Course Slide Decks & Materials
pks+ E. coli colibactin (SBS88), clonal trunk vs. branch evolution, proto-oncogenes vs. tumor suppressors (Knudson's two-hit & LOH), TP53 tetramer poisoning (15/16) & Peto's Paradox, COSMIC 96-channel mutational signatures, chromothripsis, PARP synthetic lethality, and TMB neoantigen immunotherapy.
Genomics in Medicine & The AI Frontier
Deconstructs foundational myths in modern medicine: why "normal" reference intervals are statistical fictions, how 1750 London infant mortality distorted life expectancy, the evolutionary scar of the Black Death, the economic trap of blockbuster clinical trial averages, and how structure-based genomics cured CML.
- Gaussian Distributions & Lab Intervals
- 1,000 Years of Mortality Dynamics
- The 7 Axes of Disease
- Ancient DNA & ERAP2 Immune Selection
- Evidence-Based Medicine vs. NNT
- CML & BCR-ABL Kinase Inhibition
- Live PGx Database Investigation
The Architecture of the Human Genome: Physical Molecules, Ploidy & The Missing 8%
From digital 1D code to 3D nuclear chromatin, chromosome mechanical segregation, mitochondrial heteroplasmy bottlenecks, the genetics of cis/trans phasing, the historical evolution of the gene concept, and how the Telomere-to-Telomere (T2T) consortium finally finished the 20-year missing 8%.
- Digital Code vs 3D Macromolecule
- 8 Orders of Magnitude Genome Sizes
- Chromosome Anatomy & Chr 2 Fusion
- mtDNA Heteroplasmy & Thresholds
- Diploidy & Phasing (Cis vs Trans)
- Smartphone Storage Analogy
- C-Value Enigma
- Mendel, Morgan, Avery & The Gene
- The Great Gene Count Collapse
- T2T Consortium (Nurk et al. 2022)
- Focus 1: Abstract & Introduction — Why was ~8% of the human genome missing for 20 years?
- Focus 2: Figure 1 & Figure 2 — GRCh38 gaps vs. T2T closed chromosomes; what was hidden inside the heterochromatic repeats?
- Focus 3: Section "Clinical Implications" — How unresolved repeats caused false-positive clinical variant calls.
Thousands of Tiny Nudges: GWAS, Complex Traits, and Polygenic Risk Scores
From monogenic Mendelian certainties to Fisher's infinitesimal model. Genome-Wide Association Studies (GWAS), Linkage Disequilibrium, Manhattan plots, within-family sibling controls, and the hype audit of Polygenic Indices (PGIs).
- Polygenic & Omnigenic Architecture
- 1,260 Lead SNPs (N > 1.14M)
- Missing Heritability & Reliability
- Debunking Neurotransmitter Dogma
- Within-Family Sibling GWAS
- Minimal Familial Confounding
- Spousal Assortative Mating (r_g ≈ 0)
- PGI Predictive Limits (R² ≈ 1-3%)
- Focus 1: Table 1 & Figure 1 — 1,260 lead SNPs; 82% trait-specific architecture vs. overlapping prefrontal cortex gene sets.
- Focus 2: Figure 4 & Section "Within-Family Analyses" — Sibling controls proving minimal familial confounding compared to educational attainment.
- Focus 3: Figure 2 & The Hype Audit — Why PGIs explain only 1%β3% of variance and cannot predict individual future behavior.
Structural Variation, Copy Number Variants (CNVs), and Gene Dosage in Disease
From whole-chromosome aneuploidies to submicroscopic microdeletions and prenatal cell-free DNA liquid biopsies. Explores gene dosage balance (triplosensitivity vs. haploinsufficiency in CMT1A and HNPP), non-allelic homologous recombination (NAHR) mediated by low-copy repeats, chromosomal microarray (CMA) resolution and BAF allelic tracks, the ACMG 5-tier classification framework, and Bayesian positive predictive value (PPV) dynamics in prenatal screening.
- Gene Dosage Stoichiometry (PMP22)
- Non-Allelic Homologous Recombination (NAHR)
- Paralogous LCR Architecture (>10 kb, >95% ID)
- Recurrent Microdeletions (22q11.2 DiGeorge)
- Chromosomal Microarrays: aCGH vs. SNP Arrays
- Log2 Ratio Intensity & BAF Allelic Tracks
- Copy-Neutral Loss of Heterozygosity (UPD)
- ACMG 5-Tier Evidence Classification
- Circulating Cell-Free Fetal DNA (cffDNA)
- Bayesian PPV & Maternal Age Stratification
- Confined Placental Mosaicism (CPM)
- Focus 1: Media Sensation vs. Clinical Reality — Why commercial direct-to-consumer blood tests claim certainty while clinical trial hazard ratios show complex age-dependent progression.
