Base by Base

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

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

Yan X et al., The American Journal of Human Genetics, Corrected proof - In 569 TwinsUK subcutaneous adipose biopsies, twin models and GWAS identify SCD, FADS and 3p25.2 (PPARG) loci regulating fatty acid levels and conversions. Study Highlights:System and sample: 569 female TwinsUK subcutaneous adipose biopsies with matched serum, RNA-seq and 450K methylation data were analyzed. Key methods: gas chromatography fatty acid profiling, ACE twin heritability models, GWAS of 18 fatty acids and 15 product-to-precursor ratios, colocalization with adipose eQTLs and meQTLs, and polygenic score analysis. Main quantitative results: heritability of individual fatty acids ranged from 5%–59% while 15 fatty acid ratios were heritable and GWAS identified 10 genome-wide significant loci including SCD and FADS with the SCD lead variant explaining ~7–11% of variance and ratios showing heritability up to ~54%. Functional implication: colocalizations with adipose-specific eQTLs and meQTLs and associations between metabolic polygenic scores and fatty acid levels link local genetic regulation in adipose tissue to renal and cardio-metabolic phenotypes. Conclusion:Local genetic variation in adipose tissue, including SCD, FADS and a 3p25.2 locus near PPARG, regulates fatty acid composition and conversion and is connected to renal and cardio-metabolic traits. Music:Enjoy the music based on this article at the end of the episode. Reference:Yan X., Roberts A.L., El-Sayed Moustafa J.S., Villicaña S., Al-Hilal M., Tomlinson M., Menni C., Sanders T.A.B., Freidin M.B., Bell J.T., Small K.S., Genetic regulation of fatty acid content in adipose tissue. The American Journal of Human Genetics 113, 1–18, February 5, 2026. https://doi.org/10.1016/j.ajhg.2025.12.008 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.castos.com/episodes/scd-fads-pparg-adipose

Guest, O et al., Zenodo (2025) - Position piece urging universities to resist uncritical adoption of AI technologies such as LLMs and chatbots because they undermine academic freedom, integrity, and pedagogical skills. Study Highlights:A co-authored open letter, conceptual analysis, and literature synthesis drawing on historical and contemporary sources. The authors analyse how AI industry marketing, ambiguous jargon, closed-source models, and extractive data and labour practices create institutional dependencies and conflicts of interest. They show this structural entanglement erodes research integrity, deskills students and staff, and produces environmental and social harms. As a functional implication they call for principled refusal, transparency, critical AI literacy, and policy measures to protect academic freedom and the ecosystem of human knowledge. Conclusion:Universities must reject the uncritical adoption of AI technologies and take active measures to safeguard critical thinking, expertise, academic freedom, and scientific integrity. Music:Enjoy the music based on this article at the end of the episode. Reference:  Against the Uncritical Adoption of 'AI' Technologies in Academia. Zenodo. (2025)https://doi.org/10.5281/zenodo.17065099  License:CC 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.castos.com/episodes/universities-resist-ai-adoption

Rashid AI et al., The American Journal of Human Genetics - US antitrust shifts in human genetic technologies: FTC scrutiny of Illumina’s acquisition of Grail alters NGS market oversight and could affect spin-offs and startups. Study Highlights:This perspective examines the US legal and regulatory landscape for human genetic and genomic technologies, focusing on FTC and DOJ policy changes and enforcement habits. Using a case-study approach centered on Illumina’s proposed acquisition and eventual divestiture of Grail, the authors review updated merger guidelines, non-compete rule developments, and exclusive-dealing concerns. They report that the 2023 merger guidelines lowered thresholds for presumed anti-competitiveness and that the FTC’s challenge emphasized risks to nascent mult-cancer early detection competitors that rely on next-generation sequencing platforms. The authors conclude that heightened vertical-merger scrutiny may reduce spin-offs and early-stage acquisitions, prompting firms to favor in-house R&D or alternate collaboration models. Conclusion:Heightened scrutiny of vertical mergers and attention to nascent competition in US antitrust policy is likely to reshape biotechnology strategies by reducing spin-offs and encouraging in-house development. Music:Enjoy the music based on this article at the end of the episode. Reference:Rashid AI, Rincon NA, Rihani N, Wagner JK. Competition in human genetic technologies: The current US legal landscape. The American Journal of Human Genetics. 2026;113:1–10. https://doi.org/10.1016/j.ajhg.2025.12.012 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.castos.com/episodes/illumina-grail-vertical-mergers

