️ Episode 131: pBI143: The Human Gut’s Hidden Heavyweight

In this episode of PaperCast Base by Base, we explore how a tiny 2.7 kb cryptic plasmid, pBI143, emerges as one of the most numerous genetic elements in industrialized human gut microbiomes, mobilizes across Bacteroidales, persists as monoclonal lineages with vertical transmission, and increases its copy number under stress and in inflammatory bowel disease.

Study Highlights:
The authors surveyed 4,516 globally distributed gut metagenomes and found that the 2.7 kb plasmid pBI143 is highly prevalent in industrialized populations and, when normalized by genome size, is on average at least fourteen times more numerous than crAssphage. Isolate screening and conjugation assays showed transfer between Bacteroidales species, while single‑nucleotide‑variant profiling revealed largely monoclonal populations within individuals and frequent vertical transmission from mothers to infants. In gnotobiotic mice, pBI143 imposed a small fitness cost on Bacteroides fragilis, yet metagenomic assemblies occasionally captured larger pBI143 variants bearing cargo genes that could benefit hosts and suggest a natural shuttle vector. Copy‑number measurements increased under oxidative stress in vitro and were significantly higher in metagenomes from individuals with inflammatory bowel disease, and a qPCR assay demonstrated pBI143’s sensitivity and specificity as a marker of human fecal contamination.

Conclusion:
Together these findings position pBI143 as a human-specific, ultra-abundant mobile element that serves as a sensitive biomarker of gut stress and contamination while offering a natural backbone for payload delivery in the microbiome.

Reference:
Fogarty EC, Schechter MS, Lolans K, Sheahan ML, Veseli I, Moore RM, Kiefl E, Moody T, Rice PA, Yu MK, Mimee M, Chang EB, Ruscheweyh H‑J, Sunagawa S, McLellan SL, Willis AD, Comstock LE, Eren AM. A cryptic plasmid is among the most numerous genetic elements in the human gut. Cell. 2024;187(5):1206–1222. https://doi.org/10.1016/j.cell.2024.01.039

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 130: Combining Evidence from Human Genetic and Functional Screens to Identify Pathways Altering Obesity and Fat Distribution

In this episode of PaperCast Base by Base, we explore a large-scale study that integrates genetic association testing with functional CRISPR experiments in human adipocytes to uncover mechanisms influencing obesity and body fat distribution. By analyzing data from more than 400,000 individuals in the UK Biobank and combining it with laboratory assays, the researchers highlight novel genetic contributors to lipid accumulation.

Study Highlights:
The study examined rare and common genetic variants across nine obesity-related and fat distribution traits, identifying 69 genes associated with overall adiposity or specific fat depots. Among these, 14 genes were selected for CRISPR knockdown experiments in human white adipose tissue cell lines. Knockdown of PPARG and SLTM significantly reduced lipid accumulation, while COL5A3 knockdown increased it. The results demonstrate how converging population genetics and in vitro evidence can pinpoint therapeutic targets for obesity and related conditions.

Conclusion:
This integrative approach suggests that targeting key genes regulating adipogenesis could open new therapeutic avenues for obesity and fat distribution disorders.

Reference:
Baya, N.A., Erdem, I.S., Venkatesh, S.S., Reibe, S., Charles, P.D., Navarro-Guerrero, E., Hill, B., Lassen, F.H., Claussnitzer, M., Palmer, D.S., & Lindgren, C.M. (2025). Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution. *The American Journal of Human Genetics*, 112, 1–22. https://doi.org/10.1016/j.ajhg.2025.08.013

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/

Keywords: obesity, fat distribution, exome sequencing, CRISPR, adipogenesis

️ Episode 129: Structural variation and diversification of the NPIP gene family from the human pangenome

In this episode of PaperCast Base by Base, we explore how long-read sequencing technologies reveal the structural variation, evolutionary pressures, and expression patterns of the NPIP gene family, one of the most positively selected gene families in humans and African apes.

Study Highlights:
Using long-read assemblies of 169 human haplotypes, researchers discovered extreme variability in NPIP loci organization and identified both fixed and polymorphic paralogs. They observed ongoing positive selection acting on specific NPIP copies, as well as large inversion polymorphisms and frequent gene conversion events shaping the genomic landscape. Long-read RNA sequencing enabled the construction of paralog-specific gene models, with more than half of the predicted protein isoforms previously undocumented. Expression analysis revealed that certain NPIP paralogs show brain-enriched patterns, while others maintain testis-specific expression, suggesting lineage-specific neofunctionalization.

