Base by Base

459: Cerebral palsy genetics: 515 candidate genes, evidence for 89 Sep 13, 2026 00:24:06 Arterbery et al., The American Journal of Human Genetics - Hundreds of genes have been reported as causes of cerebral palsy, yet there is no agreed model of what a pathogenic variant in a child with CP actually means. This study treats CP as a phenotypic feature that some genetic disorders make more likely, tests the reported genes against the populatio

458: Somatic or inherited? Reading TP53 risk from shared DNA Sep 10, 2026 00:25:09 MacGregor et al., The American Journal of Human Genetics - Pathogenic TP53 variants found in blood have long been read as inherited Li-Fraumeni alleles, but many turn out to be somatic clones that grew with age. Using whole-exome data from 469,391 UK Biobank participants, this study combines variant allele fraction with haplotype sharing to tell the two

457: A deletion that raises Alzheimer risk, a duplication that lowers it Sep 9, 2026 00:24:15 Quenez O et al., The American Journal of Human Genetics - Rare copy-number variants were called from 22,319 exomes covering early-onset Alzheimer disease, late-onset disease and unaffected controls, then tested gene by gene for a dosage effect. One locus came back with the cleanest signal in the field: at the central 22q11.21 region, deletions appeared

456: Beyond exons: where heritability hides as traits get more polygenic Sep 8, 2026 00:45:46 Fuhrer J et al., The American Journal of Human Genetics - Across 34 complex traits and disorders, a MiXeR-based framework partitions SNP heritability over 74 functional annotations and finds that exons carry only a minority of it, and steadily less as a trait becomes more polygenic. Exonic heritability falls from about 22 percent in less-polygenic somat

455: Agentic genomics: the bottleneck moves from code to judgment Sep 7, 2026 00:13:44 Corpas M et al., Cell Genomics - A Perspective arguing that autonomous AI agents which discover, configure and chain bioinformatics operations from natural-language instructions have shifted the bottleneck in computational biology from building pipelines to validating their output. The authors define four necessary conditions for a system to count as ag

454: Efavirenz retarda a doença priônica mexendo no colesterol do cérebro [PT] Sep 2, 2026 00:17:13 Ali T et al., JCI Insight - Um antirretroviral aprovado para HIV, dado por via oral em microdose, prolongou a sobrevida de camundongos que carregam a proteína priônica humana e foram infectados com príons de doença de Creutzfeldt-Jakob esporádica humana. O efavirenz age ativando a CYP46A1, a enzima cerebral que converte colesterol numa forma capaz de sa

453: Efavirenz slows sCJD progression by reshaping brain cholesterol Aug 31, 2026 00:20:56 Ali T et al., JCI Insight - Repurposed low-dose efavirenz slowed disease progression and extended survival in tg650 mice inoculated with MM1 sCJD prions by activating CYP46A1, raising 24S‑hydroxycholesterol and reducing PrPSc, brain cholesterol and lipid droplets at the early clinical stage. Key terms: efavirenz, CYP46A1, Creutzfeldt-Jakob disease, chol

452: Reduzir a PrP funciona em todas as linhagens [PT] Aug 28, 2026 00:28:42 Minikel EV et al., Nucleic Acids Research - Este estudo testa a redução da proteína priônica (PrP) por oligonucleotídeos antisense (ASOs) em camundongos, variando doses, esquemas de aplicação, linhagens de príon e estágios da doença. O tratamento reduziu o RNA do Prnp, prolongou a sobrevida, atrasou os sintomas e reverteu biomarcadores de lesão neuronal

451: Prion protein lowering is disease-modifying across stages and strains Aug 25, 2026 00:24:36 Minikel EV et al., Nucleic Acids Research - This study uses antisense oligonucleotides (ASOs) to lower prion protein (PrP) RNA in mice and shows dose-dependent extension of survival, efficacy across multiple prion strains, reversal of molecular biomarkers, and benefit even when treatment is delayed into symptomatic stages. Key terms: prion protein, anti

450: ASOs que reduzem PrP prolongam a sobrevida [PT] Aug 24, 2026 00:24:57 Raymond GJ et al., JCI Insight - This episode covers a 2019 study showing that sequence-specific antisense oligonucleotides (ASOs) targeting the prion protein (PrP) mRNA, delivered by bolus intracerebroventricular injection, lower PrP levels in the CNS, slow neuropathology, and markedly extend survival in prion-infected wild-type mice when given prophyl