Morsy H et al., The American Journal of Human Genetics - Exome sequencing identifies homozygous MDGA2 loss-of-function variants in nine individuals and functional neuronal assays show impaired MDGA2 trafficking with disrupted Nlgn1-dependent excitatory synapse regulation causing DEE. Study Highlights:Exome sequencing of consanguineous families identified seven distinct homozygous MDGA2 loss-of-function variants in nine individuals with severe developmental and epileptic encephalopathy. Functional evaluation used mammalian expression in HEK293T cells, heterologous synapse-formation assays, cultured hippocampal neurons, and electrophysiology. Representative nonsense variants abolished MDGA2 surface trafficking, disrupted MDGA2–Nlgn1 binding, failed to suppress excitatory synapse density, and did not reduce AMPAR- and NMDAR-mediated synaptic responses. These synaptic deficits imply disruption of excitatory-inhibitory balance, providing a mechanistic link to early-onset intractable seizures and progressive neurodevelopmental impairment. Conclusion:Homozygous MDGA2 loss-of-function variants cause an autosomal-recessive developmental and epileptic encephalopathy by impairing MDGA2 trafficking and Nlgn1-dependent suppression of excitatory synapses. Music:Enjoy the music based on this article at the end of the episode. Reference:Morsy H, Kim H, Jang G, et al. MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy. The American Journal of Human Genetics. 2026;113:1–12. https://doi.org/10.1016/j.ajhg.2025.12.015 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.castos.com/episodes/mdga2-loss-of-function-dee

Avsec et al., Advancing regulatory variant effect prediction with AlphaGenome. Nature 649, 1206–1218 ( - AlphaGenome, a 1 Mb DNA deep‑learning model, predicts base‑pair‑resolution genome tracks (RNA‑seq, splicing, chromatin) and scores variant effects, achieving state‑of‑the‑art performance across modalities. Study Highlights:AlphaGenome is a unified sequence‑to‑function deep learning model trained on human and mouse genomes that consumes 1 Mb of DNA and predicts 5,930 human genome tracks across 11 modalities using a U‑Net‑inspired encoder, transformer tower and decoder. The model was pretrained with fold splits and distilled into a single student model for efficient variant scoring, enabling base‑pair resolution outputs and splice junction prediction alongside splice site usage and RNA‑seq coverage. Quantitatively, AlphaGenome outperformed or matched external models on 22 of 24 genome track tasks and on 25 of 26 variant effect benchmarks, improving eQTL sign prediction and QTL effect correlations. The multimodal outputs enable mechanistic interpretation of variants, for example recapitulating oncogenic TAL1 enhancer mutations and identifying splice‑disrupting variants. Conclusion:AlphaGenome provides a unified 1‑Mb multimodal, base‑resolution sequence model that substantially improves genome track and regulatory variant effect prediction and enables mechanistic, cross‑modality interpretation. Music:Enjoy the music based on this article at the end of the episode. Reference:Avsec, Ž. et al. Advancing regulatory variant effect prediction with AlphaGenome. Nature 649, 1206–1218 (2026). https://doi.org/10.1038/s41586-025-10014-0 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.castos.com/episodes/alphagenome-regulatory-variant-prediction