Conclusion:
This study highlights the dynamic evolutionary trajectory of the NPIP gene family and provides a foundation for linking its variation to human phenotypes and disease.

Reference:
Dishuck, P.C., Munson, K.M., Lewis, A.P., Dougherty, M.L., Underwood, J.G., Harvey, W.T., Hsieh, P., Pastinen, T., & Eichler, E.E. (2025). Structural variation, selection, and diversification of the NPIP gene family from the human pangenome. *Cell Genomics*, 5, 100977. https://doi.org/10.1016/j.xgen.2025.100977

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/

Keywords: NPIP gene family, human pangenome, positive selection, structural variation, long-read sequencing

️ Episode 128: LINE‑1 Promoters Orchestrate Early Human Brain Development

In this episode of PaperCast Base by Base, we explore how evolutionarily young LINE‑1 retrotransposons are actively expressed in human induced pluripotent stem cells and function as cis‑acting promoters that shape primate‑ and human‑specific transcript isoforms during early neural differentiation.

Study Highlights:
The authors combine short‑ and long‑read RNA‑seq with CUT&RUN epigenomic profiling and long‑read DNA methylation analysis to map thousands of unique L1 loci expressed in hiPSCs and early cerebral organoids. L1 promoter activity correlates with H3K4me3 enrichment and hypomethylation, and the L1‑derived protein ORF1p is abundant in hiPSCs. Using an optimized KRAB‑dCas9 CRISPR interference system targeting the 5′ UTR, they achieve on‑target silencing of young, full‑length L1s and uncover nearly a hundred L1‑driven chimeric transcripts, including alternative promoter isoforms for protein‑coding genes such as ELAPOR2, PPP1R1C, and PLCB1. In cerebral organoids, L1 expression is globally reduced with differentiation‑coupled remethylation yet remains locus‑specific and variable, and L1 silencing shifts neural progenitor transcriptional programs and yields smaller organoids without altering overall cell‑type composition.

Conclusion:
LINE‑1 promoters provide a hominoid‑specific regulatory layer that tunes the exit from pluripotency and the tempo of early human brain development, with implications for human brain evolution and neurodevelopmental disease mechanisms.

Reference:
Adami A, Garza R, Gerdes P, Johansson PA, Dorazehi F, Koutounidou S, Castilla‑Vallmanya L, Atacho DAM, Sharma Y, Johansson JG, Tam O, Kirkeby A, Barker RA, Hammell MG, Douse CH, Jakobsson J. LINE‑1 retrotransposons mediate cis‑acting transcriptional control in human pluripotent stem cells and regulate early brain development. Cell Genomics. 2025;5:100979. https://doi.org/10.1016/j.xgen.2025.100979

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/

Keywords: LINE‑1 retrotransposons; alternative promoters; cerebral organoids; human iPSCs; neural differentiation

️ Episode 127: In silico generation of synthetic cancer genomes using generative AI

In this episode of PaperCast Base by Base, we explore OncoGAN, a generative AI pipeline designed to produce highly realistic synthetic cancer genomes. The study addresses the challenge of limited access to real cancer genomes due to privacy concerns by creating shareable, simulated datasets that preserve donor confidentiality.

Study Highlights:
The authors developed OncoGAN, a multimodel ensemble combining GANs, tabular variational autoencoders, and random sampling strategies trained on large-scale cancer genome datasets. The pipeline accurately reproduces somatic mutations, copy number alterations, and structural variants across tumor types, while maintaining tumor-specific mutational signatures and positional mutation patterns. Validation using DeepTumour demonstrated that the synthetic data closely mirrors real tumor genomes and can improve classification models when used to augment training datasets. Importantly, the simulated genomes are fully open access, overcoming the barriers of restricted patient data sharing and providing valuable resources for benchmarking and improving cancer genome analysis tools.

Conclusion:
OncoGAN represents a major advance in generating synthetic cancer genomes, enabling open, privacy-preserving data sharing while enhancing the development and benchmarking of genomic analysis tools.

