Base by Base

Wei Y et al., Nature Communications - A Swedish nationwide register study of 2.93 million children born 1982–2010 found that the heritability of childhood-onset type 1 diabetes remained high (~0.83) and stable over 30 years, while changes in measured environmental factors explained only a small fraction of the rise in incidence. Key terms: type 1 diabetes, heritability, Sweden, childhood-onset, en...

Nature Communications - This study used fragment-level, sequence-based DNA methylation of circulating cell-free DNA to map cellular origins of tissue damage after liver transplant. An expanded methylation atlas of liver cell types and hybridization capture bisulfite sequencing of 130 serum samples from 44 patients showed that sustained hepatocyte and biliary epithelial cfDNA within the first month...

Nature Communications - A biobank-scale study using UK Biobank and Mount Sinai BioMe exomes examines three genetic contributors to incomplete penetrance and variable severity of monogenic cardiometabolic variants: heterogeneous missense variant effects, additive polygenic background, and marginal epistasis between carrier status and common variation. Key terms: variant pathogenicity, polygenic ris...

️ Episode 85: Genomic landscape of virus-associated cancers In this episode of PaperCast Base by Base, we explore the comparative genomic analysis of virus-positive and virus-negative tumors across nine cancer types linked to five oncogenic viruses uncovering epidemiological patterns, mutational signatures, and therapeutic implications. Study Highlights: The authors aggregated genomic data from 1,...

Nature Communications - Genome sequencing identified rare NR6A1 variants in families with colobomatous microphthalmia, missing vertebrae and congenital kidney anomalies. In silico modeling, cell assays, and zebrafish knockdown/rescue experiments support pathogenicity and define NR6A1 as a pleiotropic developmental regulator. Key terms: NR6A1, coloboma, microphthalmia, vertebral anomalies, kidney a...

Perez Y et al., Nature Communications - This episode reviews a single-cell and spatial transcriptomic study of dup15q syndrome using patient postmortem cortex and hiPSC-derived cortical organoids. The work maps developmental metabolic shifts, layer-identity changes, and postnatal synaptic transcriptional burdens linked to autism. Key terms: dup15q, single-cell RNA-seq, cortical organoids, glycolys...

Maslah N et al., Nature Communications - Translational study showing ruxolitinib and JAK2 suppression select for RAS pathway–mutant clones in myelofibrosis, enhancing their fitness via MAPK activation and linking this selection to worse clinical outcomes in treated patients. Key terms: ruxolitinib, JAK2, RAS mutations, myelofibrosis, clonal evolution. Study Highlights: Longitudinal NGS of 143 myel...

Wei C-Y et al et al., Nature Communications - Retrospective analysis of 486,956 Han Chinese from the Taiwan Precision Medicine Initiative evaluated prevalence and clinical impact of actionable pharmacogenetic (PGx) variants across 19 genes and 58 drugs, with focused outcome analyses for four gene–drug pairs. Findings confirm widespread PGx variation and statistically increased risks for some adver...

Watkins WS et al et al., Nature Communications - A prospective observational study of 2,253 Pediatric Cardiac Genomics Consortium patients shows that whole-exome sequencing combined with AI genome interpretation and Bayesian networks improves prediction of adverse outcomes after congenital cardiac surgery. Damaging de novo variants in chromatin-modifying genes and recessive/biallelic variants in c...

Nature Communications - A large cross-population GWAS meta-analysis (168,007 AF cases) integrated with proteomic data identifies hundreds of AF loci, implicates cardiac and TGF-β pathways, finds causal risk factors and proteins via Mendelian randomization, and shows improved prediction when combining polygenic and protein scores. Key terms: atrial fibrillation, cross-population GWAS, proteomics, p...

Sukalskaia A et al., Nature - This Nature study identifies APOE as an interaction partner of human TTYH2, maps their endosomal colocalization and binding site by cryo-EM, and shows that TTYH2 accelerates lipid transfer from APOE-containing lipoproteins to membranes in vitro. Key terms: TTYH2, APOE, lipid transfer, endosomes, cryo-EM. Study Highlights: Using sybody pull-downs and mass spectrometry...

Bower G et al., Nature - This paper identifies a conserved cis element, REX, and a [C/T]AATTA homeodomain motif signature that are necessary and sufficient to convert short- and medium-range limb enhancers into megabase-range regulators of Shh during mouse limb development. Key terms: enhancer, long-range regulation, REX element, homeodomain motifs, Shh. Study Highlights: Transplanted short- and m...

️ Episode 76: Whole-genome Ancestry of an Old Kingdom Egyptian In this episode of PaperCast Base by Base, we explore the first 2× coverage whole-genome sequence recovered from a high-status individual of the Old Kingdom excavated at the Nuwayrat necropolis and examine the evidence for multi-regional ancestry during early Dynastic Egypt. Study Highlights: The research team extracted and authenticat...