Sierant MC et al., PNAS - MIPseq and exome sequencing of 11,555 human congenital heart disease probands implicate 60 dominant CHD genes, with NOTCH1 cysteine‑altering and transmitted MYH6 missense variants driving distinct defects. Study Highlights:We analyzed 11,555 human CHD probands from PCGC and PHN using a 248‑gene MIPseq panel and whole‑exome sequencing. A meta‑analysis of de novo and very rare transmitted/unphased damaging variants identified 60 genes with significant burden, accounting for damaging variants in 10.1% of probands with similar DNM and transmitted contributions. Mechanistically, NOTCH1 missense mutations that introduce or remove cysteines in EGF domains were highly enriched in tetralogy of Fallot and conotruncal defects, while transmitted damaging MYH6 missense variants were overtransmitted and contributed to multiple CHD subtypes. Genes with cardiomyocyte‑restricted expression correlated with isolated CHD, whereas broadly brain‑expressed genes correlated with neurodevelopmental delay, supporting genotype‑informed risk assessment. Conclusion:Targeted genomic analysis of 11,555 CHD probands identifies 60 dominant genes accounting for 10.1% of cases and supports molecular diagnosis to stratify cardiac and neurodevelopmental risk. Music:Enjoy the music based on this article at the end of the episode. Reference:Sierant MC, Jin SC, Bilguvar K, Morton SU, López-Giráldez F, Knight JR, Zhao H, Deanfield J, Giardini A, Mital S, Shend Y, Bernstein D, Yost HJ, Lifton RP, Brueckner M, et al. Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2420343122. https://doi.org/10.1073/pnas.2420343122 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.castos.com/episodes/notch1-myh6-chd-genes Chapters (00:00:20) - Deadly heart defect: The genetics of congenital heart disease(00:03:05) - How 60 genes explain the cause of heart defect(00:07:03) - Heart defects and neurodevelopmental delay(00:10:24) - These are the hidden syndromes(00:14:21) - Dazzling Sound

Chandler LC et al., PNAS - AAV-mediated RPE expression of MCT2 in rat and mouse retinitis pigmentosa models increases RPE lactate uptake and prolongs cone photoreceptor survival and function. Study Highlights:Neonatal subretinal AAV8.Best1.MCT2 delivery was tested in multiple RP models (S334ter rats, FVB and P23H mice) and produced a statistically significant increase in surviving cones and transient preservation of optomotor visual acuity. The study combined AAV gene delivery with two-photon fluorescence lifetime imaging microscopy (FLIM) using LiLac and GlucoSnFR-TS biosensors to measure lactate and glucose in RPE tissue. MCT2 localized to apical and basolateral RPE membranes, MCT2-expressing RPE showed higher intracellular lactate and greater glucose accumulation consistent with increased lactate uptake and reduced glycolysis. These metabolic changes correlated with functional cone preservation across distinct genetic causes of RP, supporting a gene-agnostic metabolic rescue strategy. Conclusion:AAV-mediated, RPE-specific expression of MCT2 enhances lactate uptake into the RPE, shifts RPE metabolism toward higher intracellular lactate and glucose, and prolongs cone survival with transient preservation of cone-mediated function in multiple RP models. Music:Enjoy the music based on this article at the end of the episode. Reference:Chandler LC, Gardner A, Cepko CL. RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2421978122. https://doi.org/10.1073/pnas.2421978122 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.castos.com/episodes/rpe-mct2-cone-survival Chapters (00:00:00) - Blending Genomics Into Your Life(00:00:28) - The starvation of RPE(00:02:48) - New science in retinal degeneration(00:03:56) - Gene therapy to save the retina(00:08:04) - Pigmented eyes to help sight?(00:10:25) - Genetics fixes blindness in mice(00:13:47) - A New way to save the brain(00:14:36) - Open the Gate, Let the Sugar Run