449: siRNA divalente para doença priônica [PT] Aug 24, 2026 00:28:46 Gentile JE et al., Nucleic Acids Research - Discovery and preclinical development of divalent siRNA candidates targeting PRNP, identifying 2439-s4 as a potent, durable human PRNP-lowering drug candidate with IND clearance. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, RNAi therapeutics. Study Highlights:Authors screened divalent siRN

448: PrP‑lowering ASOs prolong survival in prion‑infected mice Aug 23, 2026 00:25:16 Raymond GJ et al., JCI Insight - This study tests antisense oligonucleotides (ASOs) targeting Prnp in wild‑type mice infected with RML prions and shows that sequence‑specific PrP lowering by bolus i.c.v. ASO dosing delays disease and extends survival, even when given near clinical onset. Key terms: prion disease, antisense oligonucleotide, PrP lowering,

447: Divalent siRNA for prion disease Aug 23, 2026 00:23:33 Gentile JE et al., Nucleic Acids Research - This study develops and tests divalent siRNA molecules that lower prion protein (PrP) in the brain, identifies a potent human-targeting candidate (2439-s4), demonstrates survival benefit in prion-infected mice with a mouse-targeting tool compound, and reports IND-enabling toxicology supporting clinical testing

446: Cilia, Synuclein, and Survival: G51D Mice Reveal a Shared Parkinson’s Pathway Aug 23, 2026 00:28:38 Lin Y‑E et al., PNAS - Knock‑in SncaG51D/G51D mice show selective loss of primary cilia in specific striatal interneurons, astrocytes, piriform cortex PV cells and olfactory basal stem cells, with concomitant reduction in Hedgehog‑dependent neurotrophic signaling linked to Parkinson’s disease vulnerabilities. Key terms: alpha-synuclein, primary cilia, n

445: Why Thymine Survived the UV: Photodamage Pathways Explained Aug 22, 2026 00:26:55 Khosh Abady K et al., PNAS - Spectroscopic comparison of thymine and uracil under 265 nm UVC shows thymine is more photoreactive and absorbs more primordial UVC, yet channels damage into reversible CPDs rather than irreversible (6-4) lesions, supporting an evolutionary 'molecular sunscreen' role. Key terms: UV photodamage, thymine, uracil, cyclobutane p

444: Many-eyes or Sentinels? How Cost Curvature Shapes Collective Vigilance Aug 19, 2026 00:24:40 Pilgrim C et al., PNAS - A minimal analytical model shows that whether animal groups adopt distributed low-level vigilance (many-eyes) or concentrated high-vigilance roles (sentinels) depends on how individual vigilance costs scale with effort. The same dichotomy appears in selfish and cooperative groups and explains switching, edge effects, and turn-ta

443: 5D‑ASO boosts exon 51 skipping and restores dystrophin in DMD models Aug 18, 2026 00:19:35 Feng P et al., PNAS - This paper describes a bipartite antisense oligonucleotide (5D‑ASO) design that appends a short 5′ splice site decoy tail to improve exon skipping, demonstrating robust efficacy for DMD exon 51 in cells, mice, and cynomolgus monkeys with a favorable safety profile. Key terms: antisense oligonucleotide, exon skipping, Duchenne muscu

442: When pumps go missing: Ca2+ control of PMCA2 in Tmc1 deafness mutants Aug 17, 2026 00:22:57 Rolseth AB et al., Proceedings of the National Academy of Sciences (PNAS) - This study links reduced Ca2+ entry through mutant TMC1 mechanotransducer channels to decreased PMCA2 pump density in outer hair cell stereocilia. PMCA2 turnover is rapid in the early postnatal period and is regulated by stereociliary Ca2+ via insertion from an apical vesicular

441: Evolutionary mapping of Cav1.3 functional sites Aug 14, 2026 00:24:01 Tang X et al., PNAS - The authors apply an evolutionary sequence-covariation model to the Cav1.3 (CACNA1D) α1-subunit, map predicted pathogenicity onto structural models, and validate five predicted sites by patch-clamp electrophysiology and structural analysis. Predictions recapitulate known functional regions, reveal previously unrecognized clusters,

440: DENV-4: Suppressing DNA Repair and Causing Genome Damage Aug 12, 2026 00:23:41 Lamkina EN et al., PNAS - This episode reviews a PNAS brief report showing that DENV-4 infection induces marked DNA damage in infected cells while broadly suppressing transcription of DNA repair pathways, with selective upregulation of a mutagenic translesion polymerase and suppressed ATR expression. The findings raise concerns about long-term molecular