Lemke O et al., Nature - A deep structural and evolutionary analysis of 11,269 enzyme structures across Saccharomycotina reveals how metabolic context sculpts protein architecture. The study integrates AlphaFold2 models, proteomics and metabolic models to map hierarchical constraints on enzyme evolution. Key terms: enzyme evolution, metabolism, AlphaFold2, structural conservation, yeast. Study Hig...

Drost F et al., Cell Genomics - Drost et al. integrated 21 pre-trained sequence-based TCR-epitope predictors into ePytope-TCR and benchmarked them on a viral single-cell repertoire and deep mutational scans, revealing performance biases and limited generalization to rare and mutated epitopes. Key terms: T cell receptor, epitope prediction, ePytope-TCR, benchmarking, cross-reactivity. Study Highlig...

König T et al., Genetics in Medicine - A retrospective study of 701 memory clinic patients tested whether stratifying by age at onset and family history enriches for diagnostically relevant genetic findings. Using an adapted Goldman-score classification with exome sequencing and targeted genotyping in high-risk cases, the authors increased diagnostic yield and evaluated implications for APOE and C...

Vulto-van Silfhout AT et al., Genetics in Medicine - A cohort study of twelve families shows that bi-allelic loss-of-function variants in POC5 cause a multisystem syndrome characterized by rod-cone dystrophy, early-onset insulin-resistant diabetes with partial lipodystrophy, renal disease and muscle cramps. Cellular studies in patient fibroblasts reveal reduced POC5 expression due to nonsense-medi...

Dore R et al., Genetics in Medicine - This episode reviews a multi-center study that defines ELFN1 deficiency as a recessive neurodevelopmental disorder. The authors report new patients with biallelic ELFN1 variants, show that pathogenic variants impair ELFN1 surface trafficking and mGlu receptor binding, and present mouse and zebrafish models that reproduce hyperactivity and epileptiform activity...

Goldberg DC et al., Cell Genomics - This episode examines the methylation screening array (MSA), a compact Infinium BeadChip optimized for trait-associated and cell-type CpGs and compatible with matched 5hmC profiling to enable scalable EWAS, cell deconvolution, and aging analyses. Key terms: DNA methylation, 5hmC, Infinium array, EWAS, epigenetic clock. Study Highlights: The authors developed the...

Cunningham C et al., Cell Genomics - This study used orthotopic breast PDX models, pooled and arrayed CRISPR/Cas9 screens, and Direct‑Capture Perturb‑seq to search for synthetic‑dosage‑lethal (SDL) partners of PLK1 across heterogeneous tumors. IGF2BP2 emerged as a top SDL hit using independent functional genomics approaches. Pharmacologic and genetic inhibition of IGF2BP2 impaired expansion of PLK...

Tenthorey JL et al., Cell Genomics - This episode examines a study showing that insertion/deletion mutations (indels) in the v1 loop of the antiviral protein TRIM5a can create new viral specificities in a single step, whereas missense mutations often cannot. The authors used saturation missense mutagenesis, combinatorial libraries, and a novel deep indel scanning approach to compare evolutionary p...

Zhou Y et al., The American Journal of Human Genetics - This episode explores M-REGLE, a multimodal deep‑learning pipeline that jointly learns representations from ECG and PPG waveforms to boost GWAS discovery and polygenic risk prediction for cardiovascular traits, including atrial fibrillation, and validates results across multiple biobanks. Key terms: M-REGLE, multimodal learning, ECG, PPG, GWA...

Mackley MP et al., Genetics in Medicine - This episode summarizes a consensus-derived framework for mainstreaming clinical genetic testing developed from a Canadian expert focus group. The framework defines terminology, maps diagnostic pathway activities, and describes four models that vary by when genetics services become involved. Key terms: Clinical genetics, Genetic testing, Mainstreaming, Ser...

Walker S et al., Genetics in Medicine - This episode reviews a systematic analysis of ultra-rare FBN1 variants in the 100,000 Genomes Project using SpliceAI, RNA assays and minigene tests. The study identified 20 non-canonical splice variants across 23 families, confirmed splicing defects for 16 variants, and estimates these variants account for ~3% of undiagnosed FTAAD/Marfan families. The work h...

Xu H et al., Cell Genomics - This episode covers Pisces, a machine-learning framework that augments sparse drug-pair datasets by creating multiple modality-based views per drug to improve prediction of drug synergy, xenograft responses, and drug-drug interactions. Key terms: drug combination, data augmentation, multimodal, machine learning, drug-drug interaction. Study Highlights: The authors intr...