Base by Base

Gustavo Barra
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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

  1. 18 HR AGO

    326: DUO-1 protects REC-8 cohesin and synaptonemal complex stability in Caenorhabditis elegans meiosis

    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?

    25 min

  2. 2 DAYS AGO

    325: cis-pcQTL mapping reveals allelic proxitropy across neighboring human genes

    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

    24 min

  3. 3 DAYS AGO

    324: ZSWIM8–CUL3 clamp on AGO2–miR-7 reveals mechanism of targeted microRNA degradation

    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

    20 min

  4. 4 DAYS AGO

    323: Meat consumption and APOE ε3/ε4–ε4/ε4: slower cognitive decline and lower dementia risk in SNAC‑K

    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

    20 min

  5. 4 DAYS AGO

    322: Bi-allelic RNU6ATAC and RNU4ATAC variants cause infancy-onset autoimmune diabetes via minor spliceosome U12 intron retention

    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

    23 min

  6. 5 DAYS AGO

    321: Canonical nucleobases in asteroid (162173) Ryugu and ammonia-linked purine/pyrimidine ratios

    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

    30 min

  7. 19 MAR

    320: Sex-stratified cQTL mapping identifies TOX (IFN-γ) and EGFR (IL-10) regulators in Dutch and Tanzanian cohorts

    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

    23 min

  8. 18 MAR

    319: Predicting reduced-penetrance TP53 variants from functional assays and random forest models

    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

    24 min
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About

Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

Information

  • Creator
    Gustavo Barra
  • Years Active
    2025 - 2026
  • Episodes
    328
  • Rating
    Clean
  • Copyright
    © Gustavo Barra
  • Show Website
    Base by Base