Base by Base

️ Episode 229: Inhibiting PCBP2 condensates in Alzheimer’s

In this episode of PaperCast Base by Base, we explore Elevated PCBP2 forms liquid-like condensates that sequester mitochondrial and RNA-binding proteins, stabilize BACE1 mRNA, and promote amyloid pathology while the small molecule CN-0928 reduces PCBP2 via INTS1 to lower Aβ and improve cognition in AD models

Study Highlights:
PCBP2 protein is increased in AD patient brains and AD mouse models and forms enlarged, dynamic cytoplasmic condensates that undergo LLPS in vitro and in cells. PCBP2 condensates concentrate mitochondrial proteins and RNA-binding/NMD factors including UPF1, correlating with disru...

️ Episode 228: Two non-competing H3N2 stem antibodies reveal evolving antigenicity

In this episode of PaperCast Base by Base, we explore Structural and functional characterization of two group 2 H3 HA stem antibodies, 2F02 and AG2-G02, shows distinct non-overlapping epitopes, protection in mice, and antigenic changes driven by HA2 position 32 that limit AG2-G02 binding

Study Highlights:
Cryo-EM structures show 2F02 targets the central stem epitope while AG2-G02 targets the lower stem epitope and the two can bind concurrently to an HA trimer. Both antibodies neutralize diverse H3 strains in vitro and provide prophylactic pr...

️ Episode 227: 1q gain enables rescue of aneuploid hESCs during RPE differentiation

In this episode of PaperCast Base by Base, we explore This study shows that spontaneous RPE differentiation eliminates most aneuploid human pluripotent stem cells but permits expansion of cells with chromosome 1q gains when they are co-cultured with wild-type cells

Study Highlights:
Large-scale single-cell genomics revealed pervasive low-grade mosaicism in genetically balanced hPSC cultures, with 3–6% of cells carrying various aneuploidies. During undirected RPE differentiation most aneuploid lineages are purged, except for cells bearing gains of chromosome arm 1q which persist. 1q-gain cells only comp...

️ Episode 226: FGF4 protects podocytes in diabetic kidney disease

In this episode of PaperCast Base by Base, we explore This study shows that podocyte-derived FGF4 is reduced in DKD and that recombinant FGF4 preserves podocyte survival and glomerular function in diabetic models via FGFR1-AMPK-FOXO1 signaling

Study Highlights:
FGF4 expression is downregulated in kidneys from DKD patients and diabetic mouse models and localizes predominantly to podocytes. Podocyte-specific deletion of Fgf4 worsened albuminuria, reduced GFR, increased oxidative stress and podocyte loss in diabetic mice. Systemic treatment with a non-mitogenic recombinant FGF4 improved glucose in db/db mi...

️ Episode 225: VRK-1 and BAF-1 release meiotic chromosomes

In this episode of PaperCast Base by Base, we explore VRK-1 phosphorylates BAF-1 to remove chromatin from the nuclear periphery during early meiotic prophase in C. elegans, and failure of this step impairs pairing and synapsis and generates heritable genome lesions

Study Highlights:
The authors used an auxin-inducible VRK-1 depletion system and genetic perturbations to show that VRK-1 phosphorylates BAF-1 (Ser4) to release chromatin–nuclear periphery contacts during leptotene–zygotene. VRK-1 loss or a BAF-1 Ser4 phospho-mutant increases chromatin tethering at the nuclear envelope, delays homolog pairing, slows...

️ Episode 224: AntennAlive — wireless in-body sensing with engineered bacteria

In this episode of PaperCast Base by Base, we explore A bio-hybrid, battery-free implant converts engineered bacterial activity into microwave backscatter signals by controlled degradation of a biodegradable antenna

Study Highlights:
The AntennAlive system uses a magnesium split-ring passive implant antenna coupled with genetically engineered Escherichia coli that accelerate metal degradation to convert molecular detection into an electromagnetic signature. E. coli BL21 engineered to express the CcmA–H cytochrome c maturation pathway degraded the magnesium prototype faster (≈8 h) than non-engineered cells (≈14 h), causing a controlled structural transition...

️ Episode 223: Torsion Regulates DNA Replication Stalling and Restart

In this episode of PaperCast Base by Base, we explore New single-molecule angular optical trap assays reveal that DNA torsion directly controls T7 replisome stalling and reactivation

Study Highlights:
A high-resolution, label-free angular optical trap (AOT) assay was developed to track T7 replisome-driven DNA rotation and torsional slowing in real time. The combined helicase–DNA polymerase (DNAP) replisome generates ∼22 pN·nm of stall torque, about twice that of E. coli RNA polymerase, while helicase or DNAP alone produce minimal positive torque. Loss of the helicase C‑terminal...

️ Episode 222: snaR-A hijacks splicing to drive proliferation

In this episode of PaperCast Base by Base, we explore This episode examines how the cancer-associated Pol III transcript snaR-A binds core splicing factors, localizes near nuclear speckles, perturbs U2-dependent splicing to increase intron retention, and promotes cell proliferation linked to poorer patient outcomes

Study Highlights:
Proteomic pull-downs and CLIP analyses reveal snaR-A interactions with RNA chaperones (La, ILF3) and multiple splicing factors, with PAR-CLIP and CLIP-qPCR supporting a direct interaction with the U2 snRNP subunit SF3B2. HCR-RNA-FISH and SON TSA-seq place snaR-A in subnuclear fo...

️ Episode 221: Allele-resolved nanopore tour of the human placental methylome

In this episode of PaperCast Base by Base, we explore Using phased long-read nanopore and short-read sequencing across eight trios, the study maps allele-specific DNA methylation and transcription in female human placentas, identifies hundreds of DMRs and novel imprinted genes, and reports somatic placental variants

Study Highlights:
The authors combined >20x Oxford Nanopore whole-genome sequencing with Illumina WGS and RNA-seq in eight mother–father–placenta trios to phase reads into maternal and paternal alleles. They catalogued 723 differentially methylated regions, finding a strong bias toward paternal demeth...

️Episode 220: The AML cellular state space reveals NPM1 immune evasion subtypes

In this episode of PaperCast Base by Base, we explore Single-cell and bulk sequencing of 120 AML cases reveal two NPM1-mutated subtypes with distinct immune evasion mechanisms and divergent responses to hematopoietic stem cell transplantation

Study Highlights:
Bulk RNA-seq profiles are strongly confounded by variable mature cell-type signatures that can conceal subtype-specific blast programs. Single-cell multimodal sequencing of AML identified four main clusters of immature leukemic cells and separated NPM1-mutated cases into NPM1class I and NPM1class II. NPM1class I is...

