Base by Base

Steiner MC et al., PNAS - This episode examines a theoretical and empirical study showing how the geographic breadth of sampling affects discovery and observed frequencies of deleterious rare variants. The authors develop a spatial stochastic model, validate it with simulations, and test predictions using UK Biobank exome resampling. Key terms: sampling breadth, rare variants, negative selection,...

Pappas K et al., PNAS - A genome-wide CRISPR screen in Brca2‑deficient murine prostate organoids identifies loss-of-function in DNA prereplication complex genes (CDT1, CDC6, DBF4) as a reversion‑independent mechanism of resistance to PARP inhibitors; pharmacologic disruption of the Geminin–CDT1 interaction can restore sensitivity. Key terms: PARP inhibitors, BRCA2, prereplication complex, prostate...

️ Episode 61: Monkeypox on the Frontline — Developing Brazil’s First qPCR Diagnostic Assay In this episode of Base by Base, we trace the rapid development and rigorous validation of the first laboratory-developed qPCR test for monkeypox virus in Brazil’s Federal District. Back in July 2022, researchers at Sabin Diagnóstico e Saúde and the Catholic University of Brasília joined forces to design, op...

Zeng W et al., PNAS - This paper introduces Epi-PRS, a workflow that uses genomic large language models to impute cell-type-specific epigenomic features from diploid genotypes and trains nonlinear risk models to improve polygenic prediction from WGS. The method improves AUC for breast cancer and type 2 diabetes in UK Biobank and shows gains from modeling regulatory context and rare variants. Key t...

Crossnohere NL et al., Genetics in Medicine - Overview of how the PE-CGS Network defined, implemented, and evaluated strategies to engage participants and communities in cancer genomic sequencing research, and how engagement optimization using scientific methods informed study practices. Key terms: participant engagement, community engagement, engagement optimization, cancer genomics, return of re...

Fusari E et al., Cell Genomics - Fusari et al. use FLP/FRT–based mosaic methods in Drosophila imaginal epithelia to generate defined segmental monosomies and trisomies and quantify their immediate effects on clonal growth, survival, and interclonal interactions. Key terms: aneuploidy, cell competition, Drosophila, segmental monosomy, trisomy. Study Highlights: Using RS- and TSG-FRT tools, the auth...

Brown TR et al., Genetics in Medicine - This episode reviews a claims-based study of 241,060 Medicaid-enrolled children (ages 7–17) from 2008–2016 that measured use of genetic testing among those with ASD-only, ID-only, and ASD+ID. The authors report low overall testing rates, temporal shifts in test modalities from cytogenetics/Fragile X toward chromosomal microarray and gene panels, and disparit...

Woo et al et al., Cell - This study shows that interferon-driven induction of the immunoproteasome subunit PSMB8 in neurons reduces proteasome β5 catalytic activity, causing accumulation of the glycolytic regulator PFKFB3. PFKFB3 accumulation shifts neurons from the pentose phosphate pathway to glycolysis, lowering NADPH/GSH, increasing ROS and lipid peroxidation, and sensitizing neurons to ferrop...

Fu Q et al., Cell - Recovery of mitochondrial DNA from dental calculus links the Late Middle Pleistocene Harbin cranium to Denisovans and demonstrates dental calculus as a source of ancient host DNA. Key terms: Denisovan, mitochondrial DNA, Harbin cranium, dental calculus, Middle Pleistocene. Study Highlights: Researchers recovered mitochondrial DNA from dental calculus of the >146,000-year-old...

Stephenson E et al., Cell Genomics - Longitudinal single-cell multi-omics profiling of PBMCs from 61 end-stage kidney disease (ESKD) patients with COVID-19 (580,040 cells) reveals distinct temporal immune trajectories in severe versus mild disease, emergence of a dexamethasone-associated monocyte population, and expanding T cell clones enriched for SARS-CoV-2 specificity. Key terms: COVID-19, end-...

Siena LM et al., The American Journal of Human Genetics - A systematic review of 24 full economic evaluations assessing polygenic risk score (PRS)–based clinical strategies across cancer, cardiovascular disease, and other conditions, summarizing methods, cost components, and evidence on cost-effectiveness. Key terms: polygenic risk scores, economic evaluation, cost-effectiveness, screening, implem...

Keener R et al., Cell Genomics - A method-focused excerpt describing LIZS6-related experiments across multiple conditions (NoSk, LSFM) with quantitative readouts and protocol detail. Key terms: LIZS6, NoSk, LSFM, tzqom�t{z, moww. Study Highlights: The provided text documents experiments centered on LIZS6 across multiple platforms and experimental conditions such as NoSk and LSFM. Quantitative meas...