Gori K et al., PNAS - In canine transmissible venereal tumor (CTVT), deep sequencing and cytogenetics identify a 15‑Mb horizontally transferred nuclear element (N-HT1) acquired ~2,000 years ago that is transcriptionally active. Study Highlights:The authors screened 174 transmissible tumor genomes, focusing on CTVT, DFT1, and DFT2, using deep short-read sequencing, long-read PacBio sequencing, structural variant analysis, and metaphase FISH. In CTVT-A they discovered a 15-Mb dicentric element (N-HT1) assembled from 11 fragments of six chromosomes that forms the short arm of a small submetacentric chromosome after centromeric fusion. Mutation density and CpG-based dating place N-HT1 acquisition about 2,000 years ago, and transcriptome allele deconvolution shows N-HT1 is transcriptionally active and adopts the CTVT expression profile. Functional interrogation found no clear oncogenic drivers on N-HT1, with at least one rescued gene (ARFGEF3) later inactivated, consistent with the element behaving as a likely neutral passenger. Conclusion:A single host-to-tumor nuclear horizontal transfer event was detected in sampled transmissible cancers: CTVT-A acquired a 15-Mb N-HT1 element that is transcriptionally active but shows no clear evidence of positive selection. Music:Enjoy the music based on this article at the end of the episode. Reference:Gori K., Baez-Ortega A., Strakova A., Stammnitz M.R., Wang J., Chan J., Hughes K., et al. Horizontal transfer of nuclear DNA in transmissible cancer. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2424634122. https://doi.org/10.1073/pnas.2424634122 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.castos.com/episodes/ctvt-n-ht1-horizontal-transfer Chapters (00:00:00) - Blast by Bass(00:00:29) - Cancer Has Stealing DNA From Your Body(00:02:41) - Horizontal Transfer of nuclear DNA in transmissible cancer(00:07:24) - The ghost of a dog's genome(00:11:55) - Transmissible DNA in human cancer(00:14:08) - Step, Step, Close Hold

Ju X-C et al., PNAS - Human-specific ADSL A429V substitution and a common regulatory haplotype reduce ADSL activity and raise purine substrates in the brain, altering mouse behavior. Study Highlights:Model: mice humanized for ADSL carrying the modern-human A429V (with R428Q) were compared to wild-type littermates using ultraperformance LC–Orbitrap metabolomics and automated IntelliCage behavioral assays. Mechanistic/quantitative result: SAICAr and S-Ado concentrations increased up to ~2-fold in liver and 1.8–5.4-fold across cerebrum regions, and these increases correlated negatively with Adsl mRNA expression across tissues. Human genetics: a 7.8-kb haplotype (including rs8135371) at >97% carrier frequency is associated with lower ADSL expression, higher S-Ado in cerebrospinal fluid, and signals of positive selection. Functional implication: female humanized mice accessed water more efficiently under restricted conditions, linking reduced ADSL activity to altered behavior. Conclusion:Two genetic changes on the modern human lineage—a nearly fixed A429V amino acid substitution and a common regulatory haplotype—have reduced ADSL activity and expression, increasing purine substrates particularly in the brain and producing measurable behavioral effects in mice. Music:Enjoy the music based on this article at the end of the episode. Reference:Ju X-C, Huttner W, Ågren R, Machado LC, Xing J, Lee S-Y, Siepel A, Azama C, Roy MC, Pääbo S, Endo T, Fukunaga I, Zeberg H. The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior. Proc. Natl. Acad. Sci. U.S.A. 2025.122:e2508540122. https://doi.org/10.1073/pnas.2508540122 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.castos.com/episodes/adsl-a429v-purine-brain

Morris TT et al., PNAS - EA and cognition polygenic indexes (PGIs) in three British birth cohorts show EA PGI associations with years of education increased from 1946–1970 and were strongest in advantaged socioeconomic backgrounds. Study Highlights:Using three nationally representative British birth cohorts born 1946, 1958, and 1970, the authors analyzed polygenic indexes for educational attainment (EA) and cognition. They generated PGIs with clumping-and-thresholding (PRSice2) and LDpred2, used multiple imputation and inverse probability weighting, and estimated linear models including cohort-by-PGI interactions. EA PGI associations increased from approximately 0.44 to 0.67 years of education per 1-SD and incremental R2 rose from 3.5% to 5.1% across cohorts, while cognition PGI associations were broadly stable. There was strong evidence of gene–environment interaction: returns to EA genetic liability were disproportionately larger among those born into more advantaged socioeconomic backgrounds. Conclusion:Across three British birth cohorts born 1946–1970, genetic liability indexed by an EA PGI became more predictive of years of completed education while cognition PGI prediction remained stable, and EA PGI effects were amplified in advantaged socioeconomic contexts. Music:Enjoy the music based on this article at the end of the episode. Reference:Morris TT, Wright L, Shireby G, Bann D. Genetic associations with education have increased and are patterned by socioeconomic context: Evidence from 3 studies born 1946–1970. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2516460123. https://doi.org/10.1073/pnas.2516460123 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.castos.com/episodes/ea-pgi-cohort-socioeconomic-interaction Chapters (00:00:00) - Genetics and the socioeconomic gap(00:04:36) - The genetic link between school and success(00:07:42) - Genetics and educational success(00:11:42) - The Wealthy Kids and the Poor(00:12:56) - The genetics of intelligence and personality(00:15:38) - Open Access: Science Podcast(00:16:31) - Inheritance