439: Coembedding Sequence and Structure: CLSS Maps the Protein Universe Aug 11, 2026 00:23:08 Longo LM et al., PNAS - This episode summarizes a PNAS study introducing CLSS, a contrastive two-tower protein language model that coembeds domain sequences, structures, and subsequences into a shared 32-dimensional latent space. Trained self-supervised on one million ECOD domains, CLSS aligns sequence and structure modalities, yields compact embeddings

438: Mapping AIRE: a proactive atlas of 9,790 missense variants Aug 10, 2026 00:24:02 Axakova A et al., The American Journal of Human Genetics - Axakova et al. generated a variant effect map for AIRE using an insulin‑promoter GFP reporter in HEK293 cells to measure the functional impact of 9,790 missense substitutions and provide calibrated evidence for clinical variant interpretation. Key terms: AIRE, missense variants, variant effect m

437: Cell villages and Dirichlet modeling map human cell fitness genetics Aug 9, 2026 00:28:03 Hanson C et al., The American Journal of Human Genetics - Hanson et al. combine pooled multi-donor human neural progenitor cell "villages" with Townlet, a hierarchical Dirichlet regression model, to estimate donor-specific proliferation and treatment responses from Census-seq. They identify 16p11.2 deletion–associated NPC hyperproliferation and nominate

436: KIAP4 and the ARND family: building the Leishmania adhesion plaque Aug 8, 2026 00:24:51 Owino BO et al., PNAS - Using TurboID proximity proteomics and microscopy, researchers identify KIAP4 as the canonical member of a conserved Adhesion Related NTPase-like Domain (ARND) family that localizes to the Leishmania adhesion plaque. Deleting KIAP4 disrupts haptomonad adhesion in vitro and prevents colonization of the sand fly stomodeal valve wit

435: E. coli TGT binds two tRNAs — cryo-EM reveals dual engagement Aug 7, 2026 00:19:03 Ember M et al., PNAS - This episode examines a cryo-EM study of Escherichia coli tRNA-guanine transglycosylase (TGT) that solves the enzyme structure and its covalent intermediate with tRNATyr. Unexpectedly, the TGT homodimer can form covalent intermediates with two tRNAs simultaneously. The work maps peripheral RNA-binding residues required for activit

434: High‑coverage genomes recast Japan's prehistoric demography Aug 6, 2026 00:27:07 Ishiya K et al., PNAS - This episode examines a PNAS study that reports two high-coverage ancient human genomes from mainland Japan (an Initial Jomon >67× and a Middle Yayoi >46×). The genomes enable diploid genotyping, demographic reconstructions, ancestry modeling, and AMY1 copy-number analysis that reshape understanding of Jomon and Yayoi histo

433: Lactate, HSP90α and the Mitochondrial Switch Jul 23, 2026 00:23:55 Wu G et al., Proceedings of the National Academy of Sciences - This episode examines a PNAS study that identifies site-specific lactylation of HSP90α as a metabolic signal linking glycolysis to mitochondrial biogenesis in ovarian cells. Lactylation at K58 and K616 modulates HSP90α phosphorylation, enabling nuclear import of PGC1α and LRPGC1, boosting mi

432: Echovirus 18: Capsid opening releases the genome Jul 23, 2026 00:18:29 Mukhamedova L et al., Proceedings of the National Academy of Sciences - Using cryo-electron tomography and single-particle cryo-EM of infected Cos-7 cells, the authors show that echovirus 18 (E18) releases its RNA in vivo by capsid opening with loss of one to three pentamers. Binding to the neonatal Fc receptor (FcRn) expels VP1 pocket factors and prime

431: KIAP4 and the ARND family: essential proteins for Leishmania–sand fly adhesion Jul 23, 2026 00:21:33 Owino BO et al., Proceedings of the National Academy of Sciences - TurboID proximity labeling and proteomics identify KIAP4 as the canonical member of a conserved Adhesion Related NTPase-like Domain (ARND) family that localizes to the Leishmania adhesion plaque. KIAP4 deletion disrupts haptomonad adhesion and prevents stomodeal valve colonization in san

430: Proterozoic Rise: Steady Diversification of Crown Eukaryotes Jul 23, 2026 00:25:20 Sandin MM et al., Proceedings of the National Academy of Sciences - Molecular clocks and diversification models applied to a 75,975-OTU rDNA dataset, including long-read environmental sequences and 77 fossil calibrations, indicate crown-group eukaryotes diversified steadily from the mid‑Proterozoic with Archaeplastida dominating early diversity. Key ter

