Base by Base

Gustavo Barra
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  • CIÊNCIAS DA VIDA
  • DIÁRIO

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. 331: Bi-allelic NDUFA5 variants and complex I mitochondriopathy

    HÁ 12 H

    331: Bi-allelic NDUFA5 variants and complex I mitochondriopathy

    Tan et al et al., The American Journal of Human Genetics - This report identifies bi-allelic NDUFA5 variants in four individuals from three families causing an isolated mitochondrial complex I deficiency with variable multisystem features. The study combines genomic, transcriptomic, proteomic, biochemical, structural modeling, and zebrafish functional data to support pathogenicity. Key terms: NDUFA5, complex I deficiency, mitochondriopathy, proteomics, zebrafish model. Study Highlights: Bi-allelic NDUFA5 variants were found in four individuals from three unrelated families presenting with a variable multisystem phenotype including congenital heart defects, hematological abnormalities, and Leigh-like neurological features. Multi-tissue RNA-seq and RT-PCR revealed aberrant splicing and NMD, while proteomics and BN-PAGE demonstrated reduced NDUFA5 protein, isolated complex I deficiency, and stalled assembly at a Q/P intermediate. CRISPR-Cas9 ndufa5 zebrafish crispants showed developmental delays, locomotor deficits, reduced survival, and epileptiform neural activity, corroborating functional impact. Conclusion: Combined clinical, molecular, and animal-model evidence supports that bi-allelic NDUFA5 variants cause a recessive mitochondriopathy with isolated complex I deficiency and variable multisystem involvement; NDUFA5 should be considered in molecular reanalysis of undiagnosed complex I disorders. Music: Enjoy the music based on this article at the end of the episode. Article title: Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency First author: Tan et al Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.03.003 Reference: Tan et al., 2026, The American Journal of Human Genetics 113, 1–14, May 7, 2026. https://doi.org/10.1016/j.ajhg.2026.03.003 License: CC BY (http://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/ndufa5-complex-i-mitochondriopathy QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-31. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript portions describing NDUFA5 variants, splicing consequences, proteomics/BN-PAGE findings, zebrafish model outcomes, and the diagnostic paradigm shift. - transcript topics: Complex I biology and mitochondrial energy metabolism; Gene discovery via GeneMatcher and patient cohorts; NDUFA5 variant classes and their consequences; RNA sequencing and exon skipping due to synonymous variant; Protein abundance and complex I assembly defects; Blue native PAGE and assembly intermediates QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - Bi-allelic NDUFA5 variants cause a mitochondrial complex I deficiency with multisystem disease - Two distinct variant classes observed: frameshift + missense in Family 1; start-loss + synonymous splice variant in Family 2; homozygous synonymous splice variant in Family 3 - RNA-seq reveals aberrant splicing and nonsense-mediated decay for some alleles; exon 3 skipping yields a 39-amino-acid in-frame deletion - Proteomics shows ma...