️Episode 219: Multi-omic mapping of lipid dysregulation in Parkinson’s brain

In this episode of PaperCast Base by Base, we explore Targeted multi-region lipidomics with proteomic and mitochondrial data reveals region- and stage-specific lipid alterations in Parkinson’s disease that converge on mitochondrial dysfunction

Study Highlights: The study quantified 146 lipid species across eight anatomically distinct post-mortem brain regions in controls and mid- and late-stage Parkinson’s disease using targeted LC-MS/MS and integrated proteomics and mitochondrial assays. Control brains showed distinct regional lipid signatures and age-associated increases in hexosylceramides, while PD brains exhibited cortical elevations of ganglios...

️Episode 218: SIM1 and the multi-ancestry genomics of erectile dysfunction

In this episode of PaperCast Base by Base, we explore A large multi-ancestry GWAS meta-analysis identifies a dominant SIM1-linked locus and multiple genetic connections between electronic health record-defined erectile dysfunction and cardiometabolic, psychiatric, and substance-use traits

Study Highlights: Meta-analysis of 913,194 European and 125,315 African ancestry individuals (136,867 and 51,599 cases respectively) identified 40 independent variants in Europeans, two in Africans, and 51 lead SNPs in cross-ancestry analyses.

The strongest associations mapped to a non-coding region regulating SIM1, led by rs78677597 in Europeans and rs17185536 in Africans and in th...

️Episode 217: Multiscale triads of meiotic crossover patterning

In this episode of PaperCast Base by Base, we explore FFT and inverse-FFT analysis of Zip3/Zip2, Hop1 and Zip1 on yeast pachytene chromosomes reveals two interdigitated tiers of evenly spaced protein triads that correspond to canonical and minority crossovers and are differentially regulated by Pch2/TRIP13 Study

Highlights: Quantitative fluorescence profiles and Fourier analysis identify two dominant spatial periodicities centered near 0.5 µm and 1.0 µm for Zip3/Zip2, Hop1 and Zip1 along pachytene chromosomes. Inverse FFT reconstructs narrow and broad peaks that colocalize into triads of the three prot...

️ Episode 216: 53BP1-RIF1 and DNA-PKcs: distinct interactions in chromosomal break repair

In this episode of PaperCast Base by Base, we explore This episode reviews a study showing that 53BP1-RIF1 and DNA-PKcs have different genetic relationships across blunt end joining, deletion patterns, HDR, and radiosensitivity

Study Highlights:
Using EJ7-GFP and MA-del reporters in HEK293 cells, loss of 53BP1 alone did not reduce blunt No Indel EJ but amplified the decrease caused by DNA-PKcs kinase inhibition (M3814) or PRKDC knockout. Disruption of 53BP1 or RIF1, and DNA-PKcs inhibition or loss, each caused a similar sh...

️ Episode 215: Protein Set Transformer for high-diversity viromics

In this episode of PaperCast Base by Base, we explore Protein Set Transformer (PST) is a protein-based genome language model that represents genomes as sets of proteins to improve genome and protein representations across diverse viral datasets

Study Highlights:
PST embeds proteins with ESM2, concatenates positional and strand vectors, contextualizes proteins with a multi-head attention encoder, and produces genome embeddings via a learnable weighted decoder pooling. The foundation PST-TL models were pretrained on >100k dereplicated viral genomes encoding >6M proteins using a triplet-loss objective with PointSwap augmentation an...

️ Episode 214: PI(4,5)P2 Asymmetry Enables Rapid FGF2 Secretion

In this episode of PaperCast Base by Base, we explore This study shows that an asymmetric transbilayer distribution of PI(4,5)P2 lowers the energy barrier for lipidic pore formation and accelerates unconventional secretion of Fibroblast Growth Factor 2

Study Highlights:
The authors generated asymmetric LUVs and GUVs by enzymatically converting outer-leaflet PI(4)P to PI(4,5)P2 using PIP5K1C and validated PI(4,5)P2 presence with FGF2-GFP and FGF2-Halo binding assays. GUV reconstitution assays revealed that outer-leaflet enrichment of PI(4,5)P2 shortened mean FGF2-dependent po...

️ Episode 213: BRAIN-MAGNET: a functional atlas for non-coding variants

In this episode of PaperCast Base by Base, we explore BRAIN-MAGNET couples a ChIP-STARR-seq atlas of 148,198 neural regulatory elements with a validated convolutional neural network to predict enhancer activity and prioritize disease-relevant non-coding variants

Study Highlights:
The authors generated an activity-ranked functional genomics atlas of 148,198 non-coding regulatory elements in human neural stem cells. Comparative ChIP-STARR-seq revealed many elements are epigenetically primed in embryonic stem cells for later neural activity. BRAIN-MAGNET, a convolutional neural network trained on the atlas, predicts enhancer activity from DNA sequence an...

️ Episode 212: Zonal control of mutant β-catenin tumorigenesis

This study shows that hepatic zonation determines whether mutant β-catenin drives proliferation and liver cancer by forcing differentiation to a non-permissive zone 3 fate or, when reversed, enabling MAPK- and mTOR-dependent growth

Study Highlights:
β-catenin exon 3 mutations cooperate with exogenous MYC to produce a proliferative translatome that supports tumour outgrowth. Differentiation to an extreme zone 3 GLUL+Lgr5+ hepatocyte fate suppresses the pro-growth translatome and is refractory to WNT/MYC-driven tumorigenesis. Early proliferative lesions that progress show reduced WNT activation, elevated MAPK signalling and engagement of an IGFBP2–mTOR–cyclin D1...

️ Episode 211: Retention Elements in Cancer Cells

In this episode of PaperCast Base by Base, we explore the discovery of genetic elements that promote the retention of extrachromosomal DNA (ecDNA) in cancer cells, enhancing their survival and evolution.

Study Highlights:
Researchers identified a family of genomic elements known as retention elements that tether ecDNA to mitotic chromosomes, facilitating its transmission to daughter cells during division. The study utilized a novel genome-scale assay called Retain-seq, revealing thousands of retention elements that enhance the persistence of ecDNA. These elements are primarily located at gene promoters and are ch...

️ Episode 210: Tumour-Reactive CD8 T Cell Clusters in Human Melanoma
In this episode of PaperCast Base by Base, we explore how tumour-reactive CD8 T cells organize into stable clusters with melanoma cells and antigen-presenting cells, and how these structures can be isolated from patient samples to boost anti-tumour immunity.

