Base by Base

🎙️ Episode 18: Network Causality — A New Bayesian Model for Multivariable Mendelian Randomization

🧬 In this episode of Base by Base, we examine the methodological breakthrough presented by Liu et al. (2025) in Nature Communications. The authors introduce BayesMRnet, a Bayesian causal graphical model designed to perform joint Mendelian randomization (MR) across multiple exposures and outcomes. By leveraging genome-wide association ...

🎙️ Episode 17: The Structure of Human Sweetness — Cryo-EM of the TAS1R2+TAS1R3 Sweet Taste Receptor
🧬 In this episode of Base por Base, we explore a landmark cryo-electron microscopy study by Juen et al. (2025) published in Cell, which reveals the high-resolution structure of the human sweet taste receptor heterodimer TAS1R2+TAS1R3 bound to the artificial sweeteners sucralose and aspartame, providing the first detailed view of...

🎙️ Episode 16: Equity in Focus: Building a Truly Global Genomic Landscape

🧬 In this episode of Base by Base, we address one of the most pressing issues in human genomics: the need to close the ancestral data gap. Published in Cell Genomics, this commentary by Ana Luiza Arruda, Andrew Morris, and Eleftheria Zeggini calls attention to how genomic medicine remains disproportionately centered on individuals of European ancestry—jeopar...

🎙️ Episode 15: What Makes Us Human? Genetics from Neandertals to Now

🧬 In this episode of Base by Base, we travel back in time—over 600,000 years—to explore the genomic storylines of Neandertals, Denisovans, and modern humans. Published in Cell by Hugo Zeberg, Mattias Jakobsson, and Nobel Laureate Svante Pääbo, this comprehensive review deciphers the evolutionary divergences that defined—and continue to define—our species.

By compa...

🎙️ Episode 14: Beyond the Genome: Societal Value of National Genomics Programmes

🧬 In this episode of Base by Base, we discuss a thought-provoking report published in the European Journal of Human Genetics that tackles a crucial yet underexplored question: what is the actual value of large-scale national genomic programmes for society?

Led by Ruth Horn, Angeliki Kerasidou, Jennifer Merchant and the UK-FR+GENE consortium, this multi...

🎙️ Episode 13: Decoding De Novo: A Multigenerational Benchmark for Human Mutation Rates

🧬 In this episode of Base by Base, we explore a monumental study published in Nature that redefines how we understand human de novo mutation (DNM) rates. By sequencing 28 individuals across four generations from the CEPH 1463 family with five complementary technologies, this study delivers the most complete pedigree reference to date.

Led by Por...

🎙️ Episode 12: Repairing the Blueprint: Insights from MUTYH Structure and Cancer-Associated Variants

🧬 In this episode of Base by Base, we explore a pivotal study published in Nature Communications that reveals the structural and functional secrets of the human MUTYH DNA glycosylase. This landmark work provides the first crystal structure of human MUTYH bound to DNA, illuminating how its [4Fe-4S] cluster cofactor allosterically co...

🎙️ Episode 11: Targeting Mitochondria: A Therapeutic Strategy for Dnmt3a-Mutant Clonal Hematopoiesis

🧬 In this episode of Base by Base, we dive into a compelling study published in Nature Communications that reveals a novel therapeutic vulnerability in clonal hematopoiesis driven by DNMT3A mutations. The research identifies elevated mitochondrial membrane potential (Δψm) as a selective weakness in mutant hematopoietic stem and pro...

🎙️ Episode 10: Targeting the Genome: Guidelines for Antisense Oligonucleotide Therapy Eligibility

🧬 In this episode of Base by Base, we explore a transformative study published in The American Journal of Human Genetics that introduces the N1C VARIANT guidelines — a consensus framework for evaluating the eligibility of pathogenic DNA variants for antisense oligonucleotide (ASO) therapies. This pioneering effort addresses a critical...

🎙️ Episode 9: Unraveling Complexity: A Bayesian Graphical Model for Joint Mendelian Randomization

🧬 In this episode of Base by Base, we explore a groundbreaking study published in The American Journal of Human Genetics that introduces MrDAG, a Bayesian causal graphical model designed to jointly analyze multiple exposures and outcomes in Mendelian randomization (MR) studies. This innovative approach overcomes the limitations of tra...

🎙️ Episode 8: Mapping Structural Variation: A Global Reference for Clinical and Population Genomics

🧬 In this episode of Base by Base, we explore a landmark study published in Nature that presents the first high-resolution, sequence-resolved map of structural variants (SVs) across human populations. Built from 14,891 genomes analyzed through the Genome Aggregation Database (gnomAD), this study delivers a transformative resource fo...

🎙️ Episode 7: Filtering with Precision: How High-Resolution Variant Frequencies Enhance Clinical Genome Interpretation

🧬 In this episode of Base by Base, we explore a landmark study published in Genetics in Medicine that presents a statistical framework for leveraging large-scale population databases to improve the interpretation of rare genetic variants in clinical genomics.

Led by Whiffin and colleagues, the 2017 study proposes a...

🎙️ Episode 6: Cracking the Code: How TRMT1 Mutations Disrupt tRNA and Drive Neurodevelopmental Disorders

🧠 In this episode of Base by Base, we dive into a 2025 study published in The American Journal of Human Genetics that sheds light on how pathogenic variants in the TRMT1 gene disrupt tRNA modification, leading to a newly characterized neurodevelopmental disorder.

Led by Efthymiou and colleagues, the study describes 43 individual...

🎙️ Episode 5: Decoding Preterm Birth: How cfDNA Promoter Profiles Can Predict Pregnancy Risk

🩸 In this episode of Base by Base, we dive into a large-scale 2025 study published in PLOS Medicine that explores how genome-wide nucleosome footprints of plasma cell-free DNA (cfDNA) can be leveraged to predict spontaneous preterm birth (sPTB). This innovative work introduces PTerm, a promoter-profiling-based classifier built from cfDNA d...

🎙️ Episode 4: Shaping the Heart: How CXCL12 Drives Coronary Artery Anatomy

🫀 In this episode of Base by Base, we explore a groundbreaking 2025 study published in Cell that reveals how the gene CXCL12 contributes to natural variation in coronary artery anatomy across diverse human populations. The study identifies CXCL12 as a key regulator of coronary artery dominance — a developmental trait that determines whether the right, left,...

🎙️ Episode 3: Heuristics in Splicing: Rethinking Variant Impact from the Genome Up

🧬 In this episode of Base by Base, we discuss a 2025 study published in The American Journal of Human Genetics that introduces a comprehensive, data-driven framework to enhance the assessment of splice-altering variants (SAVs). These variants, often overlooked in variant classification workflows, are now being reevaluated with a new lens grounded in...

In this episode of Base by Base, we delve into a pivotal study examining how different blood collection tube additives—EDTA, citrate, heparin, and serum—affect the integrity of cell-free DNA (cfDNA). The research highlights that EDTA-plasma offers superior preservation of cfDNA due to its effective inhibition of DNase activity, resulting in minimal degradation. Conversely, heparin-plasma and serum samples exhibit higher DNase activ...

In this episode of Base by Base, we explore a recent study published in The American Journal of Human Genetics that investigates the integration of structural biology into the ACMG/AMP framework for classifying BRCA1 missense variants.

The research assesses how incorporating structure-based evidence—such as relative solvent accessibility (RSA), folding stability (ΔΔG), and AlphaMissense pathogenicity scores—can refine the applicati...