Ratnaike et al et al., The American Journal of Human Genetics - This episode reviews a Solve-RD reanalysis that integrated an mtDNA-focused bioinformatic pipeline (MToolBox) with MitoPhen HPO-based phenotype similarity scoring to prioritize mitochondrial variants from exome and genome data, leading to new diagnoses in a large rare-disease cohort. Key terms: mitochondrial DNA, MToolBox, MitoPhen, p...

Porcari S et al., Cell - Perspective reviewing current diagnostic and therapeutic advances in gut microbiome research and outlining the methodological, biological, regulatory, and educational actions needed to move microbiome science into clinical practice. Key terms: microbiome, faecal microbiota transplantation, diagnostics, therapeutics, standardization. Study Highlights: The authors synthesize...

Holt JD et al., PNAS - Using microfluidic flow assays and live-cell imaging, the authors show that environmental DNA adsorbs to chitin particles and that Vibrio cholerae can retrieve this chitin-bound DNA for natural transformation. They further identify the PilU retraction motor as essential for retrieving surface-adsorbed DNA. Key terms: Vibrio cholerae, chitin, natural transformation, horizonta...

Mackley MP et al., Genetics in Medicine - A consensus-driven conceptual framework from Canadian genetics experts describing four models for mainstreaming clinical genetic testing and the variables that determine which model fits specific clinical scenarios. Key terms: mainstreaming, genetic testing, clinical genetics, service delivery, framework. Study Highlights: An expert focus group and consens...

Kleist AB et al., Cell - A data-driven mapping of how 46 human chemokines and 23 GPCRs encode selective and promiscuous interactions. The team defines conserved, semi-conserved and variable determinants, identifies SLiMs in unstructured regions, and uses these rules to rewire a viral chemokine. Key terms: chemokine, GPCR, selectivity, SLiM, protein engineering. Study Highlights: The authors integr...

Linder B et al., Cell - This episode explores a pan-epitranscriptomic mechanism showing how m6A in coding sequences slows ribosomal decoding to trigger translation-dependent mRNA decay, and how the tRNA wobble modification mcm5s2U counteracts that effect to tune decay and impact oncogenic pathways. Key terms: m6A, tRNA modification, mcm5s2U, mRNA decay, ribosome profiling. Study Highlights: The au...

Cheng HH et al., Proceedings of the National Academy of Sciences (PNAS) - Using micropipette aspiration in Xenopus laevis oocyte nuclei, authors show the nucleolar granular component behaves as a liquid while the dense fibrillar component and fibrillar center exhibit RNA-dependent viscoelastic, partially solid-like properties; RNase A fluidizes the DFC and alters interfacial tensions. Key terms: n...

Wang F et al., PNAS - This episode examines a cryo-EM study that captures authentic proofreading intermediates of human Polε in complex with PCNA by generating a mismatch in situ. The work reveals how PCNA constrains DNA movement and how a mismatched primer is transferred from the polymerase to the exonuclease site. Key terms: DNA proofreading, DNA polymerase ε, PCNA, cryo-EM, replication fidelity...

Kjærgaard J et al., Cell - This episode reviews a study that links in vivo insulin sensitivity phenotyping with proteome and signaling-pathway mapping to define molecular-phenotype associations across heterogeneous populations. The paper emphasizes population heterogeneity and maps proteomic signatures to functional signaling pathways associated with insulin sensitivity. Key terms: population hete...

Rout SK et al., Nature Communications - A Nature Communications study shows that proteinogenic amino acids accelerate non-enzymatic RNA oligomerisation from ribonucleoside-2',3'-cyclic phosphates under dry alkaline conditions at ambient temperature, increasing yields, sequence diversity and the fraction of natural 3'-5' linkages. Key terms: RNA polymerisation, amino acids, prebiotic chemistry, 2',...

Peters R et al., The American Journal of Human Genetics - This episode reviews a nationwide survey of 2,509 Australian adults using two discrete choice experiments to quantify public preferences and the monetary value placed on genomic newborn screening (gNBS), and to identify preferred implementation features such as consent model and result delivery. Key terms: genomic newborn screening, discret...

Provided PDF (truncated source text) et al., Cell - This episode reviews a study that examines SLC7A11 (7A11) localization to lysosomes and its impact on lysosomal acidification, cystine/cysteine balance, lysosomal function, and cell viability using genetic and pharmacologic tools and isolated lysosome assays. Key terms: SLC7A11, lysosome, lysosomal pH, cystine, ferroptosis. Study Highlights: The...

Zabad S et al., The American Journal of Human Genetics - This episode covers Zabad et al.'s methods to scale summary-statistics-based polygenic risk score (PRS) inference to millions of variants. The authors introduce compressed LD storage, memory-efficient coordinate-ascent variational algorithms, and multi-level parallelism to cut storage, runtime, and RAM by orders of magnitude while retaining...