429: Validating the EAGL genetic literacy measure Jul 23, 2026 00:23:49 Barna LS et al., Human Genetics and Genomics Advances - We summarize a psychometric validation of the EAGL measure using US adult online samples. The study produced a validated 17-item EAGL-short that captures three core genetic literacy constructs and can be used to assess and target genetic communication and education. Key terms: genetic literacy, EAG

428: Genetic regulation of plasma metabolites in people with HIV Jul 23, 2026 00:28:03 Ait Oumelloul M et al., Human Genetics and Genomics Advances - Untargeted plasma metabolomics (1,930 features) in 1,244 participants of the Swiss HIV Cohort Study were paired with genome-wide genotypes to map genetic influences on metabolite levels, test colocalization with eQTLs, and apply Mendelian randomization to probe causal links with aging-relate

427: When Genes Talk to Gut: Microbiome as Mediator of Metabolic Risk Jul 23, 2026 00:25:13 Simpson RC et al., Trends in Genetics - This forum reviews evidence that host genetic variants associated with metabolic disease often overlap with loci that shape gut microbiome composition and function. Examples include LCT/MCM6 linking Bifidobacterium to reduced T2D risk, defensin locus variants affecting DEFA26 and Akkermansia abundance, and rs71332

426: ProtoCloud — Prototypical self-explaining model for single-cell analysis Jul 23, 2026 00:16:53 Guo K et al., Cell Genomics - ProtoCloud is a self-explaining deep generative model that embeds single cells around cell-type-specific prototypes to deliver accurate, uncertainty-aware cell type annotation and gene-level explanations from raw UMI counts. Key terms: single-cell, explainable AI, prototypical models, cell type annotation, uncertainty estim

425: BEAM: Bayesian reconstruction of metastatic migration histories Jul 23, 2026 00:23:31 Staklinski SJ et al., Cell Genomics 6, 101193 (2026) - This episode explores BEAM, a Bayesian framework built on BEAST 2 that jointly infers cell-lineage phylogenies and tissue-migration graphs from CRISPR-based lineage-tracing data. The method quantifies uncertainty, improves reconstruction versus parsimony-based approaches, and supports Bayes-factor h

424: LECA's Ancient Interactome and Modern Disease Jul 23, 2026 00:12:03 Cox RM et al., Cell Genomics 6, 101254 - Cox et al. reconstruct a conserved protein interaction network for the last eukaryotic common ancestor using >26,000 mass spectrometry experiments across 31 species and demonstrate how the ancient interactome predicts and explains modern human disease mechanisms. Key terms: LECA, protein interactome, co-fracti

423: How GRN Topology Shapes the Genetic Architecture of Expression Jul 22, 2026 00:25:10 Aguirre M et al., Cell Genomics - Aguirre et al. use simulated gene regulatory networks and a linear structural equation model to show how sparsity, modularity, and hub regulators shape the genome-wide distribution of cis- and trans-heritability of gene expression. Their results indicate gene expression is less polygenic but more pleiotropic than previo

422: Germline rDNA Variants and Human Complex Traits Jul 22, 2026 00:20:13 Rodriguez-Algarra F et al., Cell Genomics - This episode examines a large-scale analysis of germline ribosomal DNA (rDNA) variation in ~500,000 UK Biobank genomes that identifies high-confidence rDNA SNVs and indels associating with human complex traits, notably a cluster in the 28S expansion segment ES15L linked to body-size measures. Key terms: riboso

421: Pre-existing Cell States Predict Multi-Treatment Resistance Jul 22, 2026 00:24:03 Schaff DL et al., Cell Genomics - Schaff et al. use multi-treatment clonal tracing combined with single-cell RNA-seq to show that rare, pre-existing transcriptional states in melanoma predict resistance to diverse therapies and that high CD44 marks cells with multi-treatment tolerance. Key terms: melanoma, CD44, clonal tracing, scRNA-seq, drug resistanc

420: NOTCH2NL duplications: diversity, regulation, and human-specific changes Jul 21, 2026 00:22:05 Real TD et al., Cell Genomics - This episode examines a long-read sequencing study that resolves the complex NOTCH2NL segmental duplications on human chromosome 1, traces independent duplications in apes, documents gene conversion and structural variation across human haplotypes, and maps paralog-specific regulatory elements using Fiber-seq and long-rea