Study Highlights:
The authors used conventional and imaging flow cytometry to identify heterotypic clusters in which CD8 T cells were physically conjugated to tumour cells and antigen-presenting cells across 21 human melanoma metastases. Single-cell RNA and TCR sequencing showed that clustered CD8 T cells were more clonally expanded an...

️ Episode 209: PERT: Prime Editing tRNAs for Nonsense Mutations

In this episode of PaperCast Base by Base, we explore how prime editing can reprogram endogenous tRNAs into potent suppressor tRNAs, enabling a single therapeutic strategy to rescue many different genetic diseases caused by premature stop codons.

Study Highlights:
The authors introduce PERT, a prime editing-mediated strategy that permanently converts selected endogenous tRNAs into optimized suppressor tRNAs capable of reading through premature termination codons. Through large-scale screening of thousands of engineered tRNA variants and careful tuning of promoter, leader, terminator and tRNA sequence elements, they identify su...

️ Episode 208: ZAK, Collided Ribosomes, and the Stress Switch

In this episode of PaperCast Base by Base, we explore how collided ribosomes activate the MAP3K ZAK to drive the ribotoxic stress response and shape cell fate decisions under translational stress.

Study Highlights:
Using biochemistry, cryo-electron microscopy and crosslinking-based RNA mapping, the authors define how ZAK is constitutively recruited to ribosomes and how this engagement changes upon stress-induced ribosome collisions. They show that ZAK contacts the 40S subunit through a C-terminal eS27 pin and rRNA patches and anchors to RACK1 via a RACK1-interacting helix, wh...

️ Episode 207: Semantic Design of de novo Genes with Evo

In this episode of PaperCast Base by Base, we explore how a genomic language model called Evo can use genomic context to design entirely new DNA sequences that encode functional genes and multi-component defence systems.

Study Highlights:
Researchers trained the Evo genomic language model on long prokaryotic and phage DNA sequences and used genomic neighbourhoods as prompts to autocomplete new genes whose functions mirror those of their neighbours. They experimentally validated Evo-designed toxin–antitoxin systems and type III toxin–antitoxin modules, discovering novel protein toxins, protei...

️ Episode 206: Wild Birds and the North American H5N1 Epizootic
In this episode of PaperCast Base by Base, we explore how wild migratory birds have shaped the ecology and spread of the 2021–2023 highly pathogenic H5N1 epizootic across North America, and what this means for wildlife conservation and poultry health.

Study Highlights:
Using 1,818 haemagglutinin gene sequences from wild birds, domestic birds, and mammals collected across North America, the authors reconstruct the timing and routes of highly pathogenic H5N1 spread using Bayesian phylogeographical and phylodynamic models. They show that North America experienced around nine separate viru...

️ Episode 205: Ancient RNA Expression Profiles from the Woolly Mammoth

In this episode of PaperCast Base by Base, we explore how ancient RNA preserved in permafrost can reveal tissue-specific gene expression and regulatory dynamics in the extinct woolly mammoth.

Study Highlights:
Researchers analyzed skeletal muscle and skin from ten Late Pleistocene woolly mammoths preserved in Siberian permafrost, extracting both ancient DNA and RNA to assess the authenticity and quality of the recovered molecules. Using alignment strategies optimized for short, damaged transcripts and mapping primarily to the Asian elephant genome, they identified characteristic damage patterns, exonic en...

️ Episode 204: StealTHY CRISPR: Revealing Hidden Metastasis Regulators

In this episode of PaperCast Base by Base, we explore how the StealTHY CRISPR platform sidesteps Cas9 immunogenicity to uncover metastasis drivers in immunocompetent and humanized cancer models.

Study Highlights:
Researchers show that standard CRISPR-Cas9 tools and xenogeneic reporters provoke strong T cell responses in syngeneic and humanized mice, reshaping clonal architecture and suppressing metastasis.
To overcome this, they develop StealTHY, a “hit-and-run” knockout strategy that pairs species-autologous Thy1 reporters with transient delivery of Cas9 protein, eliminating persistent immunogenic transgenes while preserving sgRNA library complexity.
Across...

️ Episode 203: Divergent Evolutionary Dynamics of Benign and Malignant Tumors
In this episode of PaperCast Base by Base, we explore how benign and malignant tumors follow different evolutionary trajectories across birds and mammals, and what this reveals about cancer defenses across the tree of life.

Study Highlights:
The authors combine necropsy data on tumor prevalence from hundreds of bird and mammal species with Bayesian multivariate phylogenetic generalized linear mixed models to test how benign and malignant tumors relate to macroevolutionary processes. They show that prevalence of both benign and malignant tumors increases with body mass, confirming th...

️ Episode 202: Stereo-seq V2: Spatial Total RNA Mapping in FFPE Tissues

In this episode of PaperCast Base by Base, we explore how Stereo-seq V2 delivers high-resolution spatial mapping of total RNA in FFPE samples, from mouse brain to breast cancer and tuberculosis lung tissue.

Study Highlights:
The authors introduce Stereo-seq V2, a random-priming spatial transcriptomics platform that captures total RNA in situ on FFPE sections at single-cell resolution. By benchmarking against earlier Stereo-seq and other spatial methods in the mouse brain, they demonstrate improved gene detection, uniform gene body coverage, and robust profiling of non-coding RN...

️ Episode 201: Sex, Smoking, and Somatic Selection in the Bladder
In this episode of PaperCast Base by Base, we explore how ultradeep duplex DNA sequencing of normal human bladder tissue reveals sex- and smoking-related biases in the selection of somatic mutations and cancer driver clones.

Study Highlights:
Researchers applied ultradeep duplex DNA sequencing at around 5,000× coverage to 79 normal bladder urothelium samples from 45 deceased donors, targeting 16 genes known to drive clonal expansions and bladder tumors. They identified more than 64,000 somatic mutations and thousands of clonal driver events, allowing precise estimates of positive and negative selection across genes suc...

️ Episode 200: Sperm Sequencing Reveals Extensive Positive Selection in the Male Germline In this episode of PaperCast Base by Base, we explore how ultra-accurate duplex sequencing of human sperm reveals widespread positive selection in the male germline and its consequences for mutation burden and disease risk in offspring.

Study Highlights:
This Nature study uses NanoSeq duplex whole-genome and exome sequencing on sperm and matched blood samples from healthy men aged 24 to 75 years to quantify how mutations accumulate in the male germline. The authors show that sperm acquire about 1.67 substitutions per year per haploid genome, several-fold fewer than bl...

