Base by Base

A gene known for a severe childhood storage disease turned up in 14 people first seen for failing vision. In half, just enough enzyme was left to spare the body, not the retina. https://basebybase.com/episodes/idua-hypomorphic-retinitis-pigmentosa-mps-i/ @ajhgnews.bsky.social

GLP-1 drugs cost muscle along with fat. In obese mice, an RNA drug that turns on heat-burning fat added fat loss and halved lean mass loss. https://basebybase.com/episodes/zfp423-rna-therapy-beige-fat-glp1-lean-mass/ @pnas.org @pnasnexus.org @nasonline.org

Why do schizophrenia hits barely clear the bar and skew common? Brain-related traits have huge mutational targets and face stronger selection. https://basebybase.com/episodes/brain-traits-strong-selection-genetic-architecture/ @pnas.org @pnasnexus.org @nasonline.org

A gene active in the retina's blood vessels, not its photoreceptors, rises out of AMD genetics. Mice without it lose dim-light and contrast vision. https://basebybase.com/episodes/cnn2-amd-vessel-gene-low-light-vision-mice/ @pnas.org @pnasnexus.org @nasonline.org

Deleting the bipolar risk gene Ank3 from adult mouse neurons made them quieter and lowered a myelin protein made by other cells. Lithium restored that protein. https://basebybase.com/episodes/ank3-adult-neurons-activity-myelin-basic-protein-lithium/ @pnas.org @pnasnexus.org @nasonline.org

Most people carry an IRF7 variant that raises interferon. It clears virus faster and pushes autoantibodies higher. One change, both effects. https://basebybase.com/episodes/irf7-lupus-haplotype-interferon-antiviral-tradeoff/ @ajhgnews.bsky.social

515 genes have been linked to cerebral palsy. Tested against population prevalence, only 89 show statistical evidence of association. https://basebybase.com/episodes/cerebral-palsy-genetics-phenotypic-model/ @ajhgnews.bsky.social

Most pathogenic TP53 variants in healthy blood are not inherited. In 469,391 exomes, they are somatic clones, and the risk they carry is blood cancer. https://basebybase.com/episodes/tp53-somatic-germline-cancer-risk-biobank/ @ajhgnews.bsky.social

One stretch of chromosome 22 moves Alzheimer risk both ways: deletions only in early-onset cases, duplications enriched in controls. https://basebybase.com/episodes/22q11-dosage-alzheimer-risk-cnv-exome/ @ajhgnews.bsky.social

Exons are 2.5% of the genome and carry ~15% of heritability - and less the more polygenic a trait gets. Across 34 traits, heritability slides from exons toward distal intergenic regions as poly… https://basebybase.com/episodes/beyond-exons-noncoding-heritability-polygenicity/ @ajhgnews.bsky.social

AI agents can now run a whole genomic analysis from a sentence. This Perspective argues the hard part moved: producing analyses got cheap, judging them did not. https://basebybase.com/episodes/agentic-genomics-validation-bottleneck/

Um remédio de HIV aprovado, a 1/300 da dose usual, prolongou a sobrevida de camundongos com príons humanos de CJD — mudando como o cérebro limpa colesterol, não baixando a proteína priônica. https://basebybase.com/episodes/efavirenz-priao-cjd-colesterol-pt/

PaperCast Base by Base Ep.453: Low-dose efavirenz slowed disease, increased CYP46A1 and 24S‑HC, reduced PrPSc and extended survival in a humanized sCJD mouse model. Hear the breakdown https://basebybase.com/episodes/efavirenz-prion-cjd-cholesterol/

New PaperCast: ASO-mediated prion protein lowering delays disease across strains and stages, reverses biomarkers, and supports PrP‑lowering therapeutics. Listen https://basebybase.com/episodes/prion-protein-lowering-across-strains-pt/

Episode 451: ASO-mediated lowering of prion protein extends survival across strains and stages, reverses NfL and GFAP biomarkers, and shows benefit even after symptom onset. Listen https://basebybase.com/episodes/prion-protein-lowering-stages-strains-endpoints/

Os episódios 449 e 450 saem em português — os primeiros do Base by Base. São a versão brasileira dos episódios dedicados ao Lito Sousa, sobre a ciência dos ensaios para doença priônica. https://basebybase.com/episodes/divalent-sirna-prion-disease-1/

New PaperCast: PrP-targeting antisense oligonucleotides lower PrP, slow neuropathology, and markedly extend survival in prion-infected mice—even when given near symptom onset. Listen now https://basebybase.com/episodes/450-prp-lowering-asos-prion-mice/

PaperCast Base by Base — new episode on divalent siRNA for prion disease: how 2439-s4 lowers PrP, extends survival in mice, and advanced to IND. Listen now https://basebybase.com/episodes/divalent-sirna-prion-disease/

Episode 448: PrP‑lowering antisense oligonucleotides delayed pathology and extended survival in prion‑infected mice, even when given near symptom onset. Listen now https://basebybase.com/episodes/prp-lowering-asos-prolong-survival-ep448/

