Base by Base

Nature - A telomere‑to‑telomere, multigenerational study that uses five sequencing technologies to assemble and phase near‑complete diploid genomes from a 28‑member family (CEPH 1463) to measure de novo mutation rates across the genome. Key terms: de novo mutation, long-read sequencing, tandem repeats, centromeres, Y chromosome. Study Highlights: The authors generated phased, near‑T2T assemblies f...

Trasviña-Arenas CH et al., Nature Communications - This episode explores a 2025 study that reports the first human MUTYH structure bound to a transition state analog and functional profiling of cancer-associated variants near its [4Fe-4S] cluster. The authors map an evolutionarily conserved hydrogen-bond network linking the metal cluster to the catalytic Asp236 and show how specific variants disru...

Nature Communications (2025) 16:3306 et al., Nature Communications - This study shows that Dnmt3a-mutant hematopoietic stem and progenitor cells (HSPCs) sustain elevated mitochondrial membrane potential and oxidative phosphorylation, creating a selective vulnerability that can be targeted with long-chain alkyl‑TPP molecules such as MitoQ to ablate mutant clonal advantage in mouse and human cells....

Cheerie D et al., The American Journal of Human Genetics - This episode summarizes the N1C VARIANT consensus guidelines (version 1.0) that define a framework to evaluate pathogenic DNA variants for eligibility for antisense oligonucleotide (ASO) approaches, and describes the supporting tools, videos, and piloting process developed by the N¼1 Collaborative. Key terms: antisense oligonucleotides, va...

Zuber V et al., The American Journal of Human Genetics - Zuber et al. introduce MrDAG, a Bayesian causal graphical model that combines Mendelian randomization, structure learning, and interventional calculus to estimate causal effects among multiple correlated exposures and outcomes using summary-level GWAS data. The method reveals dependency structures and highlights education and smoking as key...

Collins RL et al et al., Nature - This episode reviews gnomAD-SV, a sequence-resolved reference of structural variants from 14,891 genomes that catalogs 433,371 SVs (335,470 high-quality) and integrates the resource into the gnomAD browser for population and clinical use. Key terms: structural variants, gnomAD-SV, whole-genome sequencing, dosage sensitivity, population genetics. Study Highlights:...

Whiffin N et al., Genetics in Medicine - A statistical framework uses large reference allele-frequency data (ExAC) together with disease prevalence, heterogeneity, penetrance, and sampling variance to set rigorous frequency filters that improve Mendelian variant interpretation. Key terms: allele frequency, clinical genomics, ExAC, inherited cardiovascular conditions, variant interpretation. Study...

Efthymiou S et al., The American Journal of Human Genetics - A global cohort study identifies bi-allelic TRMT1 variants that cause developmental delay and intellectual disability, links those variants to reduced tRNA m2,2G modification in patient cells, and models TRMT1 deficiency in zebrafish to reveal developmental and transcriptomic consequences. Key terms: TRMT1, tRNA modification, intellectua...

Guo Z et al., PLOS Medicine - Large multi-center case-control study shows promoter-region nucleosome footprints in plasma cell-free DNA can predict spontaneous preterm birth. The authors developed PTerm, an 83-gene SVM classifier applied to routine NIPT data, validated across three cohorts. Key terms: cell-free DNA, preterm birth, promoter profiling, NIPT, machine learning. Study Highlights: The s...

Rios Coronado PE et al., Cell - A multi-ancestry GWAS in >61,000 veterans identifies CXCL12 as a top locus influencing whether the right or left coronary tree supplies the posterior heart; fetal expression, spatial transcriptomics, deep-learning regulatory maps, and mouse heterozygous knockdown link CXCL12 regulation to coronary dominance. Key terms: CXCL12, coronary dominance, GWAS, fetal hear...

Sullivan P et al., The American Journal of Human Genetics - A concise walkthrough of data-driven heuristics and a splicing checklist derived from large-scale exon, branchpoint, and experimentally validated variant analyses to improve interpretation of splice-altering variants. Key terms: splicing, splice-altering variants, heuristics, SpliceVarDB, pseudoexon. Study Highlights: The authors analyzed...

Barra G et al., LabMed (2025) 2, 4 - A comparative study of blood collection tubes (EDTA, citrate, heparin, serum) from 15 healthy volunteers showing how anticoagulants affect baseline cell-free DNA, endogenous DNase activity, and cfDNA degradation over 24 hours at 37°C. Key terms: cell-free DNA, EDTA plasma, heparin plasma, citrate plasma, serum. Study Highlights: Baseline cfDNA was highest in se...

Ramadane-Morchadi L et al., The American Journal of Human Genetics - This episode reviews a study that evaluates how structure-based computational scores (AlphaMissense, FoldX DDG using PDB or AlphaFold2 templates, and RSA) compare with BayesDel for ACMG/AMP PP3/BP4 evidence in classifying BRCA1 missense variants. The authors used MAVE functional data and BRIDGES case-control validation to assess...