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Gilbert S. Omenn, M.D., Ph.D. University of Michigan Conference “Darwin y Medicina” Mexico City, UNAM, 25 April, 2008

Ecogenetics, Evolutionary Biology, Genomics, and Medicine. Gilbert S. Omenn, M.D., Ph.D. University of Michigan Conference “Darwin y Medicina” Mexico City, UNAM, 25 April, 2008. 15-16 February, 2001. It’s a New World. New Biology---New Technology Genome Expression Microarrays

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Gilbert S. Omenn, M.D., Ph.D. University of Michigan Conference “Darwin y Medicina” Mexico City, UNAM, 25 April, 2008

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  1. Ecogenetics, Evolutionary Biology, Genomics, and Medicine Gilbert S. Omenn, M.D., Ph.D. University of Michigan Conference “Darwin y Medicina” Mexico City, UNAM, 25 April, 2008

  2. 15-16 February, 2001

  3. It’s a New World New Biology---New Technology Genome Expression Microarrays Comparative Genomics Proteomics Bioinformatics, Computational Medicine, and Evolutionary Biology Path to predictive, personalized, preventive (P3) healthcare

  4. Break- through of the Year, 2005

  5. “Medicine Needs Evolution”Nesse, Stearns, Omenn: Science 24 Feb 2006 • Evolution: a vibrant foundation for all biology • Evolutionary thinking can help researchers and clinicians answer common questions: o Persistence of genes predisposing to depression, high blood pressure, diabetes, and other diseases o Usefulness of cough, fever, diarrhea

  6. Multi- and Interdisciplinary Research will be Required to Solve the “Puzzle” of Complex Diseases and Conditions Genes Behavior Diet/Nutrition Infectious agents Environment Society ??? [evolution]

  7. Eco-Genetics Known inherited predispositions to: Foods Food additives Infectious agents Drug chemicals Pesticides Inhaled pollutants Sensory stimuli Allergic & sensitizing agents

  8. Eco-Genetics of Food, Nutrition, and Cultural Sensitivity • Anthropology and biology of lactase persistence • “Everybody needs milk” • “Got Milk?”

  9. Digestion of Milk from the Diet • Nearly all mammals digest the sugars in Mother’s milk until weaning. • The enzyme lactase in the intestine does it. • Lactase production usually drops 90% during the first four years of life in humans, though the rate varies widely. • Certain human populations have a mutation (on chromosome 2) which results in persistence of lactase activity (gain of function).

  10. Lactose Intolerance by Group

  11. Consequences • Persistence of lactase in the intestine permits the “unnatural” continuation of milk ingestion throughout life, enhancing growth and development. One benefit is higher calcium intake, especially in northern climes where sun is insufficient to activate vitamin D. • People without this mutation shut off lactase production and become “lactose malabsorbers”; they may become “lactose intolerant” with symptoms of excess gas (hydrogen) and diarrhea upon eating lactose-containing dairy products. • The Navajo used powdered milk supplies to paint their adobe homes.

  12. Why Does Loss of Lactase Lead to Symptoms? • The lactose in milk remains undigested and unabsorbed through the intestinal wall into the bloodstream. • Gut bacteria adapt to the abundance of lactose (compared with glucose, etc) and metabolize the lactose, generating lots of gas by fermentation. • Gas can cause stomach cramps, bloating, diarrhea; the osmotic pressure rises, reducing resorption of water from the colon: a laxative effect.

  13. Are Lactose Maldigestion and Lactose Intolerance Important in Mexico? Rosado et al, J Nutrition 124:1052, 1994: Children and adults (N=926) from Sonora, Mexico, and Yucatan Milk consumption (in 1982) was 219+/-22, 128+/-25, and 19+/-1 gm/day Whole milk vs lactose-hydrolyzed milk: major intolerance symptoms uncommon (0-11% of children, 7-17% of 13-60 y/o); maldigestion by hydrogen breath test, 2-43%, highest in Yucatan.

  14. Lactose Malabsorption in Mexican-Americans Wotecki et al, Amer J Clin Nutr 30:470,1977 Prevalence 53% of Mexican-Americans and 15% of Anglo-Americans after 50 gm lactose load (glucose increase <25 mg/dl). Mean consumption of milk and dairy products was same in lactose absorbers and malabsorbers in both groups, though GI symptoms after milk was 60% vs 24%. Some reduced milk-drinking due to symptoms; others continued for laxative benefit!

  15. What is the Diagnosis? What is “Normal”? • In Europe and North America, lactose intolerance is regarded as a clinical problem, a medical diagnosis. Those who have symptoms may not know the cause; lactose intolerance actually accounts for many cases of “irritable bowel syndrome”. • In populations where most people are lactose malabsorbers, cultural nutritional practices will dominate.

