Genome+Environment = Traits, [diseases], (treatments) Hair: Baldness [alopecia](minoxidil) Eyes: [Near/Far-sightedness](glasses) Iris color [ARMD] (glasses) Face: [Developmental syndromes, Wrinkles] (Botox) Brain: ADHD(Ritalin); Depression(Prozac); Headache(analgesics) Sleep & Circadian (caffeine, amphetamine, modafinil) Motion sickness (Dramamine, and Scopolamine) Ears: Sensitivity (hearing aids) Nose: Shape [breathing disorders] (CPAP) Lip: [Cleft palate] (surgery); [Hirsutism] (calcium thioglycolate) Mouth: Halitosis, throat exams; aerosols [airborne pathogens] Digestion [reflux, gas,ulcer] (antibiotics, antacids, PPIs) Back: Strain sensitivity [IDD] (analgesics) Skin: Perspiration, Body odor, Pheromones (deodorants) Surface texture [psoriasis] (topicals, photo-treatments) Immune components [acne] (topical antibiotics) Skin color [vitamin D & sunburn] (supplements, SPF cream) Hands: Dermatoglyphics [syndromes], [Arthritis](corticosteroids) Internal sensors: Proprioceptor, Repetitive stress (NSAIAs) Body: Height [Marfan] [short stature] (hGH) Weight [anorexia] [obesity] (Orlistat, Phentermine, Sibutramine) Allergies (antihistamines, cortisone, epinephrine, theophylline) Metabolic polymorphisms (vitamins, minerals, insulin) Feet: Plantar fasciitis (orthotic shoes) Athletes foot (miconazole, itraconazole, terbinafine, salicylate) 1933

2 SNP chip vs Sequence : Breast Cancer deCODEme: does not include the high-risk but rare BRCA1 and BRCA2 breast cancer risk variants. Navigenics: Mutations in BRCA1 or BRCA2 are less common in the population and are only present in approximately 5 – 10% of families with breast and ovarian cancer. 23andme: Hundreds of cancer-associated BRCA1 and BRCA2 mutations have been documented, but three specific BRCA mutations are worthy of note because they are responsible for a substantial fraction of hereditary breast cancers and ovarian cancers among women with Ashkenazi Jewish ancestry. Knome: Nearly complete genome sequence 2x (1Mbp vs 3000Mbp)

3 Valuable Personal Genome Sequences 1526 genes are highly predictive & medically actionable (inherited & cancer) at ~$2K per gene. PKU, Tay Sachs, Cystic Fibrosis, BRCA1/2, etc. (See Genetests.org) Pharmacogenomic drug/allele combinations: Herceptin, Iressa,.. Also: Ancestry, Forensics, Social Networking, Education, Research

Prioritizing by odds ratio, actionability, FP consequences

Common Disease – Common Variant Theory. How common? ApoE allele 4 : Alzheimers dementia, & hypercholesterolemia 15% in humans, >97% in chimps>97% in chimps HbS 17% & G6PD 40% in a Saudi sample CCR5 32 : resistance to HIV 9% in caucasians

One form of HIV-1 Resistance

Association test for CCR-5 & HIV resistance Samson et al. Nature :722-5Nature :722-5

But what if we test more than one locus? The future of genetic studies of complex human diseases. RefRef (Note above graphs are active spreadsheets -- just click) GRR = Genotypic relative risk