Course Slide Decks & Materials
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%–3% 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, Recombination & Pandemic Tracking
High-throughput viral sequencing, intra-host quasispecies evolution, molecular epidemiology, recombination dynamics, and real-time genomic surveillance across HIV-1, SARS-CoV-2, and Avian Influenza (H5N1).
- Viral Quasispecies & Ultra-Deep Sequencing
- Phylodynamics & Molecular Clock Estimation
- Recombination Detection & Breakpoint Mapping
- SARS-CoV-2 Genomic Surveillance (GISAID / Nextstrain)
- Avian Influenza H5N1 Mammalian Adaptation