- Focus 2: Biomarker Sensitivity — Multi-ethnic validation: why biomarker cutoffs established in homogeneous cohorts fail in diverse urban healthcare environments.
- Focus 3: Diagnostic Prudence — The clinical ethics of screening asymptomatic individuals without disease-modifying therapeutic interventions.
The Regulatory Genome: Epigenetics, Chromatin Architecture, and Transcriptomics
How non-coding variants, chromatin folding, and chemical tags on DNA control cell identity, disease risk, and the rate of biological aging. Explores DNA methylation (5mC) and histone modifications, chromatin accessibility (ATAC-seq), topologically associating domains (TADs) insulated by CTCF, the GTEx Consortium multi-tissue regulatory atlas (v8 Science 2020), cis- and trans-eQTLs, splicing QTLs (sQTLs), single-cell deconvolution of cellular heterogeneity, and Horvath's 353-CpG multi-tissue epigenetic aging clock.
- Epigenetics & 5-Methylcytosine (5mC)
- Histone Marks (H3K4me3, H3K27ac, H3K27me3)
- Chromatin Accessibility (ATAC-seq)
- 3D Architecture & TAD Insulation (CTCF)
- Enhancer Hijacking & Oncogenesis
- GTEx Atlas: 49 Tissues (Science 2020)
- Cis-eQTLs & TSS Distance Decay
- Splicing QTLs (sQTLs) & Isoform Diversity
- Bulk Deconvolution vs. scRNA-seq
- Horvath Epigenetic Aging Clock (353 CpGs)
- Epigenetic Age Acceleration (EAA)
- Focus 1: Scope & Cis-eQTL Distance Decay (Figures 1 & 2) — 15,201 RNA-seq samples across 49 tissues; exponential clustering of regulatory variants within 100 kb of the TSS.
- Focus 2: Splicing QTLs (sQTLs) vs. eQTLs (Figures 3 & 5) — Why intron excision and transcript isoform remodeling show comparable or greater disease GWAS enrichment than total expression.
- Focus 3: Horvath Epigenetic Aging Clock — Penalized elastic net regression on 353 CpG dinucleotides predicting biological age and mortality risk across 51 human tissues.
Bacterial Genomics: Commensals vs. Pathogens (Good vs. Evil)
From the 1:1 cell count reality and symbiotic colonization resistance to hospital outbreak tracing, the antimicrobial resistance crisis, and next-generation therapeutics. Explores gut microbiome ecology and short-chain fatty acids (SCFAs), 16S rRNA amplicon vs. shotgun metagenomics, secondary bile acid biochemistry, Fecal Microbiota Transplantation (FMT) for recurrent Clostridioides difficile (van Nood et al., NEJM 2013), whole-genome sequencing (WGS) for hospital epidemiology (Snitkin et al., Sci Transl Med 2012), 41-SNV genomic barcoding of carbapenem-resistant Klebsiella pneumoniae (KPC-ST258), silent asymptomatic carrier vectors, in vivo evolution of colistin resistance (PmrB), the landmark Tom Patterson pan-drug resistant Acinetobacter baumannii bacteriophage rescue and evolutionary phage steering (Strathdee & Schooley, UCSD), and the 2024 antibacterial clinical pipeline void (Zosurabalpin & Lolamicin).
- 1:1 Cell Count Rule (Sender 2016)
- Gut Microbiome Ecology & SCFAs
- Colonization Resistance (Bile Acids)
- 16S rRNA vs. Shotgun Metagenomics
- FMT for C. difficile (van Nood 2013)
- WGS Outbreak Tracing (Snitkin 2012)
- 41-SNV Genomic Barcoding (KPC-ST258)
- Silent Asymptomatic Vectors
- Decontaminated Ventilator Reservoirs
- AMR Crisis & In Vivo Colistin Resistance
- Tom Patterson Phage Rescue (UCSD)
- Evolutionary Phage Steering
- WHO 2024 Pipeline Void
- Next-Gen Targets (Zosurabalpin & Lolamicin)
- Focus 1: The Outbreak Detective & Intra-Host Diversity (Figures 2 & 3) — 41 SNVs across 18 patients; resolving the Patient 2 vs. Patient 3 temporal inversion paradox and tracking silent carriers.
