️ Episode 186: TNFα–TGFβ Axis Disrupts Nasal Epithelium in Post‑COVID Syndrome

In this episode of PaperCast Base by Base, we explore a single‑cell RNA‑seq study of nasal biopsies showing that persistent immune signaling—not residual virus—drives aberrant epithelial differentiation in people with post‑COVID syndrome. fileciteturn1file0

Study Highlights:
Researchers profiled >56,000 cells from nasal tissue of individuals with moderate or severe post‑COVID syndrome, revealing marked depletion of proximal ciliated cells alongside expansion of basal and immune cell populations. Cell–cell communication and pathway analyses identified heightened TNFα and TGFβ signaling, with MIF–CD74 interactions and downstream NF‑κB/EGFR activity linking immune cells to epithelial remodeling. The team validated causality in air‑liquid interface cultures, where exposure to TGFβ and TNFα—alone and especially in combination—reduced ciliated‑cell differentiation and promoted basal‑cell skewing and EMT‑like programs. Viral RNA was undetectable in biopsies and inflammatory markers typical of acute infection were not elevated, indicating pathology independent of ongoing viral load.

Conclusion:
Targeting the TNFα–TGFβ inflammatory axis may help restore normal epithelial differentiation and mitigate respiratory comorbidities in severe post‑COVID syndrome.

Reference:
Reddy KD, Maluje Y, Ott F, Saurabh R, Schaaf A, Bohnhorst A, et al. scRNA‑seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post‑COVID syndrome. Nature Communications. 2025;16:9494. https://doi.org/10.1038/s41467-025-64778-0

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/

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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 185: Altered Milk Tryptophan in Women Living with HIV

In this episode of PaperCast Base by Base, we explore a longitudinal metabolomics study of human milk that reveals how maternal HIV infection reshapes tryptophan metabolism across lactation, with potential implications for infant immunity, growth, and neurodevelopment.

Study Highlights:
The authors profiled the milk metabolome from hundreds of mothers over the first 18 months postpartum and found a robust, sustained decrease in milk tryptophan alongside higher kynurenine and an elevated kynurenine-to-tryptophan ratio in women living with HIV. Targeted quantification at four months confirmed lower tryptophan and higher kynurenine in milk, and paired plasma analyses mirrored these shifts, indicating systemic depletion rather than altered transfer into milk. An initially unknown metabolite was identified as 3’-deoxy-3’,4’-didehydro-cytidine (ddhC), the free base of an interferon‑inducible antiviral ribonucleotide, and cytosine and dimethylarginine were also elevated, consistent with interferon-driven inflammation. A validation cohort of treated women showed concordant directions of effect and a higher KT ratio, supporting generalizability of the signature beyond the primary cohort.

Conclusion:
Milk tryptophan depletion and interferon‑linked metabolic remodeling in mothers with HIV may contribute to adverse outcomes in HIV‑exposed, uninfected infants and point to testable interventions targeting the kynurenine pathway.

Reference:
Tobin NH, Li F, Zhu W, Ferbas KG, Sleasman JW, Raftery D, Kuhn L, Aldrovandi GM. Altered milk tryptophan and tryptophan metabolites in women living with HIV. Nature Communications. 2025;16:9437. https://doi.org/10.1038/s41467-025-64566-w

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 184: High-Accuracy Multiethnic XGBoost for Skin Cancer Identification

In this episode of PaperCast Base by Base, we explore a large-scale study that builds a risk factor–based XGBoost model using the All of Us cohort to accurately identify patients with skin cancer across diverse ancestries.

Study Highlights:
Analyzing more than 400,000 participants, the authors quantify independent associations between genetic ancestry, lifestyle, social determinants of health, prior cancer history, and use of PDE5A inhibitors with skin cancer risk. They compare traditional logistic regression against gradient-boosted trees and show that logistic models have low precision for case identification, motivating a non-linear approach. The resulting multiethnic XGBoost model achieves high accuracy for identifying patients with any skin cancer, with F1 scores of 0.903 in individuals of European ancestry and 0.810 in non-European groups. SHAP importance and interaction analyses reveal strong non-linear effects of age and genotype principal components, and suggest that genetic and socioeconomic factors contribute more heavily to predictions in younger individuals.

Conclusion:
A multiethnic, non-linear model that integrates genetics, lifestyle, social determinants, and medication exposures can substantially improve early identification of skin cancer patients across ancestries, offering a precision-medicine tool to help reduce outcome disparities.

Reference:
D’Antonio M, Gonzalez Rivera WG, Greenes RA, Gymrek M, Frazer KA. A highly accurate risk factor–based XGBoost multiethnic model for identifying patients with skin cancer. Nature Communications. 2025;16:9542. https://doi.org/10.1038/s41467-025-64556-y

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 183: The Genetic Lottery Goes to School: Better Schools Compensate for Genetic Differences

In this episode of PaperCast Base by Base, we explore a large causal study from Norway asking whether school quality can offset genetic differences in students’ academic skills. Using parent–offspring genetic trios from the Norwegian Mother, Father, and Child Cohort (MoBa) and nationwide administrative data, the authors combine within-family polygenic indices for educational attainment with school value-added measures to test if better schools compensate for genetic disparities.