️ Episode 199: PLD4 Deficiency and Lupus: When Nuclease Failure Ignites Autoimmunity

In this episode of PaperCast Base by Base, we explore how loss-of-function mutations in the endolysosomal exonuclease PLD4 cause a monogenic form of systemic lupus erythematosus, reshaping our understanding of nucleic acid sensing and interferon-driven autoimmunity.

Study Highlights:
This study identifies biallelic loss-of-function PLD4 mutations in five patients with systemic lupus erythematosus, all presenting with severe lupus nephritis and hematologic involvement. Using whole-exome sequencing, structural modelling and biochemical assays, the authors show that these PLD4 variants markedly impair single-stranded DNA and RNA exonuclease activity, le...

️ 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...

️ Episode 197: Somatic Mutation and Selection at Population Scale
In this episode of PaperCast Base by Base, we explore how ultra-accurate NanoSeq duplex sequencing reveals the hidden landscape of somatic mutations and clonal selection across blood and oral epithelium in over a thousand adults.

Study Highlights:
This study introduces improved whole-genome and targeted versions of NanoSeq, a duplex sequencing method with error rates below five mutations per billion base pairs, enabling reliable detection of single-molecule variants in highly polyclonal tissues. By applying targeted NanoSeq to 1,042 buccal swabs and 371 blood samples from a twins cohort, the authors ma...

️ Episode 196: Impact of Chromatin Accessibility QTLs Across Immune Contexts

In this episode of PaperCast Base by Base, we explore how single-cell chromatin accessibility QTLs (caQTLs) reshape the interpretation of immune disease genetics by mapping regulatory variation across major immune cell types and disease-relevant states.

Study Highlights:
The authors harmonized ∼280,000 PBMC scATAC-seq profiles from 48 individuals—including healthy donors and COVID-19 patients—to build a unified chromatin accessibility atlas. Topic modeling uncovered continuous cell-state programs, including a CD8 effector-memory continuum associated with COVID-19, and enabled the discovery of 37,390 caQTLs plus thousands of dynamic, state-dependent effects. Compared to eQTLs...

️ Episode 195: Tiny Shields: Lymphoid Microglia in Alzheimer’s Disease

In this episode of PaperCast Base by Base, we explore how a subset of brain immune cells adopts a lymphoid-like program that helps contain inflammation and protect neural circuits in Alzheimer’s disease models.

Study Highlights:
Using mouse models of amyloid pathology and human Alzheimer’s brain tissue, the authors identify plaque-associated microglia with reduced PU.1 expression that cluster around deposits and express an unexpected set of lymphoid receptors, including CD28. By genetically tuning PU.1 levels specifically in microglia, they show that lowering PU.1 is...

️ Episode 194: Bayesian History of Science: Watson and Crick and the Structure of DNA

In this episode of PaperCast Base by Base, we explore how Bayesian reasoning can be used to reconstruct the famous discovery of the DNA double helix by James Watson and Francis Crick, following the sequence of structural models proposed in the early 1950s and the evolving evidence that supported or undermined each hypothesis.

Study Highlights:
The author applies a naïve Bayes framework to four competing models of DNA proposed by Watson, Crick, and Linus Pauling, treating each model as a tar...

️Episode 193: SARM1, DNA, and the Death Signal

In this episode of PaperCast Base by Base, we explore how the axon-degenerating enzyme SARM1 acts as a double-stranded DNA sensor that triggers NAD+ loss, cell death, and chemotherapy-induced neuropathy, opening up new possibilities for neuroprotective therapies.

Study Highlights:
The authors show that the immune adaptor SARM1 directly binds double-stranded DNA via its TIR domain and, once activated, rapidly degrades cellular NAD+ in a sequence-independent but length-dependent manner. Using a combination of biochemical assays and structural analyses, they demonstrate that SARM1 forms multimeric complexes with linear DNA, wi...

️Episode 192: At Base-Pair Resolution: Chromatin’s Cis-Regulatory Conversations

In this episode of PaperCast Base by Base, we explore how base-pair resolution maps of chromatin contacts reveal a unified, biophysical model of communication between enhancers, promoters, and other cis-regulatory elements in mammalian cells.

Study Highlights:
Using Micro Capture-C ultra (MCCu), the authors generate multidimensional chromosome conformation maps with single base-pair pixels, allowing them to resolve contacts between individual transcription factor motifs within cis-regulatory elements in mouse embryonic stem, hematopoietic progenitor, and erythroid cells. They show that nucleosome-depleted regions partition chromatin into nanoscale domains and form high...

️ Episode 191: CATphishing: Synthetic Learning as an Alternative to Federated Learning in MRI

In this episode of PaperCast Base by Base, we explore a Nature Communications study that proposes CATphishing—an approach that uses latent diffusion models to generate site-specific synthetic 3D brain MRIs for collaborative training without sharing raw data. The work spans seven institutions and 2,491 patients and evaluates whether models trained on synthetic data can match those trained via centralized data sharing or federated learning.

Study Highlights:
The authors train latent diffusion models locally at each site to capture dataset-specific MRI distributions and then...

️ Episode 190: Single-Cell Networks Reveal Cell Type–Specific Mechanisms in Type 2 Diabetes

In this episode of PaperCast Base by Base, we explore how a network-based analysis of single-cell RNA sequencing from human pancreatic islets uncovers cell type–specific gene-regulatory changes that help explain type 2 diabetes pathophysiology.

Study Highlights:
The authors develop differential Gene Coordination Network Analysis (dGCNA) to compare gene–gene coordination between non‑T2D and T2D donors in Smart‑seq2 datasets covering >8,000 islet cells from 32 individuals. In beta cells, dGCNA resolves eleven networks with strong ontological specificity, revealing de‑coordination of mitochondria, glycolysis, cy...

️ Episode 189: DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms

In this episode of PaperCast Base by Base, we explore how genome-wide DNA methylation profiling can pinpoint the organ of origin for neuroendocrine neoplasms (NEN), with a special focus on lesions detected in the liver and long-debated “primary hepatic NEN”.

Study Highlights:
Using two independent cohorts totaling 212 NEN tissues, the authors profiled methylation patterns and visualized them with dimensionality-reduction approaches, revealing distinct clusters for most organ sites. Hepatic NEN without a detectable extrahepatic primary did not form a unique liver-specific cluster and instead coloca...