    27 min
  2. 330: 5ULTRA: Mapping 5′ UTR variants that alter protein translation

    HÁ 1 DIA

    330: 5ULTRA: Mapping 5′ UTR variants that alter protein translation

    Chaldebas M et al., The American Journal of Human Genetics - Chaldebas et al. present 5ULTRA, a computational pipeline that integrates uORF databases, Kozak-motif features, splicing prediction, and a random-forest score to detect and prioritize 5′ UTR variants predicted to alter protein translation. The score correlates with proteomic and MPRA measures and is applied to population, somatic, GWAS, and rare-disease datasets to nominate candidate functional variants. Key terms: 5' UTR, uORF, Kozak motif, translation regulation, machine learning. Study Highlights: The authors developed 5ULTRA to annotate SNVs, indels, and splicing variants that create/disrupt uORFs or alter Kozak strength, integrating comprehensive uORF databases and SpliceAI. A random-forest 5ULTRA score trained on HGMD and gnomAD distinguishes likely translation-impacting variants and achieved strong cross-validation performance and AUC = 0.82 on an independent ClinVar test. The score correlates with cis-pQTL effect sizes (Spearman rho = 0.57) and with MPRA ribosome-load measurements (rho = 0.78). Genome-wide screening found thousands of candidate variants, highlighted rare/conserved signals in disease genes, and nominated examples in cancer, GWAS loci, and rare infections. Conclusion: 5ULTRA provides a validated, transcript-aware framework to detect and prioritize 5′ UTR variants that modulate translation, offering mechanistic hypotheses for noncoding variant interpretation in rare disease, cancer, and complex-trait genetics; the tool and data are publicly available under a CC BY license. QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-30. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantive auditing focused on the scientific content described in the transcript and its alignment with the AJHG article: 5ULTRA architecture, features, SpliceAI integration, validation metrics, somatic/GWAS/infectious disease applications, limitations, and open-source availability. - transcript topics: 5′ UTR regulatory elements (Kozak motif, uORFs) and translation initiation; 5ULTRA methodology and data integration (MANE transcripts, uORFdb, Ribo-uORF, SpliceAI); Machine-learning scoring (17 features; PhyloP conservation as key predictor; uORF/k Kozak annotations); Model validation (ClinVar, cross-validation AUC, accuracy); Correlation with proteomics and MPRA data (cis-pQTL, ΔMRL); Somatic cancer applications (NRAS and ABI1 examples; splicing effects; N-terminal extensions) QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 7 - claims flagged for review: 0 - metadata checks passed: 7 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license - episode_title - episode_number - season - reference Factual Items Audited: - 5ULTRA identifes and prioritizes 5′ UTR variants that affect translation via uORFs and Kozak motifs - 17 features used by the 5ULTRA random forest model; PhyloP conservation of uORF start codon as the strongest predictor - Genome-wide analysis: ~28 million 5′ UTR variants; ~137k predicted to affect translation via URFs or Kozak changes - ClinVar independent test AUC ≈ 0.82 and ClinVar threshold-based accuracy ≈ 80.8% - Cross-validation 5-fold AUC ≈ 0.981; MPRA and pQTL data show concordant translation effects (ΔMRL, Spearman ρ values ~0.78; 5ULTRA vs cis-pQTL ρ ≈ 0.57) QC result: Pass. Chapters (00:00:08) - Genome Wide Detection of Human 5 UTR Variants(00:06:41) - How a Deep Learning Algorithm Can Identify Dangerous Human Variants(00:12:35) - 5 Ultra: The computational genetics of cancer(00:18:46) - How to decode the secrets of the human genome

    23 min
  3. 329: Large future genetic diversity losses predicted despite habitat protection

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    329: Large future genetic diversity losses predicted despite habitat protection

    Mualim KS et al., PNAS - This study develops spatiotemporal population-genetic models calibrated with genomic data to predict how habitat loss and fragmentation drive changes in nucleotide diversity (π). The authors translate IUCN, Living Planet Index, and GBF indicators into estimates of current and future genetic diversity loss across thousands of species. Key terms: genetic diversity, habitat loss, fragmentation, WFmoments, conservation indicators. Study Highlights: The authors built WFmoments and SLiM-based spatiotemporal frameworks and calibrated them with population-scale genomic data from 29 species to model π dynamics after habitat loss. They translated demographic proxies from the IUCN Red List, Living Planet Index, and GBF indicators for 4,611 species to estimate genetic diversity declines. Short-term π loss is often modest, but mid- and long-term losses lag behind habitat declines and can be substantially larger, with average estimates ranging from ~1–13% already lost and mid-term projections much higher under some datasets. Habitat fragmentation can inflate species-wide π while reducing within-population diversity, and recovery of genetic diversity after restoration is slow. Conclusion: Habitat protection alone is insufficient to guarantee long-term genetic health; conservation should incorporate genetic monitoring, connectivity restoration, and policies informed by spatiotemporal genetic forecasts. QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-30. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript’s coverage of the article’s methods (WFmoments, GDAR), habitat-loss scenarios (edge contraction vs fragmentation), key results (short-term vs long-term π losses, wallund/Wahlund effect), real-world examples (Miami Blue Butterfly, Torrey Pine, E. melliodora), and global-scale predictions; excluded - transcript topics: Genetic diversity concept (π) and proxies; WFmoments framework and GDAR; Edge contraction vs fragmentation habitat-loss patterns; Wahlund/Wahlund-like effects and fragmentation inflation; Spatial population structure (FST) and migration; Empirical calibration: 29 species and 4,611 species predictions QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 7 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - Short-term π diversity loss after habitat loss is 1–13% (GDAR/π dynamics). - Long-term π diversity loss lags behind habitat loss and depends on population structure; strongly structured populations show about 27% long-term loss after 50% habitat loss. - Fragmentation can inflate species-wide π diversity due to the Wahlund effect, with increases up to about 263%. - Within-population diversity (πlocal) declines under fragmentation, even when species-wide π appears elevated. - Genetic diversity recovery after habitat restoration is slow and may take thousands to millions of generations; restoration does not rapidly rebuild lost genetic codes. - Miami Blue Butterfly example predicts mid-term genetic collapse in about 12.5 years (given specific population parameters). QC result: Pass. Chapters (00:00:20) - What's the Hidden Crisis of Genetic Diversity?(00:06:09) - How Human Development Is Wiping Out Genetic Diversity(00:11:02) - The Walland Effect on species(00:13:13) - The ticking time bomb of genetic diversity