Study Highlights:
The researchers computed polygenic indices for educational attainment for children while controlling for parental indices to isolate random within-family genetic variation and paired these with causal value-added estimates of school quality derived from population registers. They found a negative gene–environment interaction for reading, indicating that higher-quality schools reduce the impact of polygenic differences on reading scores by about six percent per one standard deviation of school quality exposure in grade 8, with the effect driven by gains among students at the lower end of the polygenic index distribution. For numeracy, the interaction was null despite clear main effects of both genetics and school value-added, a pattern consistent with higher persistence of numeracy skills during this developmental period. Validation analyses supported exogeneity of the within-family genetic component and of the school value-added measures, and sensitivity checks suggested that the findings are not artifacts of test scaling or ceiling effects. fileciteturn0file0

Conclusion:
In a causally identified framework, better schools can partially compensate for genetic differences in reading but not numeracy during lower secondary school, implying that investments in school quality may narrow genetically correlated gaps in foundational literacy.

Reference:
Cheesman R, Borgen N, Sandsør AMJ, Hufe P. The genetic lottery goes to school: Better schools compensate for the effects of students’ genetic differences. Proceedings of the National Academy of Sciences. 2025;122(43):e2511715122. https://doi.org/10.1073/pnas.2511715122

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 182: Genotypic, Functional, and Phenotypic Characterization in CTNNB1 Neurodevelopmental Syndrome

In this episode of PaperCast Base by Base, we explore a large cross-sectional cohort study that integrates genetics, cellular functional assays, and deep phenotyping to map the landscape of CTNNB1 neurodevelopmental syndrome. The authors analyze variant types across 127 individuals from 20 countries, probe Wnt/β-catenin signaling consequences in vitro, and connect genotypes to clinical trajectories and everyday function.

Study Highlights:
The cohort revealed 88 distinct CTNNB1 variants with a strong enrichment for predicted loss-of-function changes, and functional luciferase assays confirmed reduced Wnt/β-catenin pathway activity for most variants. A subset of truncating variants showed dominant-negative behavior, while a rare missense change (G575R) behaved as a gain-of-function with increased protein stability and signaling. Systematic clinical assessments documented frequent motor impairment, hypotonia, dysmorphic features, visual issues such as strabismus, and developmental delays including later independent walking. Missense variants tended to associate with comparatively milder phenotypes, with earlier walking and better communication, social, and feeding skills than frameshift, nonsense, splice, or deletion variants.

Conclusion:
By combining genomic curation, mechanistic assays, and standardized clinical measures, this study refines the natural history of CTNNB1 syndrome and highlights therapeutic avenues that may upregulate CTNNB1 expression while cautioning about variant-specific effects.

Reference:
Zakelj N, Gosar D, Miroševič Š, Sanders SJ, Ljungdahl A, Kohani S, Huang S, Leong LI, An Y, Teo MJ, Moultrie F, Jerala R, Lainšek D, Forstnerič V, Sušjan P, Lisowski L, Perez-Iturralde A, Orazem Mrak J, Chan HYE, Osredkar D. Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome. Human Genetics and Genomics Advances. 2025;6:100483. https://doi.org/10.1016/j.xhgg.2025.100483

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 181: Creatine Transporter SLC6A8: Conservation and Variant Impact

In this episode of PaperCast Base by Base, we explore how the creatine transporter gene SLC6A8 (CRT1) is evolutionarily conserved across terrestrial mammals and how disease-associated variants alter creatine uptake in vitro, shedding light on genotype–phenotype relationships in creatine transporter deficiency. fileciteturn0file0

Study Highlights:
The authors compared CRT1 amino acid sequences among multiple species and found striking conservation, with human transmembrane domains 1–10 identical across the mammals analyzed and most interspecies differences confined to terminal or loop regions. They curated benign and pathogenic missense variants from public databases and mapped them onto CRT1, observing that missense changes in N‑ and C‑termini are more often tolerated, whereas variants within core transmembrane domains and specific loop regions are frequently pathogenic. Functional assays in transfected cells demonstrated that eight of nine tested patient variants—most located in transmembrane segments—caused severe reductions in creatine transport, while a peripheral extracellular loop variant produced a more modest decrease. Integrating intolerance profiling with phylogenetic and experimental data, the study highlights a hotspot between amino acids 305–415 and underscores strong structural constraints that shape CRT1 function.

Conclusion:
Together, these results provide a practical framework for interpreting SLC6A8 variants in the clinic and suggest that domain-aware assessments can better predict which alterations are likely to impair creatine transport and contribute to neurodevelopmental disease.

Reference:
Diep T, Lipshutz GS. Evaluation of SLC6A8 species conservation and the effect of pathogenic variants on creatine transport. Human Genetics and Genomics Advances. 2025;6:100489. https://doi.org/10.1016/j.xhgg.2025.100489

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 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/

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 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/