️ Episode 188: Proteomics + Machine Learning for Lyme Neuroborreliosis Diagnosis

In this episode of PaperCast Base by Base, we explore how large‑scale mass‑spectrometry proteomics of cerebrospinal fluid and plasma, paired with supervised machine learning, can distinguish Lyme neuroborreliosis from viral meningitis and non‑LNB controls in adults.

Study Highlights:
The authors analyzed 308 CSF and 207 plasma samples across development and validation cohorts to define host‑response protein signatures and train diagnostic classifiers. CSF proteomics yielded strong discrimination of LNB against viral meningitis and against controls, with independent‑cohort AUCs around 0.92 and 0.90, respectively, and highlighted immunoglobulin chains, comp...

️ Episode 187: Gapped PARP + Tumor‑Targeted TOP1 in Advanced Tumors

In this episode of PaperCast Base by Base, we explore a phase I dose‑escalation trial that pairs a tumor‑targeted topoisomerase I inhibitor (CRLX101, a nanoparticle camptothecin) with optimized, gapped scheduling of the PARP inhibitor olaparib to reduce toxicity while preserving efficacy in advanced solid tumors.

Study Highlights:
Twenty‑four adults with advanced solid tumors received CRLX101 every two weeks with olaparib started 48 hours later; the maximum tolerated and recommended phase 2 dose was CRLX101 12 mg/m² plus olaparib 250 mg twice daily on days 3–13 and 17–26 of each 28‑day...

️ 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 inter...

️ 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 hi...

️ 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...

️ 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 contro...

️ 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...

️ 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 m...

️ 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 co...

️ 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 tho...

️ 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 in...

️ 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 varia...

️ 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 transi...

️ 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–prom...

️ 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 infe...

️ 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 co...

️ 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 Ran...

️ Episode 171: Virulence Hierarchies in the Tuberculosis Complex—What Makes Some Lineages Deadlier?

In this episode of PaperCast Base by Base, we explore a new PNAS study that directly compares the virulence of Mycobacterium tuberculosis, M. bovis, and M. orygis across natural and laboratory hosts to uncover why animal-adapted lineages can be so devastating.

Study Highlights:
The authors performed side-by-side infections in Holstein calves and C57BL/6 mice, showing that M. bovis and M. orygis consistently caused more severe disease, faster mortality, and higher bacterial burdens than M. tuberculosis. Comparative proteomics identified ESAT‑6/CFP‑10 and the SigK...

️ Episode 170: Maternal Age, Meiotic Recombination Failure, and Triploidy in Humans

In this episode of PaperCast Base by Base, we explore how maternal age and failures of meiotic recombination shape the origins of triploid conceptions in humans, drawing on large-scale preimplantation genetic testing datasets from ICSI-derived embryos.

Study Highlights:
Drawing on 96,660 embryo biopsies with an independent validation cohort of 44,324, the authors quantify the burden of ploidy-level abnormalities in ICSI-derived blastocysts and show that triploidy is about five times more frequent than haploidy at the blastocyst stage. Genotyping and sex-chromosome modeling reveal that nearly all triploid em...

️ Episode 169: Deep mutational scanning of the insulin receptor guides precision therapy for insulin resistance

In this episode of PaperCast Base by Base, we explore how a comprehensive deep mutational scan of the human insulin receptor ectodomain maps the effects of ~14,000 missense variants on surface expression, insulin binding, and downstream signalling, creating a sequence–function atlas to improve diagnosis and treatment of severe insulin resistance.

Study Highlights:
The authors constructed a saturation mutagenesis library across residues 28–955 of INSR and used barcoded, pooled cell-based assays to quantify variant effects on receptor expression, insulin or antibody binding, and ma...

️ Episode 168: Low circulating miR-190a-5p predicts progression of chronic kidney disease

In this episode of PaperCast Base by Base, we explore how unbiased small RNA sequencing and multi-cohort validation identify circulating miR-190a-5p as a prognostic marker of chronic kidney disease that reflects tubular health and points to a potential therapeutic strategy.

Study Highlights:
Using small RNA-sequencing of plasma from people with and without CKD in the context of type 2 diabetes, the authors found miR-190a-5p to be significantly reduced in those with impaired kidney function.
In an independent prospective CK...

️ Episode 167: DeepScence: Detecting Senescent Cells at Single-Cell and Spatial Resolution

In this episode of PaperCast Base by Base, we explore a Cell Genomics study introducing DeepScence, a deep-learning autoencoder that leverages a compact “CoreScence” gene set to identify senescent cells across single-cell and spatial transcriptomics data, outperforming marker- and gene set–based approaches.

Study Highlights:
The authors systematically compared nine published senescence gene sets and distilled a consensus 39‑gene CoreScence panel that is consistently associated with senescence across tissues and conditions. DeepScence models expression counts with a zero‑inflated negative binomial autoencoder whose bottleneck s...

️ Episode 166: Molecular Squeezing: How Coronin, Cofilin, and AIP1 Rapidly Disassemble Actin Filaments

In this episode of PaperCast Base by Base, we explore a Cell study that uses single-particle cryo-EM to reveal the stepwise, synergistic mechanism by which coronin, cofilin, and AIP1 drive rapid actin filament disassembly in eukaryotic cells.

Study Highlights:
The authors solve a series of cryo-EM structures showing that coronin binds cooperatively to F-actin, opens a molecular backdoor to accelerate inorganic phosphate release, and undertwists the filament to prime it for cofilin binding. Cofilin then binds in a strand-restricted cooperative manner th...

️ Episode 165: Protist Genomics: Key to Understanding Eukaryotic Evolution

In this episode of PaperCast Base by Base, we explore how accelerating protist genomics—spanning single-cell approaches, metagenomics, and long-read assemblies—unlocks deep insights into eukaryotic evolution, symbiosis, organelle origins, ecosystem dynamics, and the methodological shifts needed to go beyond plant/animal-centric standards.

Study Highlights:
This review argues that protists encompass most eukaryotic diversity yet remain severely underrepresented in genome databases, creating blind spots in phylogenomics and models of eukaryotic evolution. It synthesizes emerging wet-lab and computational strategies—such as FACS-enabled single-cell sequencing, nuclei extraction for high...

️ Episode 164: m6A in the coding sequence: linking deposition, translation, and decay

In this episode of PaperCast Base by Base, we explore how N6-methyladenosine (m6A) marks within coding sequences orchestrate a fast, translation-coupled route to mRNA decay, and how splicing- and chromatin-linked mechanisms shape where those marks are placed across transcripts.

Study Highlights:
The authors synthesize recent mapping and mechanistic studies to show that exon-junction complexes restrict METTL3 activity in coding regions, helping define the mature m6A landscape. They describe CDS–m6A decay (CMD), a translation-dependent pathway in which m6A wi...

