Genes, Environment and Health Where are the Connections?

1. Genes, Environment and Health Where are the Connections? Byron C. Jones The Pennsylvania State University

4. The Problem • The challenge of increases in greenhouse gasses, toxins and related stress on ALL organisms, including humans presents a particularly compelling case for studying individual differences in response to environmental perturbations. • Alternatively, we are getting a unique chance to see evolution in action!

5. The Premise • Most of health related biological processes are influenced by multiple genes, their interaction with the environment and with each other. • This includes: • Etiology of degenerative diseases • Etiology and course of infectious diseases • Source and course of vector-borne diseases • Etiology and course of psychiatric disorders

6. The Promise • A more thorough understanding of diseases through the study of gene-gene and gene-environment interactions • Better understanding of vector-borne diseases • New treatments for disease through pharmacogenomics • New prevention strategies – to amplify Dr. Sapego’s presentation

7. Why Study Interactions? • Genes and environment work together • Genes also influence other genes (epistasis) • Therefore: • Not everyone is equally susceptible to stressors, toxins, etc. • This is the way it really works – I did not say that life is fair!

8. How do we define GXE? • In the same sense that we can show non additive effects in any factorial design, we can show that in some cases, genes and environment, when accounted for experimentally do not cover the totality of phenotypic variance. • Thus Vp=Vg+Ve+(Vgxe)+V

9. Are there other types of genotype environment associations? • Genotype-environment correlation – how the genetic makeup of individuals leads them into specific environments. • Passive -- shy children placed into state hospitals • Reactive – response of individuals to actions of others -- interactive • Active – “Niche Picking” – selecting or creating environments to match genetic propensities

10. Evidence for GXE • Discordant identical twins – the work of Irving Gottesman on genetics of schizophrenia. • The seminal work of Robert Cloninger on alcohol typologies – one has genetic predisposition and is triggered by the environment • New research on depression, the serotonin transporter gene and stressful environments

11. Some Experimental Evidence • Gariepy, Rodriguiz and Jones, 2002 • Study of experimentally administered different environments during development in lines of mice selected for high and low aggression. • Handling vs undisturbed • Group vs Isolate housing

12. Spontaneous Activity • Open field ambulation • Unsupported rearings

14. Corticosterone Response to Testing • Serum collected 20 min after introduction into the open field • Corticosterone measured by RIA • Baseline corticosterone values obtained in separate animals, nonhandled, not isolated.

16. Dopamine D1 receptor densities • After open-field testing animals were killed by halothane overdose, and the brains removed with caudate-putamen and nucleus accumbens dissected. • Maximum binding for 3H-SCH 23390 in membrane fragments • No effects of handling or isolation in the caudate-putamen • Nucleus accumbens….

17. Isolate Housed Group Housed

18. Aggressive/Fear-like Behaviors • Latency to attack an intruder.. • Latency to freeze.. • Attacks • Freezing episodes

20. Conclusions • HPA system seems to be a major target of GXE sensitivity • Aggression also seems to be sensitive • Dopamine system seems to be refractory • Moral of the story – not all systems in an organism are equally susceptible

21. Gene-Environment – Human Studies • The seminal work of Robert Cloninger, type 1 and type 2 alcoholics • Type 2 – gender limited (no longer holds) • Type 1 – environmentally limited • The exciting new work from Avshalom Caspi and Terrie Moffitt on the effect of the 5-HTT gene on stressful situation-depression. • Serotonin transporter blockers are used to treat depression

22. Practical Considerations • New ammunition for predicting and possibly preventing psychiatric and other disorders? • New ammunition for treating some psychiatric disorders?

23. OK, So What About Other Health Issues? • Host-parasite relationships • Pharmacogenetics/toxicogenetics and genomics

24. Host-Parasite Interactions • Mosquitoes and their (and human) parasites: • Plasmodium • Filaria • Dengue • West Nile • Equine encephalitis • Etc. • How will the balance be changed by global warming?

25. Host Resistance to Filaria • Aedes egypti and Brugia pahangi • filarial parasite that in turn carries Wolbachia bacteria –affects fecundity, etc • acid hydrolase enzymes linked to host susceptibility in Aedes

26. Toxicogenetics • Follows same principles as pharmacogenetics – understanding basis of individual differences in response to environmental toxins

27. What Have We Learned? • Most of our health issues fit within the framework of “complex trait analysis” • Multiple genes/alleles are involved • Networks of genes may be players • Environmental factors vary in importance • Genes can alter the environment as well as vice versa • New analytical techniques in bioinformatics will aid in identifying individuals who are sensitive to environmental hazards • The ultimate goal is to tailor prevention and treatments based on genetically-based individual differences

28. SO WHAT? • Global warming, greenhouse gasses, new sources of energy all have probable impact on biological and ecosystems. • The exact course of the effects on health and environment cannot be precisely predicted. • Take for example the change in electromagnetic radiation incident on the oceans and impact on the thousands of species of phytoplankton. Like humans, all species show genetic-based individual differences in susceptibility to environmental perturbations…..

29. Commentary • In terms of baseball: • It’s the top of the 9th inning and we are at bat – ergo have a chance of winning the game • However, nature bats last.