Spakmana D et al., H., Hickson I. D., Peterman E. J. G., Wuite G. J. L., King G. A. Mechanistic basis for relaxation of DNA supercoils by human topoisomerase IIIα–RMI1–RMI2. Proc. Natl. Acad. Sci. U.S.A - Optical tweezers and fluorescence imaging show human Topoisomerase IIIα–RMI1–RMI2 (TRR) processively relaxes highly negatively supercoiled DNA faster than PICH loops. Study Highlights:Using torsionally constrained end-closed λ-DNA in a multichannel flow cell, the authors combined Optical DNA Supercoiling (ODS), dual-trap optical tweezers, and fluorescence imaging to measure supercoiling density and visualize TRR binding in real time. They find TRR relaxes hyper-negatively supercoiled DNA in a highly processive manner, with single TRR complexes performing thousands (>3,000) of strand-passage reactions and exhibiting a force-dependent rate described by an Arrhenius relation (δ ≈ 1.1–1.4 nm in ensemble and single-molecule fits). Ensemble TRR activity was ~10-fold lower than E. coli TopoI under the same conditions, while single- complex rates indicate a single TRR can relax PICH-generated negative loops within the reported loop lifetime. These results support a mechanistic role for TRR in relaxing PICH-generated negative supercoils that could facilitate ultrafine anaphase bridge resolution. Conclusion:Human topoisomerase IIIα–RMI1–RMI2 (TRR) relaxes highly negatively supercoiled DNA in a force-dependent, highly processive manner and can act within the lifetime of PICH-generated negative loops, supporting a role in ultrafine anaphase bridge resolution. Music:Enjoy the music based on this article at the end of the episode. Reference:Spakmana D., Biebricher A. S., Bizard A. H., Hickson I. D., Peterman E. J. G., Wuite G. J. L., King G. A. Mechanistic basis for relaxation of DNA supercoils by human topoisomerase IIIα–RMI1–RMI2. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2406949123. Published January 23, 2026. https://doi.org/10.1073/pnas.2406949123 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.castos.com/episodes/trr-supercoil-relaxation-optical-tweezers Chapters (00:00:00) - The Great Divide: When will the bridge break?(00:02:41) - Deep Dive: The mechanism of DNA supercoils by human to(00:03:49) - The Hidden Story of DNA(00:08:02) - How fast does TRR work on DNA?(00:12:40) - Why TRR Stuck to the DNA(00:17:30) - Who is the bouncer of DNA?