  16. Prevention of Symptoms • Avoid milk • Drink lactose-free milk (enzyme-treated) • Lactose-reduced (L. acidophilus) milk, as in yogurt and in hard cheeses • Lactase pills • Gene therapy?? Note: Milk sold for pet cats [remarkably, European cat breeds have a mutation similar to the human European mutation, whereas Asian breeds are particularly sensitive!]

  17. When Did This Mutation Arise? Most likely: 1. Separate events in Sweden and in the Arabian Peninsula about 4000 BC, converging as they spread, or 2. Single event in the Middle East about 4500 BC, with radiation from there. 3. Plus a more recent mutation in the East African Tutsi. A small survival advantage over the 6000-8000 years since goats, sheep, and cattle were domesticated can account for the population differences now observed.

  18. An Associated Polymorphism of Apolipoprotein A-IV-2 (His360Gln) • Apo A-IV is a 46 kD plasma glycoprotein synthesized in the intestine. • His/Gln polymorphism [in Caucasians] at codon 360 (chromosome 11) modifies milkfat absorption and chylomicron clearance. • Worldwide distribution resembles lactase persistence; across 29 population groups, r = 0.94 (p<0.000001). Highest prevalence in Iceland; probably carried into Europe by Vikings. [Weinberg, Genetic Epi 17:285, 1999]

  19. Eco-Genetics Known inherited predispositions to: Drug chemicals Pesticides Inhaled pollutants Foods Food additives Sensory stimuli Allergic & sensitizing agents Infectious agents

  20. Variation in Susceptibility to Infections • Malaria (P. falciparum type): children with sickle hemoglobin trait have greater survival. • Malaria (P. vivax type): people lacking the Duffy (Fy) red blood cell antigen are resistant to this parasite, which enters the cell through this surface antigen. • People lacking CCR5 receptors on lymphocytes are resistant to infection by HIV.

  21. Distinguishing between Host Defenses and Infectious Agent Offenses • Symptoms of host defenses include pain, nausea, vomiting, diarrhea, fatigue, anxiety • Treatment of these symptoms may suppress defenses, promoting pathogen transmission and harming patients • Shigella diarrhea: faster recovery and fewer complications without anti-diarrheal meds. • Cough suppressants raise risk of pneumonia • Acute phase response to infection, trauma, or cancers both behavioral (fever) and physiological (sequestration of Fe, Zn). Counterpart in insects.

  22. Evolution and Persistence of Virulence • Host-parasite relationships are greatly influenced by the rapidity of transmission. • When transmission is rapid, pathogens can disregard many host variables. • When transmission is slow, pathogens benefit by establishing a long-term balanced relationship with the host. • Modeling shows vaccines which prevent infection constrain prevalence and virulence; vaccines that offer only anti-toxin immunity have opposite effects.

  23. Emergence of “Meta-Genomics” • “Microbes run the world”—converting key elements of life (C,N,O,S) into accessible forms; performing photosynthesis; living in ecological and human host niches, making nutrients, metals, and vitamins available to the hosts, digesting foods, breaking down toxins, fighting off disease-causing microbes. • Microbial communities have adapted through billions of years of environmental changes. New molecular methods permit analysis of whole communities, not just individual species or isolates.

  24. Metagenomics, A New Science Revealing the Secrets of our Microbial Planet[National Research Council U.S., 2007] • Combines the power of genomics, bioinformatics, and systems biology • Involves study of sequences and functions of genomes of many organisms simultaneously, including a great many not culturable—as presented by Dr. Francino today • Libraries already prepared from oceans, coral reefs, soils, whale carcasses, thermal vents, and hot springs • Expect quite different microbial communities in oral cavity, respiratory passages, gut, genito-urinary, and skin environments of people with different genotypes and different environmental circumstances, including diets, diseases, infections, and therapies.

  25. Framework for Regulatory Decision-Making for Chemicals Epidemiology Hazard IdentificationLifetime rodent bioassays Short-term, in vitro/in vivo tests Structure / activity Potency (dose/response) Risk Characterization Exposure analysis Variation in susceptibility Information Risk Reduction Substitution Regulation / Prohibition

  26. Impetus for Susceptibility Analysis • Clinical Occupational Medicine - “Why me, Doc?” • OSH Act requires that standards be set “so that no worker…shall suffer adverse effects.” • Clean Air Act requires standards set to protect “most susceptible subgroups.” • Food Quality & Protection Act requires protection of children and other vulnerable subpopulations. • To discover mechanisms or markers for diseases that may appear only years later -- and could be prevented: getting inside the “black box”

