Base by Base

️ Episode 180: Leveraging Global Genetics Resources for Equitable Polygenic Prediction

In this episode of PaperCast Base by Base, we explore how multi-ancestry genome-wide association study resources and modern polygenic score methodologies can improve prediction accuracy across African, East Asian, and European populations, with a focus on practical, computationally efficient strategies that work even when individual-level data are unavailable.

Study Highlights:
This article systematically benchmarks leading single-source and multi-source polygenic score methods across 10 complex traits using GWAS summary statistics from Ugandan Genome Resource, Biobank Japan, UK Biobank, and the Million Veteran Program. The authors show that combining ancestry-aligned and European GWAS improves prediction in non-European targets and that independently optimized multi-source approaches often outperform jointly optimized methods while being far more computationally efficient. They introduce a generalizable use of the LEOPARD framework to estimate optimal linear combinations of population-specific scores using only summary statistics, achieving performance comparable to individual-level tuning in many settings. All methods are implemented in the GenoPred pipeline, providing an accessible, reference-standardized workflow for equitable polygenic prediction across diverse populations.

Conclusion:
Multi-source, summary-statistics–friendly approaches implemented in GenoPred offer a practical path to more accurate and equitable polygenic prediction, particularly when leveraging diverse GWAS resources and efficient tuning frameworks like LEOPARD.

Reference:
Pain O. Leveraging global genetics resources to enhance polygenic prediction across ancestrally diverse populations. Human Genetics and Genomics Advances. 2025;6:100482. https://doi.org/10.1016/j.xhgg.2025.100482

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/

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If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 179: Mosaicism for Autosomal Trisomies: Maternal Age, UPD, and Reproductive History in 1,266 Cases
In this episode of PaperCast Base by Base, we explore a comprehensive literature analysis of 1,266 reported cases of autosomal trisomy mosaicism, contrasting prenatal cohorts—true fetal mosaicism and confined placental mosaicism—with postnatal diagnoses to clarify how maternal age and reproductive history relate to outcomes and uniparental disomy.

Study Highlights:
The authors screened 596 publications and assembled 948 prenatal and 318 postnatal mosaicism cases to compare outcome patterns and demographics. They found that advanced maternal age was more common in pregnancies with normal outcomes than in those with abnormal outcomes (73% vs 56%), while pregnancies ending in fetal loss showed a 50% advanced maternal age rate. Mosaic carriers with concomitant uniparental disomy of chromosomes 7, 14, 15, or 16 had markedly higher advanced maternal age than those with biparental disomy overall (78% vs 48%), suggesting age-associated biases in trisomy rescue. Reporting of reproductive history was limited, but prior fetal loss was nearly twice as frequent among mothers in the postnatal cohort compared with the prenatal cohort (30% vs 16%), and prior chromosomal abnormalities in earlier pregnancies appeared substantially enriched relative to non-mosaic series.

Conclusion:
These findings challenge assumptions drawn from non-mosaic trisomies and indicate that maternal age and reproductive history shape both outcomes and the likelihood of uniparental disomy in autosomal trisomy mosaicism, motivating better standardized reporting and registry-based studies.

Reference:
Kovaleva, N. V.; Cotter, P. D. Mosaicism for Autosomal Trisomies: A Comprehensive Analysis of 1266 Published Cases Focusing on Maternal Age and Reproductive History. Genes 2024, 15, 778. https://doi.org/10.3390/genes15060778

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 178: TP53 Reduced Penetrance: Predictive Features and Clinical Implications

In this episode of PaperCast Base by Base, we explore how a large ClinVar-anchored analysis integrates functional assays, computational predictors, immunogenicity estimates, allele frequencies, and clinical presentation to identify TP53 variants with reduced penetrance relative to classic Li-Fraumeni syndrome.

Study Highlights:
The authors reviewed ClinVar to assemble a set of TP53 variants flagged by diagnostic labs as reduced penetrance and compared them with benign and standard pathogenic reference sets using four independent functional assays and multiple in silico tools. Reduced penetrance variants tended to show intermediate activity in functional assays—most prominently in the Kato yeast transactivation readout—and had deleterious predictions by BayesDel and AlphaMissense, but with lower scores than standard pathogenic variants. These variants occurred at higher population frequencies than standard pathogenic variants, and carriers presented with cancer at later ages and with attenuated enrichment for classic Li-Fraumeni core cancers, although early-onset breast cancer and pediatric sarcomas remained associated. A random forest model using functional scores, predictors, immune fitness, and allele frequency prioritized 106 additional TP53 variants of uncertain or conflicting significance as potential reduced penetrance candidates for future study.