- Focus 2: Ecological Reconstitution & Trial Ethics (Figures 2 & 3) — 81–94% cure in recurrent C. diff vs. 31% for vancomycin; why the DSMB halted the trial early.
- Focus 3: Last-Resort Resistance & Image Annotation Task — In vivo selection of colistin resistance (Table 2) and hands-on transmission map markup.
Viral Genomics, Rapid Evolution, and the Vaccine Revolution
From the physics of viral replication fidelity and proofreading exonucleases (nsp14) to real-time genomic surveillance, molecular clock dating (tMRCA), biophysical fitness forecasting, and the synthetic mRNA vaccine design revolution. Explores avian influenza H5N1 receptor-binding switch dynamics (α-2,3 vs. α-2,6 sialic acid linkages), mammalian adaptation markers (PB2 E627K), root-to-tip clock regression, the Εuksza & LΓ€ssig biophysical fitness model (Nature 2014) predicting seasonal influenza H3N2 clade turnover, the mutational trap of molnupiravir and viable community transmission of hypermutated lineages (Sanderson et al., Nature 2023), and the structural engineering of synthetic mRNA vaccines (Kizzmekia Corbett 2P prefusion spike lock and KarikΓ³ & Weissman pseudouridine modification).
- RdRp Error Catastrophe & nsp14 Proofreading
- Sialic Acid Linkages (α-2,3 Avian vs. α-2,6 Human)
- Avian H5N1 Mammalian Spillover (PB2 E627K)
- Molecular Clock Dating & tMRCA Estimation
- Nextstrain Real-Time Phylodynamics
- ΕukszaβLΓ€ssig Biophysical Fitness Forecasting (Nature 2014)
- Epitope Innovation vs. Mutational Load
- Molnupiravir Mutational Trap (Nature 2023)
- Prefusion 2P Proline Lock (Corbett et al.)
- Pseudouridine (Ψ) & Innate Immune Evasion (KarikΓ³ & Weissman)
- Focus 1: Clade Evolution & Dominance (Figure 1) — Branching genealogies and frequency trajectories; predicting future dominant lineages 1 year in advance.
- Focus 2: Epitope Innovations vs. Mutational Load (Figure 3) — Positive selection coefficient on hemagglutinin epitope substitutions vs. deleterious cost on non-epitope mutations.
- Focus 3: Molnupiravir Mutational Signatures (Nature 2023) — Lethal mutagenesis vs. sublethal viable transmission of hypermutated lineages.
The Double-Edged Sword: Host Immunology, HLA Diversity, and Autoimmune Disease
From the three-branch architecture of human immunity (Innate TLRs, B-Cell Antibodies, and T-Cell Scanners) to somatic DNA shuffling, high-throughput repertoire sequencing, HLA balancing selection, and precision therapies for autoimmune disease. Explores how RAG1/2 and TdT generate >1015 T-cell receptors via V(D)J recombination, how convergent recombination and public TCR clonotypes enable blood-based viral history diagnostics and HLA inference (Emerson et al., Nature Genetics 2017), how MHC/HLA Class I and Class II peptide-binding grooves enforce extreme polymorphism across human populations, how a single amino acid or small molecule breaks self-tolerance in Type 1 Diabetes (HLA-DQB1 non-Asp57), Celiac Disease (TG2 deamidation on HLA-DQ2.5), and HIV Abacavir hypersensitivity (HLA-B*57:01), and how humanized monoclonal antibodies (-zumab/-umab) and anti-CD19 CAR-T cell reboots silence autoimmune attacks.
- Innate (TLRs) vs. B Cells (BCRs) vs. T Cells (TCRs)
- V(D)J Somatic Recombination & RAG1/2 Scissors
- TdT Junctional Diversity & CDR3 Loops
- Public vs. Private TCRs & Convergent Recombination
- AIRR Immunosequencing & Overfitting (Emerson 2017)
- HLA Class I & II Groove Pockets (A–F)
- Pathogen-Driven Balancing Selection (>4,800 HLA-B Alleles)
- Thymic Central Tolerance (AIRE) & Treg Police
- Type 1 Diabetes (HLA-DQB1 non-Asp57 Electrostatic Flip)
- Celiac Disease (TG2 Gluten Deamidation & >99% NPV)
- HLA-B*57:01 Abacavir Pharmacogenomic Guardrail
- Targeted Biologics (-umab) & CD19 CAR-T Immune Reset
- Focus 1: High-Throughput Repertoire Profiling (Figure 1) — Multiplex PCR sequencing of 85+ million unique TCRβ rearrangements across 640 donors, overcoming private sequence noise.