Reference:
Díaz-Navarro, A., Zhang, X., Jiao, W., Wang, B., & Stein, L. (2025). In silico generation of synthetic cancer genomes using generative AI. Cell Genomics, 5, 100969. https://doi.org/10.1016/j.xgen.2025.100969

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/

Keywords: synthetic genomes, OncoGAN, cancer genomics, generative AI, data privacy

️ Episode 126: Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models

In this episode of PaperCast Base by Base, we explore a study that investigates the molecular and developmental mechanisms underlying Smith-Magenis syndrome (SMS) using human induced pluripotent stem cell (hiPSC)-derived cortical models. The research focuses on how the deletion at chromosome 17p11.2 disrupts cortical development and contributes to neurological deficits.

Study Highlights:
The authors developed both 2D cortical neurons and 3D cortical organoids from SMS hiPSCs to model human corticogenesis. Hi-C analyses revealed widespread chromatin miswiring, including fusion and reorganization of topological domains. Single-nucleus RNA sequencing uncovered transcriptional signatures linked to neuropsychiatric disorders and dysregulation of genes involved in metabolism, the cell cycle, and neuronal signaling. SMS organoids exhibited reduced growth, ventriculomegaly-like features, impaired progenitor proliferation, and accelerated neuronal maturation. SMS cortical neurons also displayed increased dendritic growth followed by hyperexcitability due to reduced potassium conductance.

Conclusion:
This work demonstrates that deletion at 17p11.2 disrupts multiple stages of human cortical development, highlighting how chromatin architecture changes translate into transcriptional and neurophysiological abnormalities relevant to SMS.

Reference:
Lee YJ, Chang YT, Cho Y, Kowalczyk M, Dragoiescu A, Pacis A, Kailasam S, Lefebvre F, Zhang Q, Gao X, Huang WH. Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models. Am J Hum Genet. 2025 Oct 2;112(1):1–25. https://doi.org/10.1016/j.ajhg.2025.07.020

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 125: Tackling a disease on a global scale, the Global Parkinson’s Genetics Program, GP2: A new generation of opportunities

In this episode of PaperCast Base by Base, we explore how the Global Parkinson’s Genetics Program (GP2) is addressing the critical lack of diversity in Parkinson’s disease genetics research. The article outlines the program’s mission to establish a global hub for recruitment, data generation, and collaborative discovery, while reflecting on five years of progress.

Study Highlights:
The authors describe the complex challenges of building a sustainable and equitable international research collective to study Parkinson’s disease genetics. GP2 has partnered with 275 research groups worldwide, with over 265,000 subjects committed to the program, and emphasizes the importance of transparency, training, and democratization of data. The article details GP2’s operational priorities, including capacity building in underrepresented populations, development of new infrastructure, and implementation of training programs that support the next generation of scientists. By harmonizing and openly sharing clinical and genetic data, GP2 has already facilitated new discoveries, such as ancestry-specific risk variants, and continues to expand the scope of Parkinson’s research globally.

Conclusion:
This work demonstrates how global collaboration and equitable research practices can accelerate genetic discoveries in Parkinson’s disease and pave the way for precision medicine worldwide.

Reference:
Blauwendraat, C., Noyce, A. J., Mata, I. F., Screven, L. A., Solle, J., Dumanis, S. B., Riley, E. A., Periñan, M. T., Okubadejo, N., Klein, C., Morris, H. R., Singleton, A. B., and the Global Parkinson’s Genetics Program (GP2). Tackling a disease on a global scale, the Global Parkinson’s Genetics Program, GP2: A new generation of opportunities. The American Journal of Human Genetics (2025). https://doi.org/10.1016/j.ajhg.2025.07.014

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 124: Exploring the Omnigenic Architecture of Selected Complex Traits

In this episode of PaperCast Base by Base, we explore how researchers are uncovering the organizational principles behind complex traits through the lens of the omnigenic model. The study focuses on ulcerative colitis as a case example and investigates how core and peripheral genes interact within multi-modal molecular networks to shape disease risk and regulation.

Study Highlights:
The authors employed the Speos machine-learning framework to identify core genes for ulcerative colitis and validated their predictions across multiple datasets. Core genes displayed strong tissue-specific expression and robust enrichment in disease-relevant pathways, setting them apart from peripheral genes with similar GWAS signals. Perturbation analyses revealed that nearly one-third of genetic perturbations had distinct effects on core genes compared to peripheral genes, supporting a central assumption of the omnigenic model. Furthermore, co-perturbation simulations highlighted frequent non-linear interactions among core genes, suggesting that genetic regulation involves synergistic and suppressive dynamics not previously accounted for.

Conclusion:
These findings expand the omnigenic model by demonstrating that core genes occupy central positions in molecular networks and are subject to coordinated regulation, offering new insights into the missing heritability of complex traits.