Conclusion:
The work outlines measurable features that distinguish reduced penetrance TP53 variants from both benign and standard high-penetrance variants, supporting refined classification and personalized surveillance strategies for carriers.

Reference:
Fortuno, C., Richardson, M. E., Pesaran, T., McGoldrick, K., James, P. A., & Spurdle, A. B. (2025). Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53. *Human Genetics and Genomics Advances*, 6, 100484. https://doi.org/10.1016/j.xhgg.2025.100484

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/

️ Episode 177: Biallelic MCM8/MCM9 Variants: From Hypogonadism to Cancer Predisposition

In this episode of PaperCast Base by Base, we explore a multi‑cohort clinical–genomic study that delineates the phenotype of individuals with biallelic germline variants in MCM8 or MCM9, clarifying links to polyposis and early‑onset cancers in addition to the long‑recognized association with hypogonadism.

Study Highlights:
Using population datasets (100,000 Genomes Project, UK Biobank, and gnomAD), a curated case series, and tumor sequencing, the authors assessed cancer and reproductive phenotypes among carriers of predicted deleterious variants. They found significant enrichment of biallelic MCM9 variants among participants with colonic and rectal polyps and with gastric cancer in the 100,000 Genomes Project, whereas no similar enrichment was seen for MCM8 or in UK Biobank. Across the aggregated case series (26 biallelic MCM8 and 28 biallelic MCM9 carriers), MCM9—but not MCM8—was associated with polyposis and early‑onset colorectal cancer, while both genes were linked to hypogonadism and to female germ cell tumors presenting in early adolescence. Tumor mutational‑signature analysis predominantly showed clock‑like processes without a consistent pattern of mismatch‑repair or homologous‑recombination deficiency, suggesting that many tumors in carriers are not defined by a distinctive repair‑defect signature. The authors recommend inclusion of MCM8/MCM9 on diagnostic panels for relevant clinical contexts and propose surveillance considerations for biallelic carriers.

Conclusion:
Biallelic MCM9 variants confer risk for polyposis, gastric cancer, and early‑onset colorectal cancer, and biallelic variants in either MCM8 or MCM9 are consistently linked to hypogonadism and early germ cell tumors, supporting panel inclusion and individualized surveillance strategies.

Reference:
Helderman, N. C., Yang, T., Palles, C., Terlouw, D., Mei, H., Vorderman, R. H. P., Cats, D., Díaz‑Gay, M., Jongmans, M. C. J., Ramdien, A., van de Beek, I., Eleveld, T. F., Green, A., Hes, F. J., van den Heuvel‑Eibrink, M. M., Van Der Kelen, A., Kliesch, S., Kuiper, R. P., Lakeman, I. M. M., Lashley, L. E. E. L. O., Looijenga, L. H. J., Oud, M. S., Steingröver, J., Tenenbaum‑Rakover, Y., Tops, C. M., Tüttelmann, F., de Voer, R. M., Westra, D., Wyrwoll, M. J., Golubicki, M., Antelo, M., Bonjoch, L., Terradas, M., Valle, L., Alexandrov, L. B., Morreau, H., van Wezel, T., Castellví‑Bel, S., Goldberg, Y., & Nielsen, M. (2025). Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9. *Human Genetics and Genomics Advances*, 6, 100480. https://doi.org/10.1016/j.xhgg.2025.100480

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 176: FAHD1 and the Pyruvate-Driven Evolution of Hepatocellular Carcinoma

In this episode of PaperCast Base by Base, we explore how multi-omics integration—spanning single-cell transcriptomics, spatial mapping, and causal genetic inference—uncovers a pyruvate-hyperactive epithelial subpopulation in hepatocellular carcinoma and identifies FAHD1 as a central regulator linked to poor prognosis and immune evasion.

Study Highlights:
The authors harmonized six single-cell metabolic scoring methods across tens of thousands of tumor microenvironment cells and uncovered PyHighEpi cells with elevated pyruvate metabolism, stemness, and proliferation that concentrate in tumor cores. Spatial transcriptomics traced evolutionary trajectories from stromal transition zones into malignant foci and showed that pyruvate activity scales with spatial progression. Summary data-based Mendelian randomization pinpointed FAHD1 as a causal driver of HCC susceptibility, and FAHD1+ epithelial cells engaged cancer‑associated fibroblasts via ITGB2 to sculpt a TGF‑β/VEGF‑enriched niche consistent with immune escape. Functional knockdown experiments reduced proliferation, migration, and invasion, while an eight‑gene FAHD1‑derived risk score stratified survival and predicted responsiveness to PD‑1 blockade; in silico docking also suggested tivozanib as a potential FAHD1‑targeting compound.