419: The Single-Cell Pediatric Cancer Atlas Jul 20, 2026 00:24:44 Hawkins AG et al., Cell Genomics - This episode summarizes Hawkins et al.'s presentation of the Single-Cell Pediatric Cancer Atlas (ScPCA) Portal, a publicly available resource that provides uniformly processed sc/snRNA-seq data and standardized metadata for pediatric tumors. The Portal hosts summarized expression data for over 700 samples across 55 ped

418: Translating GWAS Across Scales Jul 18, 2026 00:24:15 Felici B et al., Cell Genomics - A concise review of how post-GWAS methods are being used to move from statistical associations to translational insights by integrating drug-target prioritization, single-cell resolution of regulatory mechanisms, and imaging-derived organ phenotypes. Key terms: GWAS, drug discovery, single-cell, imaging genetics, polygen

417: Hidden Mosaic: Parental Postzygotic Mutations in 12,015 Trios Jul 18, 2026 00:21:29 Garcia-Salinas OI et al., The American Journal of Human Genetics - Garcia-Salinas et al. develop a bioinformatic pipeline to recover early parental postzygotic mutations (PZMs) from standard-depth (~30×) trio WGS and apply it to 12,015 rare-disease trios, producing a catalog of 1,015 high-confidence autosomal parental PZMs and assessing their genomic fe

416: HGT-chimeras: fusion across the tree of life Jul 18, 2026 00:26:59 Kapoor RR et al., PNAS - A systematic screen of 319 arthropod genomes reveals genes formed by in‑frame fusion of horizontally transferred nonmetazoan sequences with endogenous metazoan regions. Many of these HGT-chimeras are transcribed, conserved, and show coherent domain architectures, implicating them in diverse biological processes. Key terms: horiz

415: ERG Unlocked: Targeting the PNT Domain with PBITE-1 Jul 18, 2026 00:25:00 PNAS - This episode breaks down a PNAS study that identifies a druggable pocket in the ERG transcription factor PNT domain and describes PBITE-1, a small-molecule probe that binds this pocket to inhibit ERG-driven prostate cancer models. Key terms: ERG, PNT domain, PBITE-1, prostate cancer, small-molecule inhibitor. Study Highlights:The authors show th

414: Durability of Cas9 Gene Drives in Anopheles: A 2‑Year Cage Study Jul 17, 2026 00:31:09 Carballar-Lejarazúa R et al., PNAS (2026) - This episode summarizes a 2-year, 35-generation multireplicate cage trial evaluating three autonomous Cas9/gRNA gene-drive strains (AcTP13, AcTP43 in Anopheles coluzzii; AgTP13 in Anopheles gambiae). The study tracked drive inheritance, cassette integrity, resistance allele emergence, off-target activity, and

413: Rpc34 WH2 dynamics in RNA polymerase III Jul 12, 2026 00:15:24 Wu J-S et al., PNAS - A PNAS study using smFRET and nano-positioning triangulation maps dynamic positioning of the Rpc34 WH2 domain in yeast Pol III elongation complexes and presents a thiol-capping SPAAC labeling strategy to enable selective site-specific fluorophore attachment. Key terms: RNA polymerase III, Rpc34, winged helix, smFRET, bio-orthogonal

412: Fault Lines in Forensic Proficiency Testing Jul 12, 2026 00:28:15 Scurich N et al., PNAS - A concise breakdown of a PNAS perspective that analyzes forensic proficiency testing practices using the 2023 CTS firearms test as a case study. The authors identify test design and administration flaws—easy items, consensus scoring, handling of inconclusives, nonblind verification, shot‑to‑shot variability, and contextual bias—

411: EKV cells and the Human Prion Assay: a scalable platform for sCJD infectivity Jul 9, 2026 00:26:33 Nihata A et al., PNAS - This PNAS study describes the development of EKV, a humanized dividing cell line that propagates bona fide sporadic CJD (sCJD) prions, and the Human Prion Assay (HPA), a cell-based method that quantifies infectivity with sensitivity comparable to transgenic mouse bioassay while enabling rapid therapeutic screening. Key terms: sCJ

410: Nucleotide diversity is a poor predictor of short-term adaptive potential Jul 8, 2026 00:21:48 Abson KL et al., PNAS - A cross-species synthesis and theory paper showing that simple molecular diversity metrics poorly predict short-term adaptive potential. The authors compiled >2,100 quantitative genetics estimates (evolvability and heritability) across ~193 eukaryotic species and compared them to nucleotide diversity (π) and microsatellite het