New PaperCast: divalent siRNA lowers PrP, extends survival in prion mice, and yields lead candidate 2439‑s4 with IND clearance — hear the science and implications https://basebybase.com/episodes/divalent-sirna-prion-disease/

New PaperCast Episode 446: G51D α‑synuclein mice lose primary cilia and cilia‑dependent neurotrophic signaling in vulnerable neurons — a convergent pathway in Parkinson’s disease. List… https://basebybase.com/episodes/cilia-synuclein-g51d-parkinsons-pathway/ @pnas.org @pnasnexus.org @nasonline.org

Episode 445: New spectroscopy shows thymine absorbs more UVC but channels damage into reversible lesions—how that may have shaped DNA’s choice over uracil. Listen now https://basebybase.com/episodes/uv-photodamage-thymine-vs-uracil/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast: How cost curves decide whether groups use many-eyes or sentinels — insights from a PNAS model of vigilance strategies. Listen https://basebybase.com/episodes/many-eyes-or-sentinels-cost-curvature-vigilance/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast: How cost curves decide whether groups use many-eyes or sentinels — insights from a PNAS model of vigilance strategies. Listen https://basebybase.com/episodes/many-eyes-or-sentinels-cost-curvature-vigilance/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast Base by Base: 5D‑ASO uses a short U1‑decoy tail to boost exon 51 skipping, restore dystrophin and improve phenotype in DMD models — Listen now https://basebybase.com/episodes/base-by-base-443-5d-aso-dmd/ @pnas.org @pnasnexus.org @nasonline.org

PaperCast Base by Base Ep442: Tmc1 mutations reduce MET Ca2+ influx and PMCA2 pump insertion in neonatal hair cells, linking pump loss to deafness. Listen now https://basebybase.com/episodes/ca2-regulation-pmca2-tmc1/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast ep. 441: Evolutionary modeling maps functional sites in Cav1.3 and electrophysiology validates variants that shift gating from nonconducting to gain- or loss-of-fun… https://basebybase.com/episodes/evolutionary-modeling-cav1-3-functional-sites/ @pnas.org @pnasnexus.org @nasonline.org

New episode: DENV-4 causes DNA damage while suppressing DNA repair genes, creating possible long-term molecular scars—hear the findings on Base by Base https://basebybase.com/episodes/base-by-base-denv4-dna-repair/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast: CLSS coembeds protein sequences, structures, and subsequences to map protein space and outperform current PLMs. Hear how compact 32‑D embeddings reveal functio… https://basebybase.com/episodes/clss-contrastive-sequence-structure-protein-space/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast episode: We break down Axakova et al.'s AIRE missense variant effect map—9,790 variants assayed, VUS reclassification, genotype–phenotype links, and UK Biobank findings. Listen https://basebybase.com/episodes/s2-e438-aire-variant-effect-map/ @ajhgnews.bsky.social

New PaperCast: Pooling 12–39 donor NPCs + Townlet Dirichlet modeling maps genetic effects on proliferation and lead sensitivity, highlighting 16p11.2 overgrowth and ZFHX3/ARNT2 loci. Listen https://basebybase.com/episodes/cell-villages-dirichlet-modeling-human-cell-fitness/ @ajhgnews.bsky.social

New PaperCast Base by Base episode: how KIAP4 and the ARND family enable Leishmania to stick to sand flies and why that matters for blocking transmission. Listen now https://basebybase.com/episodes/kiap4-arnd-leishmania-adhesion/ @pnas.org @pnasnexus.org @nasonline.org

New PaperCast: cryo-EM shows E. coli TGT dimer binds two tRNAs and enables high-affinity dual-TAG RNA design — implications for antibiotics and RNA labeling tools. Listen https://basebybase.com/episodes/ecoli-tgt-dual-trna-cryoem/ @pnas.org @pnasnexus.org @nasonline.org

Back from ADLM & glad to return! Base by Base Ep. 434 is out today 🧬 High-coverage Jomon + Yayoi genomes recast Japan's prehistory: divergent demography & high AMY1 (starch genes) before rice farming. Thanks for listening! https://basebybase.com/episodes/high-coverage-ancient-genomes-japan/

New PNAS genomes reshape Japan's prehistory: high-coverage Jomon and Yayoi genomes reveal divergent post-LGM demography and high AMY1 before rice farming — PaperCast Base by Base Ep. 434 https://basebybase.com/episodes/high-coverage-ancient-genomes-japan/ @pnas.org @pnasnexus.org @nasonline.org

🎥 We're on YouTube! Every Base by Base episode — one open-access paper audited claim by claim, with its original song — is now watchable there too. Come subscribe 👇 https://www.youtube.com/channel/UC0hF-N9STdlbVlX1J8N5zYw

✈️ Our host Gustavo is off from Brazil to Anaheim, CA for the ADLM congress! New episodes pause for a week — but we dropped a whole batch yesterday, so enjoy the binge. 🎧 We'll be back with news from the meeting. See you in a week! 🧬