Behavioral Genetics

1. Behavioral Genetics A bridge between the Neuro and Genetics courses

2. Behavioral Genetics Many news sources are filled of late with evidence (some of it pretty good, but needing careful interpretation) for genes that determine or affect certain behavioral abilities.

3. It is clear that aspects of many behaviors and behavioral abilities are influenced by one’s genetic makeup. One sees this in a broad array of aspects of life: often, when presented with extraordinary talent, we just assume “it must be genetic!”

6. In addition, as our knowledge of molecular genetics has grown, possibly so has our ability to attribute differences in behavior to genetic influences

7. Scientists create a genetically engineered 'smart mouse'September 1, 1999PRINCETON, New Jersey (CNN) -- Can intelligence and memory be genetically enhanced? Princeton University scientists say the answer is yes, at least in mice.Research published in this week's edition of the journal Nature suggests similar processes may one day be used to boost human intelligence and memory, though such applications are still far from reality.Princeton neurobiologist Joe Tsien and colleagues genetically engineered a single gene into a strain of mice they then named "Doogie" -- after the child genius doctor from the television show "Doogie Howser, MD.""This points to the possibility that enhancement of learning and memory or even IQ is feasible through genetic means, through genetic engineering," said Tsien.The gene in question, called NR2B, controls the production of a brain chemical called NMDA, a neurotransmitter that has been identified in previous studies as a key player in learning and memory.

8. Gene expression tied to social behavior in honey beesCHAMPAIGN, Ill. -- Genes and behavior go together in honey bees so strongly that an individual bee's occupation can be predicted by knowing a profile of its gene expression in the brain, say researchers at the University of Illinois at Urbana-Champaign.This strong relationship surfaced in a complex molecular study of 6,878 different genes replicated with 72 cDNA microarrays that captured the essence of brain gene activity within the natural world of the honey bee (Apis mellifera). Even though most of the differences in gene expression were small, the changes were observable in 40 percent of the genes studied, the scientists report in the Oct. 10 issue of the journal Science."We have discovered a clear molecular signature in the bee brain that is robustly associated with behavior," said principal researcher Gene E. Robinson, a professor of entomology and director of the Neuroscience Program at Illinois. "This provides a striking picture of the genome as a dynamic entity, more actively involved in modulating behavior in the adult brain than we previously thought."

9. And, of course, the ability to manipulate genetic outcomes to our benefit is far older than our knowledge of how this works at a molecular genetic level. Consider the behavior of human bred pit bull dogs vs. cocker spaniels.

10. Thus insights of Behavioral Genetics should not really surprise anyone Behavioral-psychiatric disorders with a genetic component (select examples) Major depression Schizophrenia Alcoholism Personality disorders Autism (Lecture notes closely linked to Fadem Board Review Series textbook)

11. Sources of evidence regarding genetic components • Pedigree - family tree (good for single-gene disorders--pattern of inheritance can be evident) • Relatedness and risk (degree of relationship; first degree: parent, sibling, DZ twin) • Twin studies, especially concordance in monozygotic (isogenetic) vs. dizygotic (typically genetic siblings) twins. (Twins maximize environmental similarities.) • MZ > DZ concordance indicates genetic component

12. Relatedness and Risk of Developing Schizophrenia • No relationship: 1% • First degree relative (child, sibling, DZ twin): 10% • Child of 2 parents with schizophrenia: 40% • Monozygotic twin of patient with schizophrenia: 50% • Not a simple single-gene disorder

13. Symptoms of schizophrenia • Positive: Delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior • Negative: Reduced expression of emotion, impoverished speech, impaired initiation of goal-directed behavior • Categories, e.g., paranoid (multiple delusions of persecution)

14. Relatedness and Risk of Developing Bipolar Disorder Higher heritibility: • No relationship: 1% • First degree relative (child, sibling, DZ twin): 20% • Child of 2 parents with bipolar disorder: 60% • Monozygotic twin of patient with bipolar disorder : 75%

15. How might defective gene expression relate to mental disorder? • Dopamine hypothesis of schizophrenia: postulates overactivity of mesolimbic and mesocortical dopamine neurons that project from the ventral tegmental area to the basal forebrain, limbic cortex and neocortex • Postulates that D2 dopamine receptors of schizophrenic patients are hyperactive or hypersensitive to the neurotransmitter dopamine

16. Origins of Dopamine Hypothesis • Chlorpromazine, haloperidol (neuroleptics) remarkably effective in treating schizophrenia symptoms • Chlorpromazine blocks D2 dopamine receptors (Parkinson like symptoms can arise with long-term use: rigidity, tremor, movement initiation difficulty; tardive dyskinesia: involuntary movements of face and jaw) • Atypical neuroleptics (clozapine, risperidone) don’t directly block D2 receptors