409: A systems-level atlas of carbon-response transcriptional states in Escherichia coli Jul 7, 2026 00:27:15 Shin J et al., PNAS - This episode examines a large transcriptome compendium (PRECISE-NP881) that profiles E. coli K-12 MG1655 across 43 carbon substrates. Independent component analysis resolved 137 iModulons, including 25 carbon-catabolism modules that organize substrates into four activity-defined groups tied to growth rate, substrate chemistry, meta

408: Tau, mitochondria, and the fusion switch Jul 6, 2026 00:24:42 Tsakiria E et al., Proceedings of the National Academy of Sciences (PNAS) - Using Tau knockout mice and the C. elegans PTL-1 deletion, this study shows that loss of wild-type Tau promotes a conserved shift toward mitochondrial fusion, increases respiratory activity, membrane potential and mitophagy, raises ROS, and enhances stress resilience. The adapti

407: SLC11A2 withholds metals from Salmonella in the gut epithelium Jul 5, 2026 00:21:54 Norberg ES et al., Proceedings of the National Academy of Sciences - Using metal‑responsive fluorescent Salmonella reporters, calf intestinal loops, and CRISPR edited epithelial cells, this study shows that the divalent metal transporter SLC11A2 is recruited to Salmonella‑containing vacuoles and restricts Fe2+ and Mn2+, limiting intracellular bacterial

406: Temperature & Age Shape Gut Susceptibility to HCoV-229E Jul 1, 2026 00:19:53 Synowiec A et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study using fetal, pediatric, and adult human intestinal enteroids to show that physiological temperature and developmental stage jointly determine susceptibility to HCoV-229E, with implications for extrapulmonary coronavirus infection and therapeuti

405: PRDM9 and the Hotspot Trade-off Jul 1, 2026 00:23:33 Úbeda F et al., Proceedings of the National Academy of Sciences (PNAS) - A population-genetic model explains why sequence-specific PRDM9-guided recombination hotspots can evolve and persist alongside non-PRDM9 hotspots by trading off reduced overall binding for increased symmetric binding that more often yields crossovers. Key terms: PRDM9, recombinatio

404: RUNA Reveals Surface DNA on Exosomes Jun 30, 2026 00:21:02 Bošković F et al., Proceedings of the National Academy of Sciences - This study introduces RUNA, a reversible chemistry that selectively labels uridine/thymidine to map nucleic acids across membranes, and uses it to show that most exosomal DNA is surface-exposed, increases after PARP inhibitor treatment, and alters macrophage uptake and activation. Key

403: HRD-GIS Evidence for BRCA1/2 Variant Classification Jun 26, 2026 00:22:51 Schnaiter et al et al., The American Journal of Human Genetics - Schnaiter et al. pooled Myriad MyChoice HRD+ CDx results from four cohorts (4,943 HGOC tumors) to test whether tumor HRD-related genomic instability scores (HRD-GIS) provide evidence for BRCA1 and BRCA2 variant classification under ACMG/AMP criteria. Key terms: homologous recombination def

402: When Polygenic Scores Miss: Rare Variants in Misaligned Individuals Jun 25, 2026 00:20:26 Baya N et al., The American Journal of Human Genetics 113, 1–19 (2026) - Baya et al. applied a misalignment framework to UK Biobank polygenic scores and exomes and found that individuals whose observed phenotypes deviate from polygenic expectation are enriched for rare damaging variants across multiple traits and diseases. Key terms: polygenic scores, r

401: LDB1 variants split neurodevelopmental outcomes by location and mechanism Jun 23, 2026 00:24:28 Fluri R et al., The American Journal of Human Genetics - This episode examines a cohort study of 16 individuals with de novo LDB1 variants that reveals two overlapping but distinct neurodevelopmental phenotypes tied to variant location. Functional assays and Drosophila models demonstrate loss-of-function effects for N-terminal variants and dominant-nega

400: Complete chromosome 21 centromere sequencing and Down syndrome Jun 23, 2026 00:22:30 Mastrorosa F et al., The American Journal of Human Genetics - Long-read assemblies and epigenetic mapping of chromosome 21 centromeres in families with trisomy 21 reveal centromere size diversity, two cases of extreme maternal centromere size asymmetry, and no global enrichment of small centromeres in affected individuals. Key terms: trisomy 21, centrom