  27. Eco-Genetic Polymorphisms Tissue susceptibility G6PD deficiency Alpha1-anti-trypsin deficiency Biotransformation enzymes Acetylator phenotype Debrisoquine hydroxylation (Carbon oxidation - P450) Paraoxonase activity

  28. Occupational Bladder Cancer(Huddersfield, U.K. Data) % Slow Acetylators Controls 57 Bladder CA 67 Dye workers (naphthylamines) 96 Clerical workers 40 Machine oils workers 44

  29. Acetylator Phenotype: bimodal distribution of plasma level of active drug (INH) @ 6 hours after standard dose Genetics: Single gene Enzyme: N-acetyl-transferase in liver Other drugs that require acetylation hydralazine dapsone & other sulfas phenalzine cyclophosphamide What about occupational or environmental chemicals that are detoxified by acetylation? Industrial anti-oxidants Naphthylamines Benzidines, biphenyls

  30. Susceptibility to Chronic Beryllium Disease • An immune-mediated pulmonary granulomatous • disease among exposed workers • HLA-DP gene contains a Glu lysine mutation • at position 69 (Glu-69) predisposes to CBD: • a genetic biomarker of susceptibility • Can be combined with lymphocyte proliferation • test for evidence of sensitization to beryllium • Value-of-information from mandatory and • voluntary screening programs has been • estimated for risk reduction possibilities: • social, legal, and ethical issues are crucial

  31. Molecular Signatures • Numerous studies underway using gene expression microarrays and proteomics to identify and utilize chemical-specific “molecular signatures” for exposures, early effects, and evidence of variation in susceptibility. • Model chemical: acetaminophen--toxigenomics and toxicoproteomics of liver damage.

  32. The “Thrifty Genotype” and Maladaptation to Modern Environments • Humans adapted to the Paleolithic environment of hunters and gatherers are maladapted to modern lifestyles. • Phenotypes are obesity, high BP, metabolic syndrome, and adult-onset diabetes. • Most humans consume much more fat, sugars, and salt, but less fiber and phytochemicals. Not simply digestive and cardiovascular systems, but how our brains perceive and process stimuli from food sources. • The evolution from quadripedal to bipedal gait puts pressure on the lower spine, with low back pain, complications of childbirth, and tendency to fainting and circulating problems.

  33. Evolution and High Blood Pressure[A. B. Weder, Hypertension 2007; 49:260] Sodium Hypothesis to explain higher incidence of high blood pressure in African-Americans– “thrifty genotypes” to maintain sodium levels, prevent excretion in kidneys, in times of poor diets, including slave ships. When BP increases, kidney output of Na+ and water are increased, and BP falls: feedback. Hypertension is viewed as an “emergent property” of the entire cardiovascular system with feedback loops. Epi studies: 30-50% of HBP risk due to heritable factors.

  34. Genes/Alleles Predisposing to High BP • Angiotensinogen, AGT -6A • G-Protein, beta-3 subunit, GNB3, 825T These two are in genomic regions of broad linkage disequilibrium and low haplotype diversity—hence arose recently, were exposed to positive selection • Beta-2 adrenergic receptor, 47A and 79C • Epithelial sodium channel alpha-subunit (--946G) • Cytochrome P450, CYP3A5*1 All 5 sodium-conserving ancestral variants are much more prevalent in African (equatorial) populations.

  35. Growth & Development and Evolution of High Blood Pressure (HBP) Fetus is programmed to survive nutritional scarcity in the mother; if born into an environment of excess sodium and calories, leads to metabolic syndrome, obesity, and high BP. Fetal growth retardation with decreased glomerular filtration capacity: set for higher range of BP Thus, good maternal nutrition could prevent or delay onset of some HBP cases.

  36. Allometry and Kidney Growth • Kidney weight is proportional to body weight with an allometric constant of 0.8, while blood volume scales with constant 1.0. • Kidney growth ceases at sexual maturity; smaller as menarche and andrarche move to younger ages. Adaptation sets blood pressure and sodium excretion higher.

  37. Uricase and Uric Acid • Serum uric acid levels are higher in humans that most other mammals (except guinea pigs and Dalmatian dogs). • Humans lack hepatic uricase. • Uric acid can help maintain BP via vasoconstriction in low sodium environments • In high-sodium societies, high uric acid may cause subtle renal injury, induce chronic salt sensitivity, and lead to high BP.

  38. Dopamine-4 Receptor Repeat Polymorphism and High Blood Pressure • Dopamine release in the kidney increases renal sodium excretion. In essential hypertension, DA effect on sodium excretion is blunted. • DA-4 receptors are expressed in juxtaglomerular and cortical collecting cells; associations between long allele in exon 3 and slight increases in systolic BP, diastolic BP, and history of alcohol use. • DA-1 receptor (A48G) and GPCR kinase-4 gene (GRK3gA142V) polymorphisms also associated with high BP.