    22 min

  4. HÁ 4 DIAS

    328: Variant selection boosts R2 for haptoglobin (HP) in cis‑Mendelian randomization

    Zhou A et al., Human Genetics and Genomics Advances - Comparing LD‑pruning, COJO, SuSiE and PCA in haptoglobin (HP) cis‑region data, the study finds including non‑lead variants substantially increases variance explained (R2) and MR precision. Key terms: haptoglobin, cis-Mendelian randomization, LD-pruning, SuSiE, COJO. Study Highlights: The study analyzed circulating haptoglobin (HP) using Fenland protein GWAS summary statistics with LD from UK Biobank, compared four variant selection methods (modified LD‑pruning, COJO, SuSiE, PCA), and extended results with simulations and 15 additional gene regions. In the HP region, incorporating non‑lead variants produced a median proportional gain in R2 of 145.1% and a median reduction in MR standard error of 36.3% relative to the lead variant alone. In simulations with one or two causal variants the methods recovered the expected genetic variance (≈40%) and, when causal variants were removed, non‑lead‑inclusive methods recovered more variance than lead‑only. The functional implication supported by the data is that including correlated non‑lead variants can materially increase instrument strength and precision in cis‑MR, but may raise risks of pleiotropy and numerical instability. Conclusion: Variant selection methods that incorporate correlated non‑lead variants reliably improve instrument strength (R2) and MR precision in cis‑MR compared with the lead‑variant‑only approach; comparisons with the lead variant are advised to detect instability. Music: Enjoy the music based on this article at the end of the episode. Article title: Variant selection to maximize variance explained in cis-Mendelian randomization First author: Zhou A Journal: Human Genetics and Genomics Advances DOI: 10.1016/j.xhgg.2026.100573 Reference: Zhou A, Karhunen V, Tian H, Pott J, Patel A, Slob EAW, Burgess S. Variant selection to maximize variance explained in cis-Mendelian randomization. Human Genetics and Genomics Advances. 2026 Apr 9;7:100573. https://doi.org/10.1016/j.xhgg.2026.100573. 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/hp-variant-selection-cis-mr QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-27. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing: (1) the four variant selection methods and their rationale; (2) HP region results including R2 gains and SE reductions; (3) simulation studies with known causal variance (40%); (4) extension to 15 gene regions; (5) pleiotropy concerns and safeguards; (6) practical recommendat - transcript topics: Four variant selection methods (LD-pruning, COJO, SuSiE, PCA); Modified LD-pruning with adjusted R2 and LD-matrix checks; HP region results: variance explained (R2) gains and MR precision; Simulations with known causal variance (40%); Two-causal-variant scenario and lead variant variance explained; Extension to 15 additional gene regions QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 8 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - doi - article_title - article_journa... Chapters (00:00:20) - How a single matrix can cripple genomics(00:01:34) - Deep Dive: The Search for genetic instruments without breaking the math(00:05:59) - The Hidden Problem with Standard LD Pruning(00:11:13) - The Lead Variants vs Non-Lead variants in disease prediction(00:15:27) - Multivariant Analysis: The Right Mix of Variants