- Focus 2: Machine Learning Classifier & Overfitting (Figure 2) — Calibrating the Fisher's exact test cutoff at P ≤ 10−4 (142 public TCR features, CV AUROC = 0.93) to prevent overfitting on private patient sequences.
- Focus 3: HLA Class I Restriction & Autoimmunity (Figure 3) — 57 HLA-restricted public TCR clonotypes, reverse HLA typing from blood, and the evolutionary trade-off driving autoimmune disease.
Cancer Genomics I: The Rogue Genome — Evolution, Mutational Signatures, and Hallmarks
From 1.7-million-year-old hominin osteosarcomas and the 27-year smoking-to-lung-cancer lag to somatic Darwinian evolution, two-hit tumor suppressor kinetics, and 96-channel COSMIC mutational forensics. Explores the Armitage–Doll multi-stage power-law model (I(t) ∝ tk−1), Tomasetti & Vogelstein's stem-cell division correlation (r = 0.81, R2 = 65%) reconciled with ≥40% epidemiological preventability, early-onset colorectal cancer (<50 yr) and childhood pks+ E. coli colibactin mutagenesis (COSMIC SBS88, Diaz-Gay et al., Nature 2025), Nowell's clonal evolution and TRACERx spatial heterogeneity (Gerlinger et al., NEJM 2012), dN/dS driver vs. passenger selection (the Titin TTN 109-kb target-size trap), proto-oncogenes vs. tumor suppressors (Knudson's two-hit hypothesis & Loss of Heterozygosity in RB1), TP53 dominant-negative tetramer poisoning (15/16 = 93.75%) and Peto's Paradox (20 elephant TP53 copies), NMF deconvolution of 96-channel COSMIC signatures (SBS1 aging clock, SBS2/13 APOBEC kataegis, SBS4 tobacco smoke, SBS7 UV pyrimidine dimers, SBS3 BRCA1/2 HRD, SBS6 MSI-High), chromothripsis & ecDNA, PARP inhibitor synthetic lethality, and TMB neoantigen checkpoint blockade.
- Paleopathology & History of Cancer (1775–2026)
- Armitage–Doll Power Law (k − 1 ≈ 5–6 Hits)
- Stem-Cell Divisions (R2 = 65%) vs. Preventability
- Early-Onset CRC & Colibactin SBS88 (Nature 2025)
- Trunk vs. Branch Clonal Evolution & ctDNA
- Drivers (dN/dS ≫ 1) vs. Giant-Gene Passengers (TTN)
- Proto-Oncogenes (KRAS, BRAF, BCR-ABL1, HER2)
- Knudson's Two-Hit Hypothesis & LOH (RB1)
- TP53 Tetramer Poisoning (15/16) & Peto's Paradox
- COSMIC 96-Channel Signatures (6 × 4 × 4)
- SBS1, SBS2/13 (Kataegis), SBS3 (HRD), SBS4, SBS6, SBS7
- Chromothripsis, ecDNA & Hallmarks OncoPrints
- PARP Synthetic Lethality & TMB Anti-PD-1
- Focus 1: The Early-Onset Colorectal Cancer Paradox — Why colorectal cancer incidence has doubled in adults under 50 while falling in older adults, and how COSMIC SBS88 + ID18 (from
pks+E. coli colibactin) is enriched 3.3-fold in patients under 40. - Focus 2: cBioPortal Lollipop Plots vs. OncoPrints — Distinguishing 1-hit gain-of-function oncogene missense hotspots (KRAS G12D, BRAF V600E) from 2-hit loss-of-function tumor suppressor truncations (APC, RB1) and dominant-negative TP53 tetramer poisoning.
- Focus 3: Forensic Mutational Signatures & Precision Therapy — Using 96-channel spectra to solve Cancers of Unknown Primary (CUP) and match SBS3 (HRD) to PARP inhibitors and TMB-High (SBS4/6/7) to anti-PD-1 immunotherapy.