The Evolution of the Genetic Paradigm and Human Genetic Studies in the 21 st Century

1. The Evolution of the Genetic Paradigm and Human Genetic Studies in the 21st Century Charlie Sing and Jim Cheverud Influenced by conversations with Berry, Boerwinkle, Hixson, Holland, Lamkey, Lewontin, Morowitz, Nelson, Rea, Stengard, Strohman, Templeton, Wagner, Zerba and many others who have been uneasy with the prevailing genetic paradigm.

2. “If I had observed all the rules, I’d never have gotten anywhere.” Marilyn Monroe

3. 19th Century Mendel - Darwin - Bateson - Johannsen 20th Century Garrod - Nilsson Ehle - Fisher - Haldane - Wright - Cockerham First Half Discrete Genotype Quantitative Phenotype Environment Physics Chemistry DNA Phenotype Conceptual/Metaphysical/ Theoretical Genetic Models THE PAST Delbrück - Schrödinger - Watson - Crick - Collins Second Half

4. Anderson – Cheverud – Noble - Morowitz - Goodwin - Waddington - Meany - Lewontin – Wagner - Strohman - Jirtle 21st Century Conceptual/Metaphysical/ Theoretical Genetic Models THE PRESENT Quantitative Genotype Quantitative Phenotype Environment Epigenetics in life cycle time E Gene Action Evolution in species life time Genome Organization and Variation E P

5. Complex Adaptive Systems View Risk of Disease MENDELIAN SEGREGATION OF DISEASE Health SINGLE GENE Crick Mendel Mendel LIPID CARBOHYDRATE METABOLISM METABOLISM Morgan BLOOD HAEMOSTASIS PRESSURE REGULATION ENVIRONMENT GENOME ------ PRESENT----- Conceptual/Metaphysical Paradigm Shift Cartesian-Mendelian View Garrod Collins -----THE PAST--------

6. Research On Common Chronic Diseases Of HumansTHE PRESENT • Progress is being driven by technology, available resources and politics. • Measurement of genetic variation has become faster and cheaper. • The result has been an explosion in the dimensionality of genomic data. • Statistical methods and study designs have improved but are woefully inadequate for addressing relevant questions. • Research is characterized by three groups of workers: • 1) Those who know the questions but not the answers. • 2) Those who know the answers but not the questions. • 3) Those who are mimicking those who know the answers.

7. A REALITY CHECK No Agreed Upon Definition Of A Gene A SNP is not a gene. A combination of SNPs is not a gene. Where does a gene start and stop? Is the “junk” DNA really useless? A CONCEPTUAL DEFINITION A gene is a combination of genomic agents embedded in a complex adaptive system whose emergent quantitative functions depend on historical and contemporary genetic and environmental context.

8. A REALITY CHECK Proteins Local Ecology …AGTGCTAACA… …AGTGCTAACA… …AGTGCTAACA… …AGTGCTAACA… …AGTGCTAACA… …AGTGCTAACA… Gene Expression …AGTGCTAACA… …AGTGCTAACA… Biochemistry & Physiology …AGTGCTAACA… Individual No Unifying Biological/Etiological Model Global Ecology DNA Sequence

9. A REALITY CHECK A complete understanding of etiology is beyond the reach of the scientific method because of: incompleteness of logic of math Kurt Gödel (1906-1978)uncertainty of measurementWerner Heisenberg (1901-1976)

10. Complex of closely linked genetic elements G10 G4 L1 G17 G13 G8 G20 G3 G16 G12 G5 L2 Genetic Network G9 G19 Disease G1 G14 G6 perturbation perturbation L3 G11 G18 G2 G15 G21 G7 L4 Environment

11. Co-Dependency Of Genes And Environment “The claim that the environment of an organism is causally independent of the organism and that changes in the environment are autonomous and independent of changes in the organism itself is clearly wrong. It is bad biology and every ecologist and evolutionary biologist knows that it is bad biology.” R. Lewontin, The Triple Helix, 2000

12. What is Epigenetics? Epi·ge·net·ics - “above genetics” Epigenetics research is the study of heritable changes in gene function that occur without a change in the sequence of the DNA. (i.e. DNA methylation & chromatin structure) http://www.geneimprint.com

13. Guanine 5-Methyl-cytosine Methyl group Chemical changes to DNA, (such as the addition of methyl groups pictured), may alter gene expression without altering the gene’s DNA sequence. JAMA, March 19, 2008—Vol 299, No. 11 p. 1249

14. Epigenetics DNA packaging (methylation, histone modification, etc.) affects gene expression cell differentiation response to environment genomic imprinting (parent-of-origin effects)

15. Reciprocal Cross Design ♂/♀ RI1 RI2 RI3 . . . F1 F1 F1 F1 B6 ♀ B6 ♂ F1 F1

16. Difference between B6 and RI mothers Differences between RI mothers

17. Difference between B6 and RI mothers Differences between RI mothers

18. Difference between B6 and RI mothers Differences between RI mothers

20. Methylation state of glucocorticoid receptor in the hypothalamus in response to maternal care Michael Meaney

21. Diet affects expression of Avy through methylation methylated unmethylated Folic acid in diet Randy Jirtle

22. Slightly Mottled Heavily Mottled Pseudo- agouti Yellow Mottled BPA Diet* Control Diet Avy Offspring (%) * 50 mg Bisphenol A/kg diet Dolinoy et al., PNAS, August 7, 2007, vol. 104, no. 32, p. 13057

23. Mapping Epigenetic Effects Genomic Imprinting – Can cause different expression of alleles inherited from the mother and father resulting in phenotypic differences between reciprocal heterozygotes (LS ≠ SL) = ≠ ≠ S L L S S L L S L S S L

24. Imprinting QTL’s 1 2 3 4 5 6 7 8 9 10 K K,H,T F GME L, F, H, K, W L, K, H, S, T, W L, S, W 11 12 13 14 15 16 17 18 19 X L, F, K, S, W L, F, K, W 25 cM L, T, W

25. Examples of various patterns

26. Patterns change through time

27. A Research Strategy for the Future • Admit That Etiology Is Complex • Test Commonly Held Assumptions • Ask Relevant Questions • Refocus On Measurement Of The Environment • Develop Nontraditional Analytic Methods • Replicate To Sort Out Invariant And Context-Dependent Genetic Effects From Type I errors • Train Scientists For A Biocomplex Future • Place Value On A Synthetic Mind Set In Promoting Young Scientists