DNA and Behavior

1. DNA and Behavior Is Our Fate in Our Genes? Robert E. Pyatt, Ph.D.

2. Contamination Control Tools of the aDNA (Molecular Genetics)Trade Keep it Clean • Surface decontamination of bone helps (Bouwman et al 2006) • Bleaching of bone helps (Kemp & Smith 2005; Malmstrom et al 2007) • DNase I (Eshleman and Smith 2001) cleanup of reagents and tubes • Positive Pressure HEPA-filtered air in the lab • Regular UV-irradiation and bleaching of surfaces • Controlled and limited access to the lab • Dedicated and disposable laboratory clothing and shoes Prevent Carryover • Uni-directional travel between extraction and PCR laboratories • Use of dUTP (Uracil) and pre-digestion of subsequent PCR reactions (and ideally) Independent confirmation(in temporally separate extraction/amplification procedures and possibly at another laboratory, clone problematic samples) • Split the samples first! Why analyze contamination twice?

3. Human Behavior is Affected by our Genes • What behaviors? Any human pattern • Law: violence, addiction, arson, rape, gambling • What genes? • Associated with a syndrome or Isolated • What else is involved (environmental factors)? • How extensive is the influence? • How sure are we that the behavior will occur?

4. How do we know there is a genetic contribution to behavior? • Heritability studies • Adoption studies • Twin studies • Animal Models • Medicine

5. Syndromic Behavioral Genetics Syndrome: Set of symptoms or conditions associated with a specific disease or disorder.

6. Smith-Magenis Syndrome   • IQ between 20-78 (most 40-54) • Similar course facial features • Deep voice • Sleep disturbances • Cardiac defects, eye defects • Insensitivity to pain • Characteristic self-injurious behavior: • Head banging, wrist biting, pulling out nails, • Deletion on chromosome 17

7. Prader Willi Syndrome • Hypotonic at birth- poor feeding • Motor/language delayed • Some degree of cognitive defect • Distinct Behavioral Pattern • Temper Tantrums • Stubbornness • Manipulative behavior • Obsessive-compulsive • Hyperphagia- lack of food satiety • Deletion on chromosome 15q11.2/ maternal uniparental disomy

8. Williams Syndrome • Characteristic Facial Features • Cardiovascular Disease • Hyperflexible Joints • Mild Mental Retardation • “Cocktail Party Personality” • Deletion on Chromosome 17 involving Elastin gene

9. Syndromic Behavior • There are conditions where our genes can directly influence our behavior • Common genetic alterations can result in similar (but not exact) behaviors • These are complex disorders with multiple features- 1 of which is behavioral • What about direct genetic influence on behavior apart from syndromes?

10. Isolated Behavioral Genetics Monoamine Oxidase A Serotonin Transporter

11. Monoamine Oxidase A MAOA: Regulates neurotransmitters by degrading serotonin, norepinephrin, & dopamine.

12. MAOA is on the X Chromosome p11.3 ♀ ♂ 46, XX 46, XY 2 copies of MAOA gene 1 copies of MAOA gene

13. MAOA Dutch Kindred

14. MAOA Mutation Glu 296 Stop Males with mutation have NO MAOA activity

15. MAOA Dutch Kindred

16. Dutch Study Conclusions • “Syndrome” identified in this family • Mental Retardation • Violent behavior • “Behavior” varied over time and across generations • Caused by mutation in MAOA eliminating enzyme • Extremely rare- no more cases reported

17. Dunedin Multidisciplinary Health & Development Study • 1,037 kids (52% ♂) assessed every 2-3 years birth to age 26 (~ general population) • Genotyped VNTR in MAOA promoter • 3 repeats associated with low MAOA activity • 4 repeats with high MAOA activity • Note this is not the MAOA mutation • Mutation= NO MAOA activity • Polymorphism= altered (more or less) activity • Compare 2 polymorphisms with environmental factors

18. 1.0 0.75 0.5 0.25 0 -0.25 Dunedin Multidisciplinary Health & Development Study

19. Dunedin Multidisciplinary Health & Development Study • In general-Abused boys more likely to show anti-social behavior than those not abused • Those abused with low MAOA allele more likely to show antisocial behavior than those abused with high MAOA allele • 12% of study w/ abuse & low MAOA allele committed 44% of the crimes • Those with abuse and low MAOA 3x more likely to be convicted of a violent crime by age 26.

20. Dunedin Multidisciplinary Health & Development Study • In absence of abuse, low MAOA allele had No effect on aggressive tendencies • Between groups (low & high) no differences in • MR, IQ, social class • Gene (MAOA) x Environment (Abuse) interaction predispose for behavior (Aggression)

21. Why do some individuals become depressed or suicidal when faced with life stress?

22. Serotonin Transporter Re-uptake of Serotonin limiting it to post-synaptic neuron

23. Serotonin Transporter Alelles(SLC6A4 or 5-HTT) • “Long” allele associated with high activity • “Short” allele with low activity

24. Serotonin Transporter Results • Again examine Dunedin group (1,037) • Recorded stressful events between age 21 & 26 • 1 (heterozygous) or 2 (homozygous) copies of short allele exhibited more depressive symptoms, diagnosable depression, & suicide • Compared to those with 2 long alleles (homozygous) • MAOA status had no measured effect

25. Dunedin Study- Serotonin

26. Behavioral Genetics & the Law • Limited use of behavioral genetic info as evidence • Most in drug cases trying to demonstrate a predisposition to addiction • State v Boushack, 1995 Wisc • United States v Moore • Attempts largely rejected by courts • Preliminary- not established science • Predisposition not proven biologically (testing) • “Intoxication does not excuse criminal conduct”

27. Genetic Behavioral Testing • Stephen Mobley- Filed motion to have MAOA mutation testing- denied by court • As of 2004 Vanderbilt Forensic Psychiatry included MAOA/SLC64A allele (not mutation) testing in pre-trial evaluation • Part of comprehensive Psychiatric evaluation

28. Genetic Behavioral Testing • By Feb 2006 • Tested 9 men 1 women • Testified regarding MAOA/SLC64A status in 4 trials • As of July up to 20 individuals tested • Results will appear in Nov J Forensic Science • Evaluate abuse history along with genetics • So evaluate genotype and envionment

29. Genetic Behavioral Testing • Additionally tested 3 samples from outside psychiatric practice • All “school age” kids • 1 kicked out of preschool indefinitely • Is this an appropriate population to screen?

30. Thank You