    24 min

  5. HÁ 4 DIAS

    327: Bi-allelic ATG12 variants impair ATG12-ATG5 conjugation, LC3 lipidation and neural development

    Lambton J et al., The American Journal of Human Genetics - Bi-allelic ATG12 variants disrupt ATG12‑ATG5 conjugation and LC3 lipidation, impairing autophagy in patient cells and model systems and causing cerebellar vermis hypoplasia. Key terms: ATG12, autophagy, neurodevelopmental disorder, zebrafish, LC3 lipidation. Study Highlights: The study characterized six affected individuals with bi-allelic ATG12 variants using patient fibroblasts, HeLa ATG12 knockout complementation, yeast complementation, and CRISPR zebrafish models. Methods included WES/WGS and Sanger sequencing, immunoblotting, LC3/p62 flux assays, HaloTag-LC3 processing, LDH sequestration, AlphaFold-Multimer structural modeling, yeast GFP-Atg8 assays, and zebrafish behavioral and imaging assays. Structural modeling and biochemical data indicate variants map to ATG12 interfaces with ATG5 and ATG3, destabilize ATG12 or its conjugate with ATG5, reduce LC3/Atg8 lipidation and autophagic flux in a variant-dependent manner. Functionally, ATG12 disruption associates with neurodevelopmental phenotypes including cerebellar vermis hypoplasia, ataxia and seizures in humans, and causes growth, brain-structure and locomotor defects with reduced survival in zebrafish. Conclusion: Bi-allelic ATG12 variants impair ATG12 function and autophagy, producing a recessive neurodevelopmental disorder marked by cerebellar vermis hypoplasia and neurological deficits. Music: Enjoy the music based on this article at the end of the episode. Article title: Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder First author: Lambton J Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.03.002 Reference: Lambton J, Asano S, Huang Y, Suomi F, Eguchi T, Petree C, Huang K, Prigent M, Imam A, McCorvie TJ, Warren D, Hobson E, McCullagh H, Misceo D, Bjerre A, Smeland MF, Klingenberg C, Frengen E, Naik S, Ryan G, Sudarsanam A, Foster K, Vasudevan P, Samanta R, Rahman F, Maqbool S, Udani V, Efthymiou S, Houlden H, McFarland R, Collier JJ, Maroofian R, Yue WW, Varshney GK, Klionsky DJ, Legouis R, McWilliams TG, Mizushima N, Oláhová M, Alston CL, Taylor RW. Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder. The American Journal of Human Genetics. 2026 May 7;113:1–18. https://doi.org/10.1016/j.ajhg.2026.03.002 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/biallelic-atg12-autophagy-disorder QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-27. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited substantive scientific content from the transcript, focusing on the patient cohort, molecular mechanism (ATG12-ATG5 conjugation, LC3 lipidation), structural modeling, model organisms (yeast, zebrafish), and neurological phenotype. - transcript topics: Bi-allelic ATG12 variants and patient cohort; ATG12-ATG5 conjugation and LC3 lipidation; AlphaFold/structural modeling of ATG12 interactions; Yeast and zebrafish functional assays; Cerebellar involvement and mitophagy; Therapeutic implications of autophagy modulation QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 7 - c... Chapters (00:00:20) - Why a single gene is completely lethal in humans(00:05:26) - Flip-flopping mutations in the brain(00:10:47) - Mitophagy 7, The cell survival paradox(00:14:10) - Autophagy Defective in the brain