️ 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 relati...

️ Episode 162: Spatially Resolved microRNA Expression in Tissues: Technologies, Challenges, and Opportunities

In this episode of PaperCast Base by Base, we explore how emerging “spatial miRNomics” methods map microRNA expression directly within intact tissues, revealing cell- and region-specific regulatory patterns that bulk and even single-cell assays can miss.

Study Highlights:
This review charts the field from established singleplex imaging with LNA probes and miRNAscope to early multiplex strategies and sequencing-based workflows that add poly(A) tails in situ to capture small RNAs. It explains how spatial total RNA sequencing (STRS) and Patho-DBiT adapt commercial spatial transc...

️ Episode 161: Decoding Genomic Landscapes of Introgression

In this episode of PaperCast Base by Base, we explore how modern population genetics dissects the genomic footprints of introgression across species, reviewing summary statistic approaches, probabilistic modeling, and supervised learning, and showing how these methods reveal adaptive and ghost introgression and the functional roles of introgressed loci.

Study Highlights:
The authors organize the field into three complementary pillars: summary statistics for fast exploratory scans, probabilistic models for principled inference of local ancestry and selection, and supervised deep learning for scalable, high‑resolution predictions. They explain why windowed stat...

️ Episode 160: The Long‑Read Leap in Single‑Cell Omics

In this episode of PaperCast Base by Base, we explore how long‑read, single‑molecule sequencing has collided with single‑cell technologies to illuminate “dark” regions and events in the genome, epigenome, and transcriptome that short reads routinely miss.

Study Highlights:
This review maps the rapid maturation of Pacific Biosciences and Oxford Nanopore platforms alongside single‑cell methods, showing how full‑length isoform sequencing reveals complex alternative splicing at single‑cell resolution. It details single‑cell long‑read genome assays such as SMOOTH‑seq and dMDA that sensitivel...

️ Episode 159: The Untapped Potential of Short‑Read Sequencing in Biodiversity Research

In this episode of PaperCast Base by Base, we explore how modern short‑read sequencing and genome skimming are reshaping biodiversity science—from rapid species identification and biomass estimation to scalable phylogenomics and holobiont studies—while keeping costs and sample requirements low.

Study Highlights:
This review synthesizes how low‑coverage short‑read data can recover organellar genomes and high‑copy nuclear markers, enabling robust taxonomic identification and phylogenetic inference across diverse taxa. It explains assembly‑free and mapping approaches that extract universal single‑copy orthologs or k‑...

️ Episode 158: Interruptions in Repeat Expansion Diseases: How Are They Gained and Lost?

In this episode of PaperCast Base by Base, we explore how small sequence changes—“interruptions”—within expanded tandem repeats shape the onset and severity of repeat expansion disorders, and a new mechanistic model that may explain how these interruptions are gained and lost across generations.

Study Highlights:
Interruptions within repeat tracts can dampen somatic expansion and shift clinical trajectories, helping to explain variability in age at onset and phenotype across disorders such as Huntington’s disease, myotonic dystrophy type 1, spinocerebellar ataxias, and fragile X. A...

️ Episode 157: Synthetic gametes and the non-identity problem: the babies of tomorrow

In this episode of PaperCast Base by Base, we explore how synthetic DNA technologies may enable the creation of synthetic gametes and why this possibility forces a rethinking of identity, harm, and responsibility in human reproduction.

Study Highlights:
The authors argue that while building a full human genome remains infeasible today, engineering haploid genomes for gametes is a nearer-term and more tractable objective, drawing on advances such as synthetic chromosomes in yeast. They analyze how synthetic gametes differ ethically from embryo editing an...

️ Episode 156: RAEFISH: Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution

In this episode of PaperCast Base by Base, we explore RAEFISH, a reverse-padlock amplicon-encoding FISH method that delivers whole-transcriptome imaging at single-molecule resolution without sequencing. The study demonstrates genome-scale coverage across cells and intact tissues and extends to direct readout of CRISPR guide RNAs, enabling high-content functional screens with spatial context.

Study Highlights:
RAEFISH introduces a “reversed” padlock design with splint-assisted ligation, rolling-circle amplification, and MERFISH-style sequential readouts to barcode >20,000 transcripts while remaining compatible with cost-efficient oligo pool amplification. In A549 cells, the authors report an ave...

️ Episode 155: EIF3A/EIF3B Loss-of-Function: A Cardiocraniofacial Neurodevelopmental Syndrome

In this episode of PaperCast Base by Base, we explore how loss-of-function variants in EIF3A and EIF3B—core components of the eIF3 translation initiation complex—cause a multisystem disorder marked by congenital heart defects, craniofacial differences, and mild neurodevelopmental features. The study brings clinical genetics together with functional zebrafish models to establish gene–disease validity and illuminate developmental mechanisms.

Study Highlights:
An international cohort of eighteen individuals was assembled with de novo or loss-of-function variants in EIF3A (n=4) or EIF3B (n=14), r...

️ Episode 154: Multiple-testing corrections in selection scans using identity-by-descent segments

In this episode of PaperCast Base by Base, we explore how Temple and Browning develop principled genome-wide significance thresholds for IBD-based scans of recent positive selection by explicitly modeling correlation along the genome.

Study Highlights:
The authors model standardized IBD-rate scan statistics as an Ornstein–Uhlenbeck process and derive both an analytical threshold and a fast simulation-based alternative that control the family-wise error rate while adapting to genetic-map spacing and autocorrelation. In extensive coalescent simulations, the approach achieves approximate FWER control and shows that Bonferroni can...

️ Episode 153: Skeletal muscle eQTL meta-analysis implicates genes in the genetic architecture of muscular and cardiometabolic traits

In this episode of PaperCast Base by Base, we explore a large skeletal muscle eQTL meta-analysis that integrates GTEx and FUSION data to pinpoint regulatory variants and genes underlying muscular and cardiometabolic traits.

Study Highlights:
Combining RNA-seq and whole-genome data from 1,002 individuals across two cohorts, the authors identified 18,818 conditionally distinct eQTL signals affecting 12,283 genes, with 35% of genes harboring multiple signals. Colocalization with 26 GWAS datasets yielded 2,252 signal pairs and nominated 1,342 candidate genes, and strikingly 22% of the colocalizations involved non‑prim...