399: Ménière disease: inner ear development and retinoic acid pathways Jun 22, 2026 00:21:44 Shi Z et al., The American Journal of Human Genetics - A large GWAS meta-analysis across five biobanks (8,969 cases, 1,962,542 controls) identifies five genome-wide significant loci for Ménière disease, implicating developmental regulators EYA1/EYA4 and retinoic acid metabolism genes including CYP26A1. Integrative fine-mapping, eQTL, and single-cell exp

398: Modeling JAK2V617F Clonal Expansion in the General Population Jun 21, 2026 00:24:52 Snyder J et al., Proceedings of the National Academy of Sciences (PNAS) - Longitudinal VAF measurements from 67 JAK2V617F-positive participants in the Danish GESUS study were analyzed with a Moran-process stem cell model and ABC-SMC to infer per-individual self-renewal advantages and assess prognostic value for MPN progression. Key terms: JAK2V617F, clo

397: SciPhy: Bayesian phylogenetics for sequential genetic lineage tracing Jun 20, 2026 00:23:27 Seidel et al., Nature Communications - SciPhy is a BEAST2-integrated Bayesian framework that models sequential CRISPR‑based insertion edits to jointly infer time-scaled single-cell lineage trees, editing dynamics, and population growth. The authors validate SciPhy on simulations and apply it to HEK293T monoclonal expansion and murine gastruloid datasets

396: Physical homology recognition between DNA duplexes Jun 18, 2026 00:23:26 Stannard A et al., Proceedings of the National Academy of Sciences (PNAS) - This episode summarizes a PNAS study that uses a FRET-responsive DNA tweezers nanosensor to detect and quantify sequence-dependent interactions between intact double-stranded DNA duplexes in ionic solutions. Key terms: homologous recognition, double-stranded DNA, electrostatic i

395: Extended sequence context shapes mutational bias in Escherichia coli Jun 18, 2026 00:22:43 Green R et al., PNAS - Collating >100,000 base-pair substitutions from 32 mutation-accumulation experiments, this study shows that sequence context well beyond adjacent bases — up to ±6 bp and even hundreds of bp — shapes mutational biases in E. coli and interacts with DNA repair. Key terms: mutational bias, sequence context, Escherichia coli, mismat

394: Benchmarking LLMs for cfRNA biomarker discovery Jun 17, 2026 00:22:34 Gaudio HA et al., Nature Communications - This episode examines a systematic benchmark of six commercial large language models applied to plasma cell-free RNA across three clinical cohorts, assessing LLM-driven gene-panel nomination and autonomous classifier construction versus conventional statistical workflows. Key terms: large language models, cell-f

393: Hidden Resistance: tNGS Reveals Rifampicin and Bedaquiline Resistance in Eswatini Jun 17, 2026 00:21:20 Vambe D et al., Nature Communications - This study reports the programmatic introduction of targeted next-generation sequencing (tNGS) in Eswatini and shows that tNGS detected large amounts of rifampicin and bedaquiline resistance missed by routine diagnostics. Among 234 patient samples, tNGS reclassified many infections, revealed frequent co-occurrence

392: GWAS of Cocaine Self-Administration in Heterogeneous Stock Rats Jun 12, 2026 00:23:23 Lara MK et al et al., Nature Communications - Large GWAS in 836 outbred HS rats identifies six loci linked to cocaine self-administration traits, highlighting Ces1 carboxylesterase genes and other loci overlapping human substance-use genetics. Key terms: cocaine use disorder, GWAS, Heterogeneous Stock rats, Ces1, addiction-like behavior. Study Highligh

391: The Kaufmann Protocol — Why We Age and How to Stop It Jun 12, 2026 01:06:28 Dr. Sandra Kaufmann, The Kaufmann Anti-Aging Institute - Dr. Sandra Kaufmann — physician, scientist and athlete — set out to understand aging and fight it with science. This episode is a guided overview of her book, featured with the author's permission: why our cells age (mitochondria, genetic information systems, quality control and maintenance, immun

390: Daunorubicin, Mutual Destruction, and Layered Antiphage Defense Jun 9, 2026 00:22:59 Gätgens C et al., PNAS - This episode examines how DNA-intercalating molecules like daunorubicin block bacteriophage infection at an early stage, causing an abortive-infection-like outcome via toxic phage products and showing synergy with nucleic-acid targeting defenses. Key terms: daunorubicin, abortive infection, bacterial immunity, phage-host interac