    19 min

  6. HÁ 5 DIAS

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

    Strand LG et al., Proc. Natl. Acad. Sci. U.S.A - 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. Key terms: DUO-1, Caenorhabditis elegans, synaptonemal complex, REC-8, auxin-inducible degron. 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. Article title: Active maintenance of meiosis-specific chromosome structures in Caenorhabditis elegans by the deubiquitinase DUO-1 First author: Strand LG Journal: Proc. Natl. Acad. Sci. U.S.A DOI: 10.1073/pnas.2532671123 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 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-25. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the spoken scientific content reflecting the paper's core findings: DUO-1’s continuous maintenance of meiosis-specific chromosome structures, SC/axis stability, REC-8 cohesin protection, RAD-51 dynamics, AID-time course revealing separable roles, and the DUO-1–PARG-1 interaction revealed by TurboID. - transcript topics: Meiotic prophase architecture (SC/axis) and DUO-1 roles; Duo-1 mutant phenotypes: SC assembly failure and polycomplexes; REC-8 cohesin distribution and sister chromatid cohesion; RAD-51 dynamics and SPO-11 dependency; COSA-1 foci and recombination intermediates; Auxin-inducible degradation (AID) reveals separable roles in assembly, maintenance, and compaction QC Summary: 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

  7. 24 DE MAR.

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

    Lawrence et al., The American Journal of Human Genetics - 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. Key terms: pcQTL, allelic proxitropy, GTEx, colocalization, HOXB. 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. Article title: Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants First author: Lawrence Journal: The American Journal of Human Genetics DOI: 10.1016/j.ajhg.2026.02.022 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 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-24. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections presenting the conceptual shift to neighborhood gene regulation (allelic proxytropy), the cis-pcQTL (pcQTL) methodology, GTEx tissue clustering, key quantitative results (novel pcQTLs, clusters, colocalizations), and concrete examples (HOXB cluster, IL-18 receptor genes), plus discussion - transcript topics: Conceptual shift to gene neighborhoods and allelic proxytropy; cis-pcQTL (pcQTL) methodology and PCA-based signal extraction; GTEx tissue clusters and gene-neighborhood calling; pcQTL discovery statistics (clusters, pcQTLs per tissue, novel signals); pcQTLs and GWAS colocalizations; HOXB cluster example (HOXB3 vs HOXB4) and PC4 QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - pcQTLs reveal novel multi-gene regulatory variants missed by single-gene eQTLs - average pcQTLs per tissue is 1,396 -... 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

  8. 23 DE MAR.

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

    Farnung J et al., 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. Key terms: ZSWIM8, AGO2, target-directed miRNA degradation, cryo-EM structure, E3 ubiquitin ligase. 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. Article title: The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation First author: Farnung J Journal: Nature DOI: 10.1038/s41586-026-10232-0 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 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-23. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript portions describing TDMD mechanism, ZSWIM8–CUL3 E3 ligase architecture, AGO2–miRNA–trigger complex recognition, CYRANO/HSUR1 triggers, RNA flanking regions and RBEs, PAZ-pocket vacancy, dimeric clamp, and broader biological implications. - transcript topics: TDMD overview and cellular context; ZSWIM8–CUL3 E3 ligase architecture and dimer clamp; AGO2–miRNA–trigger complex recognition by ZSWIM8; Trigger RNAs (CYRANO, HSUR1) and pairing architecture; RNA flanking regions and RBEs in ZSWIM8 binding; PAZ pocket vacancy and RNA trajectory QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 8 - claims flagged for review: 0 - metadata checks passed: 6 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license - episode_title - episode_number - season Factual Items Audited: - TDMD is mediated by ZSWIM8–CUL3 E3 ligase polyubiquitylating AGO2–miRNA in the presence of a trigger RNA - ZSWIM8 preferentially binds AGO–miRNA–trigger ternaries over AGO–miRNA–seed... 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

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Sobre

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.

Informações

  • Criado por
    Gustavo Barra
  • Anos de atividade
    2025 - 2026
  • Episódios
    333
  • Classificação
    Livre
  • Copyright
    © Gustavo Barra
  • Site do podcast
    Base by Base