Palacio T et al., PNAS - Reconstituted Saccharomyces cerevisiae mismatch repair shows the Mlh1–Pms1 endonuclease directly generates single-strand gaps to excise mispairs independent of Exo1 and Rad27. Study Highlights:We reconstituted Saccharomyces cerevisiae mismatch repair with purified Msh2–Msh6 or Msh2–Msh3, Mlh1–Pms1, PCNA, RFC, RPA, and DNA polymerases and analyzed products by restriction mapping, Mung Bean nuclease, electron microscopy, and APOBEC3A deamination. The Mlh1–Pms1 endonuclease, activated by RFC-loaded PCNA and Mn2+, generates strand-specific single-strand gaps on the preexisting nicked strand. Electron microscopy and deamination mapping revealed a broad distribution of gap sizes with a peak around 128 ± 17 nucleotides and most gaps under 500 nucleotides. These gaps can be filled by DNA Polε or low levels of DNA Polδ, providing an Exo1- and Rad27-independent route for mispair excision and explaining redundancy among excision pathways. Conclusion:Mlh1–Pms1 catalyzes strand-specific single-strand gap formation that mediates Exo1- and Rad27-independent mispair excision in reconstituted S. cerevisiae mismatch repair. Music:Enjoy the music based on this article at the end of the episode. Reference:Palacio T, Calil FA, Bowen N, Griffith JD, Putnam CD, Kolodner RD. DNA mismatch repair mediated by Mlh1–Pms1 endonuclease-catalyzed mispair excision. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2528670122. https://doi.org/10.1073/pnas.2528670122 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.castos.com/episodes/mlh1-pms1-gap-excision Chapters (00:00:00) - Base by Bass(00:00:29) - Who is the real repairman of DNA?(00:02:39) - The spell-checker for our DNA(00:04:23) - The ghost mechanic of DNA repair(00:07:02) - The secret to DNA repair(00:09:48) - How DNA repair works: The 3 pathways(00:13:43) - How to Stop cancer with a single drug

Cail RC et al., PNAS - Recombinant human β-cardiac myosin M493I studied by optical trapping and stopped-flow kinetics disrupts the super-relaxed state and increases actin attachment and contractile force. Study Highlights:System: recombinant human β-cardiac heavy meromyosin (cHMM) expressed in C2C12 cells. Methods: ensemble actin gliding, stopped-flow kinetics, NADH ATPase, mantATP single-turnover, and single-molecule three-bead optical trap assays. Main results: M493I preserves Pi release and the two-step 4.7–5 nm working stroke but slows ADP release ~5-fold, doubles steady-state ATPase Vmax, reduces SRX occupancy (KSRX/DRX from ~0.33 to ~0.53), and prolongs actin attachment with increased high-force, long-duration interactions. Functional implication: the combined increase in DRX head availability and prolonged AM·ADP lifetimes produce higher sustained force and faster actin reattachment consistent with a mechanism for HCM hypercontractility and impaired relaxation. Conclusion:The M493I relay-helix mutation disrupts the SRX off state and, together with slowed ADP release and prolonged actin attachment, increases myosin head availability and force production, explaining its hypercontractile HCM phenotype. Music:Enjoy the music based on this article at the end of the episode. Reference:Cail RC, Barua B, Báez-Cruz FA, Winkelmann DA, Goldman YE, Ostap EM. A myosin hypertrophic cardiomyopathy mutation disrupts the super- relaxed state and boosts contractility by enhanced actin attachment. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2521561122. https://doi.org/10.1073/pnas.2521561122 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.castos.com/episodes/m493i-beta-myosin-srx-disruption Chapters (00:00:00) - Heart Hypertrophic Cardiomyopathy: The genetic puzzle(00:04:48) - Myosin motors: Do they Pull or Float?(00:07:50) - Heart Disease: M493I mutant causes heart to slow(00:12:16) - Heart dysrhythmias: The sticky insomniac motor(00:17:54) - Hold on Hold On

Englander SW et al., PNAS - Hydrogen exchange (H-T and NMR H-H) on DNA and RNA reveals two distinct base-pair opening modes: single-base microsecond openings and multi-base millisecond soliton-like loops. Study Highlights:Systems studied include long polynucleotides (DNA, duplex RNA, synthetic long duplexes) and short oligonucleotides; key methods are H-T (tritium) exchange, stopped-flow H-D, and NMR H-H (water relaxation) measurements. H-T exchange of long polymers reports opening-limited EX1 imino exchange with kop ~1/s, reclosing kcl ~20/s and Kop ~10^-2 consistent with multi-base open loops with ms lifetimes. NMR H-H on short oligos reports catalyzable EX2 behavior dominated by single base-pair openings with kcl ~10^6/s and Kop ~10^-6 and microsecond lifetimes. The selective detection implies short oligonucleotides cannot host extensive loops while multi-base soliton-like loops in polynucleotides could dynamically expose sequences for protein or nucleic acid recognition. Conclusion:Both H-T and NMR H-H exchange provide accurate but complementary views: long polynucleotides exhibit frequent multi-base, ms-lived open loops (Kop ~10^-2, kcl ~20/s) while short oligonucleotides reveal rare single-base, μs-lived openings (Kop ~10^-6, kcl ~10^6/s). Music:Enjoy the music based on this article at the end of the episode. Reference:Englander SW. Nucleic acid base pair open states by hydrogen exchange. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2520855122. https://doi.org/10.1073/pnas.2520855122 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.castos.com/episodes/dna-basepair-opening-soliton Chapters (00:00:00) - Papercast: The mystery of DNA(00:02:42) - Breaking down the mystery of DNA(00:03:26) - How does DNA open? The '(00:07:43) - DNA is Not Like Longer Strands(00:11:32) - The physics of DNA replication(00:16:10) - I'm 1% Open