  39. Metabolic Syndrome in Mexico and in Mexican Americans[Bastarrachea et al, Human Biology 79:121, 2007] • GEMM Family Study; so far, 375 individuals in 21 extended families. • All metabolic and clinical endpoints significantly heritable. • Previous U.S. study: Mexican-Americans have highest prevalence (32%) of metabolic syndrome (ATP-III definition); non-Hispanic whites 24%, African Americans 22%.

  40. Population Genetics: From Evolutionary History to Genetic Medicine[Jorde et al, Human Mol Genetics 2001] • The effective human population size is surprisingly small, about 10,000, far less than the census size, based on mitochondrial DNA, Y chromosome variation, and autosomal polymorphisms. • Human population probably expanded rapidly in late Pleistocene—tell-tale rare variants • Genetic diversity between the major continental populations is only 10-15% vs 85-90% within each continent. • Much evidence supports African origin of modern humans, with subset colonizing Asia and Europe about 100,000 years ago. Most persuasive: haplotypes found outside Africa are usually subsets of those found within Africa.

  41. Genome-wide Detection and Characterization of Positive Selection in Human Populations (1) Dense maps of human genetic variation: 3 million polymorphisms (HapMap2). Long-range haplotype methods identify alleles segregating in a population undergoing recent selection. Cross-population comparisons help discover alleles swept to near-fixation in a population. Found >300 strong candidate regions; focused on 22 strongest regions. .

  42. Genome-wide Detection and Characterization of Positive Selection in Human Populations (2) Identified 26 non-synonymous, coding, SNPs showing regional evidence of positive selection. Found 2 genes in a common biological process with positive selection in the same population: • LARGE and DMD in West Africa, related to infection by Lassa virus • SLC24A5 and SLC45A2 in Europe, related to skin pigmentation • EDAR and EDA2R in Asia, involved in hair follicle development. [Sabeti et al. Nature 2007;449:913-919]

  43. Genome-wide Detection and Characterization of Positive Selection in Human Populations (3) • The most differentiated genes among 3 million markers studied globally are those determining skin pigmentation. • May have been linked to risk of ricketts (failure of bone production) if there is not sufficient vitamin D and activation of vitamin D by sunlight, as in northern European populations.

  44. A Genome-Wide Association Study of Global Gene Expression (1)[Dixon et al. Nature Genetics 2007;39:1202-1207] • Aim: build a database to systematically examine potential effects of disease-associated variants on transcript expression. • Created a global map of effects of polymorphisms on gene expression in 400 children from 206 British families [in asthma study]. Looking for regulatory effects (non-coding SNPs). • Genotyped 408,000 SNPs; measured gene expression of 54,000 transcripts from 20,599 genes in lymphoblastoid cell lines. • 28% of transcripts, representing 6600 genes, had narrow heritability H2 >0.3.

  45. A Genome-Wide Association Study of Global Gene Expression (2) • Highly heritable expression levels are best evidence that trait is genetically regulated. • LCL cells provide general indicator of gene expression. • Use Affy chips for gene expression, Illumina beads to genotype • Identified 88 genes separately associated with 3 or more SNPs (cis and trans). • Only 3 SNPs ass’d with >5 transcripts—no evidence for “master regulators”

  46. A Genome-Wide Association Study of Global Gene Expression (3) • Used Gene Ontology to identify genes enriched among highly heritable traits • Greatest enrichment: “response to unfolded proteins”--chaperonins and heat shock proteins • May represent an evolutionary response to cellular stress; unfolded proteins key in prion disease, Alzheimer disease, diabetic pancreatic beta cells • Cell cycle, RNA processing, DNA repair, and immune response genes also highly heritable.

  47. Genome-Wide Association Study (4) Applied to Childhood Asthma[Moffatt et al, Nature 2007; 448: 470-47 • New susceptibility locus: non-coding SNPs residing within a 206-kb segment on chromosome 17q23. • Of 19 genes in this region, the expression database pointed to ORMDL3 (p<10-22), correlated (r=0.67) with asthma. Codes a transmembrane protein anchored in endoplasmic reticulum. • Disease-associated alleles accounted for 30% of variance of expression. • Can expose LCL cells to asthma triggers.

  48. Other Disease-Associated Genome-Wide Studies (5) • Crohn’s disease: PTGER4, chromosome 5 • Type 2 adult-onset diabetes: PHACS on chr 11 • Fetal hemoglobin expression in adults: markers upstream of HBS1L on chr 6q23. • LDL and HDL cholesterol levels: 11 genes confirmed, 7 novel genes identified

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