17. Reduced neuropil hypothesis of schizophrenia (P. Goldman-Rakic) • Neurons in prefrontal cortical areas (9,10) more densely packed • Loss of synapses in prefrontal cortex (David Lewis) • Premorbid period/onset often occurs in or following adolescence, a period of prefrontal cortical synapse elimination (J. Geidd) • Synapse elimination is a normal developmental process (P. Huttenlocher)

18. 1997 Visual Prefrontal <= Prefrontal Ctx Auditory Losses of synapses correspond to gains in development

19. Simple inheritance: Phenylketonurea • Autosomal recessive genetic disorder; phenyalanine hydroxylase, which converts phenyalanine to tyrosine. • Excess phenylalanine (some is converted to a ketone form excreted via urine) builds up, alters amino acid transport => amino acid insufficiencies in the brain => mental retardation.

20. Simple inheritance: Phenylketonurea • Each parent of a child with PKU carries at least one defective gene. In a recessive condition, both genes must be defective in order to have the disorder. • Individuals with only one defective gene are "carriers," show no symptoms, and may be unaware of their status until they have an affected child.

21. Simple inheritance: Phenylketonurea • For a child to inherit PKU, both parents must be PKU carriers. When this occurs, there is a one in four chance of their producing an affected child with each pregnancy. • Until the 1960s, most infants born with PKU developed mental retardation and cerebral palsy. Now, postnatal detection and institution of a low phenylalanine diet are routine and usually sufficient to prevent symptom development.

22. PKU and gene-environment interactions • Phenylketonurea (PKU) provides a simple model for understanding how genes and their environment may interact. • If a child with PKU comes into a dietary environment with normal (or at least typical) levels of phenylalanine, disordered neurobehavioral development will occur. • If the same child receives a diet low in phenylalanine (tolerance may increase with age), essentially normal mental development is typical.

23. Medicine is replete with gene-environment interactions • In genetically-susceptible individuals, consumption of excess saturated fats leads to a predisposition towards coronary artery disease. • Genetic bases of susceptibility are less clear, but negative impacts of smoking, excess alcohol consumption, excess caloric intake, etc., on health are widespread, but not universal.

24. Fragile X Syndrome • Single gene disorder located on the X chromosome • Nucleotide triplet (CGG) repeat disorder • Unaffected individuals approx 50 repeats • Carriers >50, <200 repeats • Affected >200 repeats, hypermethylation, silencing gene (no transcription)

25. Griffiths et al. (2000) Fragile X SyndromeAbsence of functional FMRP • Affects 1:2000 males and 1:4000 females • Behavioral Manifestations: • Mental Retardation • Hyperactivity • Autistic-like behaviors • Seizures • Physical profile • Macro-orchidism • Large forehead • Elongated ears • Cognitive Deficits • Spatial Processing, Math skills • Executive function • Visual-Motor impairment Warren S.T. (1997) Trinucleotide Repetition and fragile X Syndrome.Hospital Practice.

26. Fragile X Syndrome illustrates the value of animal models of disorders • Simple gene knockout: insertion of “stop” codon at an early point in the sequence. • Conditional knockouts that allow transcription to be turned on or off at specific points in development or maturity • Is development without the gene irreversibly harmed? Can behavioral function be restored by the presence of the protein in adulthood?

27. Some uses of animal models of FXS • Assess “behavioral phenotype” to develop basis for evaluation of drugs and other therapeutic treatments • Study brain anatomy and cell biology to assess nature of functional damage • Determine “cargo” mRNAs bound by FMRP and which are differentially expressed in absence of FMRP

28. Current models for biological basis of Fragile X • FMRP regulator of synaptic protein synthesis • mRNA translation at synapses impaired in absence of FMRP • The mRNAs that FMRP binds and helps translate at synapses may be important for synaptic plasticity Single-gene  multiple gene disorder; Gene disorder that interacts with other (possibly some defective) genes

29. Dendritic spine abnormalities(common in MR syndromes) (Hinton et al., 1991)

30. Summary • Many medically important conditions involve defective genes that influence behavior. • Inheritance patterns for behavioral effects follow the same rules as for somatic effects. • Behavioral syndromes with important genetic contributions include major depression, schizophrenia, alcoholism, personality disorders, mental retardation and autism.

31. Summary • Risk-relatedness comparisons can identify genetic contributions and lead to novel hypotheses regarding cellular mechanisms. • Phenylketonurea, an autosomal recessive disorder, illustrates the inheritance of behavioral characteristics and the importance of environment in determining gene effects.

32. Summary • Gene-environment interactions are very commonly addressed in medicine and much less commonly viewed this way. • Fragile X syndrome illustrates gene-gene interactions that affect neural development and behavior.