Conclusion:
By linking mitochondrial pyruvate control to stromal crosstalk and immune suppression, the study positions FAHD1 as a therapeutic entry point and proposes risk-guided, metabolism‑plus‑immunity strategies for difficult‑to‑treat HCC.

Reference:
Huang, J., Liang, S., Sun, J., & Chen, H. (2025). FAHD1‑mediated pyruvate metabolism in hepatocellular carcinoma: Multi‑omics and causal genetic evidence. *Human Genetics and Genomics Advances*, 6, 100494. https://doi.org/10.1016/j.xhgg.2025.100494

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 175: Predictive Prioritization of Pancreatic Enhancers Linked to Disease Risk

In this episode of PaperCast Base by Base, we explore how enhancer–promoter 3D chromatin maps from five primary human pancreatic cell types were transformed into graph “tree” models to quantify enhancer connectivity and prioritize elements most critical for cell-type-specific gene expression, creating a framework to connect noncoding variants to function in pancreatic disease.

Study Highlights:
The authors profiled H3K27ac HiChIP and ATAC‑seq across 28 donors, building enhancer–promoter tree models that capture direct and indirect loops and reveal modular “forests” centered on promoter–promoter hubs.
They developed EPIC, a k‑nearest‑neighbors model using chromatin features and tree topology to rank enhancers by their predicted effect on cell‑type‑specific transcription and validated top predictions in primary human cells using CRISPRa/i with single‑cell RNA FISH readouts.
Direct E1 enhancer loops predominated and multiple enhancers additively boosted expression of lineage‑defining genes, while EPIC‑prioritized enhancers overlapped germline risk variants for type 2 diabetes and pancreatic ductal adenocarcinoma.
GWAS integration pointed to unexpected enrichment of PDAC‑associated variants in acinar enhancers and experimental perturbation at the XBP1 locus reduced transcripts in line with predicted effect sizes.

Conclusion:
Enhancer tree models coupled with the EPIC prioritization algorithm provide a scalable route to nominate and validate functional noncoding elements and their target genes in the human pancreas, sharpening variant‑to‑function studies and disease mechanism discovery.

Reference:
Wang L, Baek S, Prasad G, Wildenthal J, Guo K, Sturgill D, Truongvo T, Char E, Pegoraro G, McKinnon K, The Pancreatic Cancer Cohort Consortium, The Pancreatic Cancer Case‑Control Consortium, Hoskins JW, Amundadottir LT, Arda HE. Predictive prioritization of enhancers associated with pancreatic disease risk. Cell Genomics. 2026;6:101040. https://doi.org/10.1016/j.xgen.2025.101040

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 174: TMEM217–SLC9C1: Wiring the cAMP Switch for Sperm Motility and Male Fertility

In this episode of PaperCast Base by Base, we explore a PNAS study revealing how TMEM217 forms a complex with the sperm-specific Na+/H+ exchanger SLC9C1 to organize cAMP signaling, sustain motility, and enable fertilization in mice.

Study Highlights:
Using phylogenetic profiling and interactomics, the authors identified TMEM217 as a conserved partner of the exchanger SLC9C1 and showed that both proteins localize to the principal piece of the sperm flagellum. Knockout of Tmem217 produced severe motility defects and infertility with hairpin flagellar bending, accompanied by loss of SLC9C1 and full-length soluble adenylyl cyclase, reduced cAMP levels, and dampened PKA and tyrosine phosphorylation. Co-immunoprecipitation and AlphaFold3 modeling demonstrated that TMEM217 binds the voltage-sensing domain of SLC9C1, supporting a mechanism that assembles the SLC9C1–sAC–cAMP axis during spermiogenesis. Pharmacologic boosting of cAMP paired with membrane-conditioning media restored motility and fertilization in vitro, yielding viable offspring after embryo transfer.

Conclusion:
Dissecting the TMEM217–SLC9C1 interface and local cAMP control suggests diagnostics and mutation-agnostic therapeutic strategies for asthenozoospermia and male infertility.

