi.org/10.1073/pnas.2535701123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/drosophila-mtg3pdh-gpo1

Korpela K et al., Gut Microbes - Review finds maternal fecal microbiota transplantation and targeted probiotics can restore Bifidobacterium and Bacteroides after C‑section or intrapartum antibiotics, with breastfeeding aiding recovery. Study Highlights:This review focuses on term infants, particularly C‑section and intrapartum antibiotic–exposed neonates, synthesizing cohort and intervention data using 16S rRNA gene amplicon sequencing and metagenomic approaches. Maternal fecal microbiota transplantation (maternal FMT) shifted C‑section infants’ gut communities to resemble vaginally born infants and uniquely restored Bacteroidaceae, while a Bifidobacterium–Lactobacillus–FOS supplement increased bifidobacteria; vaginal seeding did not normalize overall gut composition. The authors link restoration of key taxa to potential reductions in risks such as allergy and overweight and emphasize breastfeeding as an essential adjunct to restoration strategies. Conclusion:Evidence supports action to address early-life gut microbiota disruption: probiotics and maternal FMT show promising restorative effects, but optimal, scalable solutions and long-term immune outcomes remain to be established. Music:Enjoy the music based on this article at the end of the episode. Reference:Korpela K, de Vos WM. Infant gut microbiota restoration: state of the art. Gut Microbes. 2022;14(1):e2118811. https://doi.org/10.1080/19490976.2022.2118811 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/maternal-fmt-bifidobacterium-restoration

Li Z et al., Human Genetics and Genomics Advances. 7 ( - LASI-DAD 30× whole-genome sequencing of 2,680 Indian participants produced a 69.5M-variant LD panel that improves genotype imputation accuracy and PRS performance for Indian populations. Study Highlights:Using 30× WGS of 2,680 LASI-DAD participants, the authors constructed an LD lookup panel (69.5 million variants), phased with Eagle2.4, and identified LD structure with LDetect and Big-LD. They compared regional varLD to 1000G super-populations and evaluated imputation with Minimac4 and meta-imputation against TOPMed and GAsP. LASI-DAD increased imputation accuracy (aggregated r2) by a mean 38% versus TOPMed and 27% versus GAsP across allele frequencies and improved PRS predictive performance by 2.1%–35.1% across traits and studies. Finer-scale stronger LD and regional LD differences in LASI-DAD translate into more accurate LD estimates and better imputation and PRS transferability for Indian sub-populations. Conclusion:LASI-DAD is the largest nationally representative Indian WGS reference panel to date and it improves LD estimation, genotype imputation accuracy, and PRS construction for Indian and South Asian populations. Music:Enjoy the music based on this article at the end of the episode. Reference:Li Z, Zhao W, Zhou X, Leung YY, Schellenberg GD, Wang L-S, Schönherr S, Forer L, Fuchsberger C, Dey S, Lee J, Smith JA, Dey AB, Kardia SLR. A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India. Human Genetics and Genomics Advances. 7 (2026) 100579. https://doi.org/10.1016/j.xhgg.2026.100579. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/lasi-dad-india-reference-panel