389: Crotonylation impedes c-Myc oncogenic activity Jun 9, 2026 00:25:28 PNAS - This study identifies crotonylation as a posttranslational modification of c-Myc that reduces its transcriptional and oncogenic activity. Key lysines K289 and K298 are crotonylated; loss of crotonylation (including a cancer-derived K298N mutant) enhances Skp2 binding and tumorigenesis. Key terms: c-Myc, crotonylation, Skp2, posttranslational modi

388: Base by Base | Episode 388 — In situ CAR‑macrophage alleviates liver fibrosis Jun 9, 2026 00:21:01 Huang X et al., Proceedings of the National Academy of Sciences (PNAS) - This episode summarizes a PNAS study reporting CD163‑targeted lipid nanoparticles that deliver FAP‑specific CAR mRNA to liver macrophages in situ, producing CAR‑macrophages that clear activated hepatic stellate cells and promote fibrosis resolution in mouse models. Key terms: FAP‑C

387: Homotypic Dengue Reinfections and Long-Term Antibody Decay Jun 9, 2026 00:21:36 Andrade J et al., PNAS - Analysis of three long-term cohorts in the Philippines and Thailand shows antibody titers wane over years and that homotypic dengue reinfections are common and required to explain population-level age–titer patterns. Key terms: dengue, homotypic reinfection, antibody kinetics, cohort study, mathematical modelling. Study Highlig

386: Genome Doubling and the Bioeconomy Jun 5, 2026 00:24:26 Peeters MKR et al., Proceedings of the National Academy of Sciences (PNAS) - A perspective outlining how genome doubling (polyploidy) reshapes genomes, phenotypes, and ecological interactions and how its immediate effects can be harnessed across agriculture, aquaculture, industrial biotechnology, and medicine to advance a sustainable bioeconomy. Key ter

385: Growth under Pressure: Polyploidy Induced by Stress Jun 4, 2026 00:24:49 Sarabia Olivera L et al., PNAS - A perspective that surveys how diverse stresses trigger whole‑genome doubling (polyploidy) across fungi, plants, and animals, outlines common cell‑cycle mechanisms that produce polyploid cells, and evaluates the beneficial and detrimental consequences for genomes, cells, tissues, and applied contexts. Key terms: polyploi

384: RNA Brake on Cholera Phage: CisR Controls CTXϕ Jun 3, 2026 00:23:10 Haycocks JRJ et al., PNAS - This episode examines the discovery of CisR, a small RNA produced from the 3’UTR of prtV in Vibrio cholerae, which posttranscriptionally represses the CTXϕ-encoded cep mRNA via Hfq-mediated base-pairing. CisR accumulation is controlled by HapR and CRP and processed by RNase E, linking quorum sensing and carbon status to phage

383: Genetics of the Circulating Proteome: pQTLs, Pathways, and Disease Links Jun 2, 2026 00:23:10 Koprulu M et al., Cell - A 38-cohort proteogenomic meta-analysis of up to 78,664 people maps fine‑mapped protein quantitative trait loci (pQTLs) across 1,116 circulating proteins, uses machine learning to assign trans effector genes, and triangulates genetic and observational evidence to highlight disease mechanisms and therapeutic opportunities. Key te

382: How animal blood cells evolved from unicellular ancestors Jun 2, 2026 00:26:12 Nagahata Y et al., PNAS - A transcriptome-driven reconstruction of blood cell evolution shows modern animal blood lineages arose by repurposing an ancestral unicellular toolkit. The study traces macrophage-like origins, a bilaterian mast/killer split, and later deuterostome/vertebrate innovations. Key terms: blood cell evolution, macrophage, mast cell,

381: Light-written spatial barcodes enable tunable multiomic sequencing (BALI) Jun 1, 2026 00:26:00 Battistoni G et al., PNAS - This paper presents BALI, a light-driven method that writes combinatorial DNA spatial barcodes directly onto biomolecules in tissue by iterative photocleavage and ligation, enabling user-defined, scalable spatial profiling of RNA, chromatin accessibility, or both from the same section and automation via a LightScribe instrume

380: Prime-SGE maps drug-resistance variants at scale May 29, 2026 00:11:38 Abadie FMC et al., Cell Genomics - Abadie et al. present prime‑SGE, a pooled prime‑editing framework that installs thousands of precise point mutations across multiple oncogenes and identifies drug‑resistance variants by sequencing integrated pegRNAs after positive‑selection with kinase inhibitors. The method resolved known resistance mutations (e.g., E

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