Reference:
Iida-Norita R, Miyata H, Ninomiya A, Emori C, Kamoshita M, Pan C, Wang H, Ikawa M. Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility. Proceedings of the National Academy of Sciences. 2025;122(42):e2513924122. https://doi.org/10.1073/pnas.2513924122

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 173: Bottlebrush Block Copolymer Shields Muscles and Prevents DMD Onset

In this episode of PaperCast Base by Base, we explore a PNAS study showing how a synthetic bottlebrush block copolymer can act as a powerful membrane stabilizer to protect dystrophin-deficient muscle in Duchenne muscular dystrophy.

Study Highlights:
Researchers engineered and tested an amphiphilic bottlebrush diblock polymer, B–PEO43_10–PPO15_5, as a membrane stabilizer in the mdx mouse model of Duchenne muscular dystrophy. At nanomolar doses, the polymer rapidly restored twitch contractility in single dystrophin‑deficient fibers and showed ~150,000‑fold greater potency than optimized linear PEO–PPO copolymers. Early systemic dosing from postnatal day 1 to 21 prevented the surge of serum creatine kinase and blocked histologic hallmarks of damage in tibialis anterior and diaphragm while routine liver and kidney panels remained normal. In adult mice, pretreatment prevented IgG entry into myocardium during isoproterenol stress and significantly improved survival during combined handling and β‑adrenergic stress tests.

Conclusion:
This work positions bottlebrush block copolymers as fast‑acting, mutation‑agnostic membrane stabilizers with potential to preserve skeletal, respiratory, and cardiac muscle when deployed early and to complement gene‑based therapies.

Reference:
Cohen H, Bez Batti Angulski A, Quick JD, Kuebler TS, Thompson BR, Bauer J, Hahn D, Townsend D, Hassler JF, Hackel BJ, Lodge TP, Sham YY, Bates FS, Metzger JM. Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy. Proceedings of the National Academy of Sciences. 2025;122(42):e2513599122. https://doi.org/10.1073/pnas.2513599122

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 172: When Random DNA Fights Back: De Novo Gene Birth as Antiphage Defense

In this episode of PaperCast Base by Base, we explore a PNAS study showing that short, previously nongenic DNA sequences can quickly evolve into genes that help bacteria survive phage attack, illuminating early steps of gene birth and the host–virus arms race. fileciteturn2file0

Study Highlights:
The authors screened two massive libraries totaling ~100 million (semi-)random open reading frames in Escherichia coli and recovered thousands of sequences that improved survival during T4 phage challenge. A set of short proteins, dubbed Random Inhibitors of Phage infection (Rips), broadly protected cells by activating the Rcs envelope-stress pathway and triggering colanic-acid capsule production that physically blocks adsorption. A second class of hits, Random T4 Inhibitor Products (rtp1–4), acted with specificity by reducing expression of the OmpC outer-membrane receptor, thereby limiting T4 and other OmpC-dependent phage entry; for some rtp genes the protective molecule was RNA rather than protein. Transcriptomics, reporter assays, and adsorption measurements supported these mechanisms while showing minimal growth penalties, and evolved T4 variants rapidly gained baseplate mutations that restored adsorption and infectivity.

Conclusion:
Random sequence space harbors many routes to immediate fitness gains, with de novo protein- and RNA-based functions rewiring bacterial envelopes and receptors in ways that both reveal mechanisms of gene birth and suggest new antiphage strategies.

Reference:
Frumkin I, Vassallo CN, Chen YH, Laub MT. Emergence of antiphage functions from random sequence libraries reveals mechanisms of gene birth. Proceedings of the National Academy of Sciences. 2025;122(42):e2513255122. https://doi.org/10.1073/pnas.2513255122 fileciteturn2file0

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/

Danchuk S et al., Proceedings of the National Academy of Sciences - Virulence Hierarchies in the Tuberculosis Complex—What Makes Some Lineages Deadlier?

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Virulence hierarchies within the
Mycobacterium tuberculosis
complex

First author:
Danchuk S

Journal:
Proceedings of the National Academy of Sciences

DOI:
10.1073/pnas.2507104122

Reference:
Danchuk S.N., Duffy S.C., Sullivan J., Beenish Rufai S., McIntosh F.A., Lupien A., et al.. Virulence hierarchies within the
Mycobacterium tuberculosis
complex. Proceedings of the National Academy of Sciences, 122. (2025). https://doi.org/10.1073/pnas.2507104122

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