️ Episode 152: One-Well Multiplex ddPCR for Hereditary Alpha Tryptasemia

In this episode of PaperCast Base by Base, we explore a validated single‑well multiplex digital droplet PCR (ddPCR) assay that reconstructs the TPSAB1 locus by quantifying α‑ and β‑tryptase copy numbers to diagnose hereditary alpha tryptasemia (HαT) in symptomatic patients.

Study Highlights:
The authors designed a triplex ddPCR assay that simultaneously measures α‑ and β‑tryptase copy numbers and an internal reference in one well, avoiding cross‑reactivity and excessive signal “rain” while achieving clear cluster separation and straightforward thresholds. In analytical validation across 281 cases, copy‑number calls tightly clustered a...

️ Episode 151: EQA of ctDNA Mutation Testing Across the COIN Consortium

In this episode of PaperCast Base by Base, we explore how 16 Dutch laboratories evaluated their real‑world workflows for circulating tumor DNA (ctDNA) mutation testing across BRAF, EGFR, and KRAS using a coordinated external quality assessment within the COIN consortium.

Study Highlights:
The team distributed six plasma samples—three commercial references with predefined variants and three patient‑derived diagnostic leukapheresis samples—to participating labs, asking them to run their routine preanalytical and analytical pipelines, including ddPCR, small PCR panels, and next‑generation sequencing. Performance was scored o...

️ Episode 150: Patrilineal segmentary systems and the post‑Neolithic Y‑chromosome bottleneck

In this episode of PaperCast Base by Base, we explore a Nature Communications study that proposes a peaceful, socio‑cultural explanation for the sharp decline in male effective population size observed 3,000–5,000 years ago. Instead of widespread violence, the authors show that the dynamics of patrilineal segmentary systems—where lineages split and reproductive success varies between descent groups—can alone generate the Y‑chromosome bottleneck while female lineages continue to expand.

Study Highlights:
The team builds forward‑time simulations of villages structured by patrilocal residence and patr...

️ Episode 149: Cultural Hitchhiking and the Post‑Neolithic Y‑Chromosome Bottleneck

In this episode of PaperCast Base by Base, we explore how patrilineal social structures and intergroup competition can reshape genetic diversity, offering a cultural explanation for the striking male‑specific bottleneck observed 5,000–7,000 years ago across the Old World.

Study Highlights:
The authors synthesize anthropological theory, population genomics, and mathematical modeling to test whether competition among patrilineal kin groups could drive a sharp reduction in Y‑chromosome diversity while leaving mitochondrial lineages relatively stable. They introduce an analytical Lotka–Volterra framework and a computational grid simulation to...

️ Episode 148: Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants

In this episode of PaperCast Base by Base, we explore a comprehensive functional assessment of splice-site variants in CHEK2 using reporter minigenes, revealing how disrupted pre-mRNA splicing contributes to hereditary breast cancer risk and how these readouts can support clinical variant classification.

Study Highlights:
The authors screened 128 intron–exon boundary variants from large breast cancer cohorts with in silico tools and selected 52 candidates for minigene assays that collectively span all 15 CHEK2 exons.
In transfected MCF-7 cells, 46 of the 52 vari...

️ Episode 147: Comprehensive Annotation of Complete ABO Alleles and Resolution of ABO Variants

In this episode of PaperCast Base by Base, we explore a groundbreaking study that introduces an improved long-read sequencing method to fully resolve ABO haplotypes, spanning from the 5′ to the 3′ untranslated regions. This work addresses a major gap in blood group genomics by delivering the most comprehensive annotation of complete ABO alleles to date.

Study Highlights:
Researchers analyzed specimens from 79 blood donors and 47 ABO variants using an optimized ultra-long-range PCR method combined with PacBio SMRT sequencing. They successfully amplified and sequenced the full 2...

️ Episode 146: Automated and Decentralized Genomic Profiling of Plasma Cell-Free DNA in Solid Tumors

In this episode of PaperCast Base by Base, we explore the clinical feasibility of an automated and decentralized cfDNA sequencing system designed to identify actionable and resistance alterations in advanced solid tumors.

Study Highlights:
Researchers evaluated plasma cfDNA from 298 patients with advanced cancers using the Oncomine Precision Assay GX and Genexus integrated sequencer. Sequencing success rates were higher for cfDNA compared to tumor tissue, and 50% of patients had detectable ctDNA mutations. Concordance between plasma and tumor results reached 72%, with detection influenced by...

️ Episode 145: A Validated Highly Sensitive Microsatellite Instability Assay Identifies PMS2 Variants in CMMRD

In this episode of PaperCast Base by Base, we explore a study that validates a next-generation sequencing-based highly sensitive microsatellite instability (hs-MSI) assay for the diagnosis of constitutional mismatch repair deficiency (CMMRD), a rare childhood-onset cancer predisposition syndrome. The work focuses on improving detection of PMS2 pathogenic variants, the most frequent but technically challenging cause of CMMRD.

Study Highlights:
The researchers applied the hs-MSI assay to a blinded cohort of 66 blood and 24 tumor samples from individuals with CMMRD and controls, demonstrating a...

️ Episode 144: Revised time estimation of the ancestral human chromosome 2 fusion

In this episode of PaperCast Base by Base, we explore a study that revisits one of the most defining events in human evolution: the fusion that gave rise to chromosome 2. This work refines previous estimates and provides a clearer timeline for when this pivotal genomic change occurred.

Study Highlights:
The authors developed an improved algorithm to analyze biased clustered substitutions, allowing more precise dating of genomic events. By comparing the genomes of humans with those of chimpanzees and bonobos, they estimated that the chromosome 2 fu...

️ Episode 143: The genetic history of the Southern Caucasus: 5,000 years of continuity despite high mobility

In this episode of PaperCast Base by Base, we explore a comprehensive archaeogenomic study tracing 230 ancient individuals from Georgia and Armenia over 5,000 years, from the Bronze Age to the Early Middle Ages. The research investigates how extensive mobility and cultural interactions shaped the genetic landscape of the Southern Caucasus.

Study Highlights:
The analysis of genome-wide data revealed a remarkably persistent local gene pool across millennia, even as populations absorbed ancestry from Anatolia, Iran, and the Eurasian Steppe during the Middle to...

️ Episode 142: Specifications of the ACMG/AMP Guidelines for PALB2 Variant Interpretation

In this episode of PaperCast Base by Base, we explore how the Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) developed gene-specific ACMG/AMP guidelines for the interpretation of PALB2 germline sequence variants, a key gene in hereditary cancer syndromes.