Vatsa A et al., PNAS - In HPV31-positive keratinocytes (CIN612), TOP1α and TOP3β are upregulated and required for viral transcription and replication, acting via distinct effects on R-loop accumulation and topoisomerase-mediated DNA breaks. Study Highlights:Using HPV31-positive CIN612 cells and primary HFK controls, the authors applied ChIP, RADAR, DRIP, alkaline COMET, RNA-seq, and shRNA knockdown to map topoisomerase binding and function. They found TOP1α and TOP3β, but not TOP3α, are elevated in HPV-positive cells and bind the viral URR, and that shRNA depletion of TOP1α or TOP3β reduced episomal viral DNA and early viral transcripts. Knockdown decreased DNA breaks (~50% reduction in COMET tail formation and reduced γH2AX) and altered R-loop levels differentially, with TOP1α depletion increasing viral R-loops by ~50% and TOP3β depletion causing >3-fold R-loop accumulation at viral and cellular loci. Transcriptome changes included reduced IL6/STAT3-AKT signaling after TOP1α loss and marked downregulation of EGR3 (>5-fold) after TOP3β loss, linking distinct mechanistic effects to impaired viral replication. Conclusion:TOP1α and TOP3β are differentially required for maintenance of HPV episomes and viral gene expression through distinct regulation of DNA breaks, R-loop dynamics, and specific host signaling pathways. Music:Enjoy the music based on this article at the end of the episode. Reference:Vatsa A, Templeton CW, Laimins L. Differential roles of type I topoisomerases in regulating HPV pathogenesis. Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2526296123. https://doi.org/10.1073/pnas.2526296123 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.castos.com/episodes/top1alpha-top3beta-hpv-replication Chapters (00:00:00) - How HPV solves its torsional stress(00:02:49) - How do HPV mutations cause cancer?(00:06:16) - HPV cell cancer(00:10:12) - HPV cancer: The DNA damage crisis(00:13:54) - Untie the Loop

Yu C et al., Proc. Natl. Acad. Sci. U.S.A - Genetic mapping and comparative genomics show the lncRNA ANTSR multiallelic locus in Aculeata directs female development via heterozygosity despite lacking sequence homology. Study Highlights:The study analyzed 41 hymenopteran genomes and performed whole-genome resequencing and genetic mapping in Bombus terrestris and Vespa velutina nigrithorax to locate the sex-determining region. The ANTSR locus is a multiallelic noncoding interval between CRELD2 and THUMPD3 that is highly polymorphic and heterozygous in females but homozygous in diploid males across ants, bumblebees, and hornets. Comparative synteny shows the CRELD2–THUMPD3 block originated ~160–200 Mya and the locus has functioned as a zygosity-based female determinant for over 150 million years. Despite this deep functional conservation, alignments and phastCons analyses reveal no detectable sequence homology among distant aculeate lineages, and heterozygosity at ANTSR provides an actionable molecular sex marker for breeding and conservation. Conclusion:The ANTSR multiallelic noncoding locus is an ancient, positionally conserved zygosity-based sex determinant across Aculeata that has retained function for over 150 million years despite complete sequence divergence. Music:Enjoy the music based on this article at the end of the episode. Reference:Yu C, Moog S, Pan Q, Keller Valsecchi CI, Dupont S, Darrouzet E, Darras H, Hodapp D, Colgan TJ, et al. Deep evolutionary conservation of a sex-determining locus without sequence homology. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2522417123. https://doi.org/10.1073/pnas.2522417123 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.castos.com/episodes/antsr-aculeata-sex-locus