Reference:
Ratajczak F, Heinig M, Falter-Braun P. Exploring the omnigenic architecture of selected complex traits. Am J Hum Genet. 2025 Sep 4;112(1):1–23. https://doi.org/10.1016/j.ajhg.2025.07.006

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/

Keywords: omnigenic model, core genes, ulcerative colitis, machine learning, complex traits

️ Episode 123: Dominant‑Negative ATP5F1A Variants Uncouple Complex V and Drive Neurological Disease

In this episode of PaperCast Base by Base, we explore how de novo heterozygous ATP5F1A missense variants disrupt mitochondrial ATP synthase and manifest as pediatric neurological disorders, revealing a dominant‑negative mechanism and an isolated Complex V defect.

Study Highlights:
The authors describe six probands with developmental delay, dystonia, pyramidal tract signs and failure to thrive, each carrying ATP5F1A variants clustered at the α–β or α–γ interfaces of the F1 sector of ATP synthase. In vivo CRISPR knock‑ins of orthologous variants in C. elegans behaved dominantly, slowed development and locomotion, and activated a mitochondrial stress response that was dose‑dependently suppressed by adding wild‑type gene copies. Patient‑derived cells showed reduced abundance and ATPase activity of Complex V, with increased oxygen consumption but decreased mitochondrial membrane potential and ATP levels, indicating uncoupled oxidative phosphorylation. Structural modeling supported disrupted subunit interactions, and proteomics demonstrated an isolated Complex V deficiency distinct from earlier reports for other ATP5F1A alterations.

Conclusion:
This work expands the genetic and phenotypic spectrum of ATP5F1A‑related disease and establishes ATP5F1A as a leading nuclear cause of Complex V deficiency while highlighting organismal modeling as a powerful approach to resolve variants of uncertain significance.

Reference:
Fielder SM, Friederich MW, Hock DH, Zhang JR, Valin LM, Rosenfeld JA, Booth KTA, Brown NJ, Rius R, Sharma T, Semcesen LN, Worley KC, Burrage LC, Treat K, Samson T, Govert S, DaCunha S, Yuan W, Chen J, Lesinski J, Hoang H, Morrison SA, Ladha FA, Van Hove R, Michel CR, Reisdorph R, Tycksen E, Baldridge D, Silverman GA, Soler‑Alfonso C, Conboy E, Vetrini F, Emrick L, Craigen WJ, Undiagnosed Diseases Network, Sykes SM, Stroud DA, Van Hove JLK, Schedl T, Pak SC. Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders. EMBO Molecular Medicine. 2025.  https://doi.org/10.1038/s44321-025-00290-8

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/

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Keywords: ATP5F1A; Complex V; dominant negative; mitochondrial uncoupling; neurological disorders

️ Episode 122: Patient Stratification Reveals the Molecular Basis of Disease Co-Occurrences

In this episode of PaperCast Base by Base, we explore a study that investigates the molecular underpinnings of why certain diseases tend to co-occur. By using large-scale RNA sequencing data, the authors present a novel approach to identify disease co-occurrences, revealing a shared molecular basis in many comorbidities, particularly involving the immune system. The study introduces patient stratification based on gene expression profiles, which uncovers known and potential new disease associations, providing a framework for personalized approaches to managing comorbidities.

Study Highlights:
The researchers developed a Disease Similarity Network (DSN) that uses gene expression data to map disease relationships, explaining 64% of known disease co-occurrences. They demonstrate that many comorbidities, such as inflammatory bowel disease (IBD) and various cancers, share common molecular pathways, particularly immune-related processes. The study also identifies previously underdiagnosed comorbidities, offering insights that could inform therapeutic strategies. A web application is provided for exploring these molecular insights and the relationships between diseases and their associated molecular mechanisms.

Conclusion:
This work underscores the importance of patient stratification and molecular profiling in understanding disease co-occurrences, potentially improving diagnosis and treatment by revealing hidden connections between diseases.

Reference:
Urda-García, B., Sánchez-Valle, J., Lepore, R., & Valencia, A. (2025). Patient stratification reveals the molecular basis of disease co-occurrences. *Proceedings of the National Academy of Sciences, 122*(35), e2421060122. https://doi.org/10.1073/pnas.2421060122

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/

On PaperCast Base by Base, you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Keywords: disease co-occurrence, RNA sequencing, patient stratification, immune system, molecular mechanisms.