Study Highlights:
The HBOP VCEP assembled an international team of experts to refine the 2015 ACMG/AMP framework specifically for PALB2, a tumor suppressor gene involved in homologous recombination repair. They systematically reviewed 28 evidence codes, advising against the use of 13, li...

️ Episode 141: RetiGene, a comprehensive gene atlas for inherited retinal diseases

In this episode of PaperCast Base by Base, we explore RetiGene, an expert-curated resource that consolidates genetic, transcriptomic, and functional information on inherited retinal diseases (IRDs). The study highlights the urgent need for a unified gene catalog to guide diagnosis and research in one of the most genetically heterogeneous groups of human disorders.

Study Highlights:
The authors identified and curated 470 genes strongly associated with IRDs, supported by extensive literature review, variant databases, and gene expression data. Another 196 genes were classified as candidate genes, while 17 we...

️ Episode 140: Landscapes of missense variant impact for human superoxide dismutase 1

In this episode of PaperCast Base by Base, we explore a large-scale functional analysis of missense variants in SOD1, a key gene implicated in amyotrophic lateral sclerosis (ALS). The study addresses the challenge of classifying variants of uncertain significance by systematically testing their functional impact across nearly all possible amino acid substitutions.

Study Highlights:
Using saturation mutagenesis combined with multiplexed yeast and human cell-based assays, researchers generated variant-effect maps covering 86% of all possible SOD1 missense variants. These maps measure both enzymatic activity and protein ab...

️ Episode 139: MosCoverY: A new method to estimate mosaic loss of Y chromosome from sequencing coverage data

In this episode of PaperCast Base by Base, we explore the development of MosCoverY, a computational method designed to detect and quantify mosaic loss of the Y chromosome (mLOY) from exome and whole-genome sequencing data. This condition, the most common somatic mutation in men, is strongly linked with aging and several diseases.

Study Highlights:
The researchers introduced MosCoverY, a tool that focuses on single-copy genes of the Y chromosome and normalizes their coverage against carefully matched autosomal exons. Th...

️ Episode 138: Social exposome and brain health outcomes of dementia across Latin America

In this episode of PaperCast Base by Base, we explore how a multidimensional social exposome across the lifespan—covering education, food insecurity, financial status, assets, access to healthcare, childhood labor, subjective socioeconomic status, childhood experiences, traumatic events, and relationships—relates to brain health and dementia outcomes in Latin America. The study analyzes 2,211 participants from Argentina, Brazil, Chile, Colombia, Mexico, and Peru, spanning healthy controls, Alzheimer’s disease, and frontotemporal lobar degeneration.

Study Highlights:
Researchers built a global multidimensional social exposome score using expert c...

️ Episode 137: Rethinking RNA-binding proteins: Riboregulation challenges prevailing views

In this episode of PaperCast Base by Base, we explore how a sweeping expansion of the RNA-binding proteome has reframed long‑held assumptions about RNA–protein interactions, spotlighting ‘non‑canonical’ RBPs and the emerging concept of riboregulation—RNA directly regulating protein function.

Study Highlights:
The authors synthesize discovery platforms that tripled the number of candidate RBPs, including UV crosslinking–based interactome capture (RIC/eRIC), silica‑based workflows (TRAPP/2C), and organic‑phase methods (OOPS/XRNAX), together with mass spectrometry to map RNA‑binding regions across the proteome. T...

️ Episode 136: Gene Context Drift Identifies Drug Targets to Mitigate Cancer Treatment Resistance

In this episode of PaperCast Base by Base, we explore RECODR, a graph‑embedding pipeline that reads single‑cell and single‑nucleus transcriptomes as co‑expression networks to quantify “gene context drift” during therapy and expose druggable vulnerabilities that drive relapse across aggressive cancers.

Study Highlights:
RECODR constructs co‑expression graph networks from sc/snRNA‑seq data and uses Node2Vec/Word2Vec embeddings to score how each gene’s neighborhood shifts between normal, tumor, and treatment states, revealing resistance drivers that expression level alo...

️ Episode 135: Global impact of micronutrients in modern human evolution

In this episode of PaperCast Base by Base, we explore how dietary micronutrients have influenced modern human evolution. The study investigates the role of essential minerals in shaping genetic adaptation and highlights the health risks posed by imbalances in micronutrient availability worldwide.

Study Highlights:
Researchers analyzed 276 genes linked to 13 micronutrients across 40 diverse human populations. Using whole-genome data and evolutionary simulations, they identified widespread signatures of positive selection in genes associated with nutrient uptake, metabolism, and regulation. Their findings suggest that deficiencies in elements such as se...

️ Episode 134: Single-Cell Maps Link Intestinal Metaplasia to Esophageal Adenocarcinoma Risk

In this episode of PaperCast Base by Base, we explore how single-cell RNA sequencing of Barrett’s esophagus (BE), esophageal adenocarcinoma (EAC), and matched normal tissues reveals which cell types carry germline-linked risk and shape progression toward cancer.

Study Highlights:
The authors profiled epithelial, stromal, endothelial, and immune cells with 10x scRNA-seq and integrated genome-wide association data using partitioned heritability to map risk to specific cell types. They show that EAC development is driven more by local cellular programs than BE, with intestinal metaplasia cell...

️ Episode 133: Culture-Independent Meta‑Pangenomics Reveals Gut Genome Links to Child Growth

In this episode of PaperCast Base by Base, we explore how long‑read metagenomics enables recovery of complete metagenome‑assembled genomes directly from fecal samples of Malawian toddlers and applies meta‑pangenomics and microbial GWAS to connect microbial genetics with pediatric linear growth and breastfeeding status.

Study Highlights:
Long‑read sequencing with PacBio and Oxford Nanopore generated 44–64 times more complete genomes per gigabase than short‑read approaches, with PacBio yielding the most accurate and cost‑effective assemblies. A longitudinal cohort produced 986 complete genomes, 839 circular, across 4...

️ Episode 132: Tumor transcriptome classifiers predict treatment sensitivity in advanced prostate cancer

In this episode of PaperCast Base by Base, we explore how transcriptome-wide RNA expression classifiers from advanced prostate cancers can inform treatment selection and improve patient outcomes.

Study Highlights:
Researchers analyzed tumor transcriptome profiles and immunohistochemistry markers from 1,523 patients enrolled in landmark phase 3 trials with up to 14 years of survival follow-up. High androgen receptor signaling was associated with longer survival, while increased proliferation predicted shorter survival. The Decipher classifier was both prognostic and predictive, identifying metastatic patients who benefited significantly from docetaxel. Additionally, a...

️ 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 l...

️ 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, id...