Sengstack J et al., Proc. Natl. Acad. Sci. U.S.A - TRDP with Perturb-seq in human fibroblasts found that manipulating TFs (EZH2, E2F3, STAT3, ZFX) reversed aging hallmarks, and EZH2 overexpression rejuvenated aged mouse livers. Study Highlights:The study used passaged human neonatal dermal fibroblasts and aged mouse liver as model systems and applied the Transcriptional Rejuvenation Discovery Platform (TRDP) with Perturb-seq and CRISPRa/CRISPRi screens. Overexpressing E2F3 or EZH2 and repressing STAT3 or ZFX reversed global gene expression toward earlier passage states and ameliorated cellular aging hallmarks including increased proliferation, proteasome activity, and mitochondrial function. In aged mice, AAV8-mediated liver-specific EZH2 overexpression (log2fc ≈ 2.9) reversed thousands of age-associated gene changes (R_rej = -0.42), reduced steatosis and fibrosis, and improved glucose tolerance. Downstream transcriptional programs converged across perturbations, suggesting shared molecular requirements for cellular and tissue rejuvenation. Conclusion:Single transcription factor perturbations identified by TRDP can reverse cellular aging hallmarks in human fibroblasts and, in the case of EZH2 overexpression, partially rejuvenate aged mouse liver with improved histology and glucose tolerance. Music:Enjoy the music based on this article at the end of the episode. Reference:Sengstack J, Li H, Aghayev T, Bier G, Mobaraki M, Zheng J, Lin J, Deng C, Villeda SA, et al. Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2515183123. Published January 9, 2026. https://doi.org/10.1073/pnas.2515183123 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.castos.com/episodes/ezh2-liver-rejuvenation

Perera J et al., R., Thadke S. A., Thrikawala S. W., Wilson W. D., Tan K. W. R., Chand N. Z. W., Phan A. T., Ly D. H., et al. A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1. Proc. Natl. Acad. Sci. U.S.A - Gamma-PNA triplet ligands with Janus bases selectively bind expanded rCUG repeats, displace MBNL1, and show length-dependent cooperativity with partial splicing rescue. Study Highlights:The authors designed compact three-unit bifacial nucleic acid ligands (Janus bases on a γPNA backbone) and evaluated them against rCUG repeat duplexes and DM1 patient-derived myotubes using molecular dynamics, EMSA, SPR, AFM, and cellular splicing assays. MD and EMSA/SPR show cooperative, length-dependent binding with Kd values decreasing to ~0.56 µM for rCUG98 and Hill coefficients rising to ~5, driven by enhanced hydrogen-bonding and π–π stacking between adjacent ligands. AFM revealed a 0.348 nm increase in RNA helix contour height on binding, consistent with a pothole-filling insertion mechanism that selectively recognizes hairpin duplexes over single-stranded RNA. Functionally, a cell-permeable LG2c analog reduced nuclear foci and partially restored mis-splicing of Serca1, cTNT, and IR in DM1 myotubes, though cellular uptake remains limiting. Conclusion:Short bifacial γPNA triplet ligands selectively recognize pathogenic rCUG hairpins via a pothole-filling mechanism, displace MBNL1, and can partially restore splicing in DM1 myotubes while cellular delivery requires further optimization. Music:Enjoy the music based on this article at the end of the episode. Reference:Perera J. D. R., Thadke S. A., Thrikawala S. W., Wilson W. D., Tan K. W. R., Chand N. Z. W., Phan A. T., Ly D. H., et al. A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2507065123. https://doi.org/10.1073/pnas.2507065123 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.castos.com/episodes/pothole-filling-rcug-gamma-pna