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Human Genetics

Human Genetics. Behavioral Genetics. Behavior. Some behaviors can be transmitted from parent to child. What proportion of a behavior results from the action of genes? What proportion of a behavior is learned?

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Human Genetics

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  1. Human Genetics Behavioral Genetics

  2. Behavior • Some behaviors can be transmitted from parent to child. • What proportion of a behavior results from the action of genes? • What proportion of a behavior is learned? • Behavioral genetics is the study of the genes involved in the development and regulation of the nervous system.

  3. Genes and Behavior • Early 20th century - Extremes of the schools • Freud and the psychoanalysis schools • all environmental • Eugenic movements • all bad genes • What are the risks of “Blaming Genes”

  4. How do you define a behavior? • need to define the abnormal phenotype • need to clearly demarcate it from the "normal"phenotype • need to clearly separate it similar "aberrant behaviors“ •  Alcoholism • Phenotype - characteristic deviant behaviors associated with excessive consumption of alcohol •  If there is a genetic basis, the phenotype should be mapped to chromosomal markers (RFLP, Microsatellites, SNPs)

  5. Critical Periods of Development • Organs develop at different times in development: • A critical period can vary. • During its critical period, an organ is vulnerable to toxin, viruses, and genetic abnormalities. • Altering the normal development may cause birth defects.

  6. Tobacco • About 20% of women still smoke while they are pregnant • twice the rate of premature delivery • infants weigh less than normal – < 5 lbs • low birth rate is a leading predictor of infant mortality

  7. Tobacco • Nicotine constricts the blood vessels of the placenta • less blood flow to the infant • Nicotine crosses placenta blood barrier • affects brain development • impairs cell growth and mental development • IUGR - intrauterine growth retardation

  8. Alcohol • Alcoholism affects about 1-2% women of child-bearing age • Moderate alcohol during early pregnancy can cause abnormal development • Fetal Alcohol syndrome 1-2 per 1000 • Alcoholics • binge drinking episode • women - 5 or more drinks in one sitting over 2 or 3 days

  9. Maternal alcohol abuse is the most common cause of mental retardation • Just one drink a day is believed to cause fetal alcohol effects-behavior and learning problems • modest drinking in third trimester • Decrease in birth weight • Constricts placenta blood flow • Hypoxia – decrease growth and development

  10. Fetal Alcohol Effects • Greatly increase chance for spontaneous abortion • IUGR - intrauterine growth retardation • Mental retardation • Mimics Autism

  11. How do we study behavior? • Model systems • Inbred strains of mice • role of vasopressin receptors in prairie voles and mice • selectively breed for behaviors

  12. Gene for Fidelity- in Rodents • Single genes can have large behavioral consequences • Male mice - quite promiscuous • Prairie vole - known for its sociable nature and dedication to one mate • What makes their behavior different?

  13. Why? • Scientists have transformed promiscuous male mice into more faithful partners and doting dads by inserting a single gene (vasopressin 1a receptor) from a prairie vole. • Hormone vasopressin 1a receptors in the spatial memory region of the vole's brain makes them faithful. If not in that region, the voles are not faithful.

  14. Most behavioral traits are multifactorial • Attention deficit disorder (ADD) or • Attention deficit/Hyperactivity disorder (ADHD) Siblings of affected child show 3-5x greater risk than those without an affected sibling. • Twins studies indicate ~ 80% heritability. • Linkage studies indicated dopamine pathway may be involved in ADD/ADHD.

  15. How do we study behavior? • Model systems • Drosophila • From the fruit fly – we have learned about genes that regulate learning, sexual behavior and motor behavior • have been cloned using mutational analysis • many of these genes have human homologs

  16. The brain is composed of neurons. Transmitting neuron Receiving neuron (Presynaptic neuron) (Postsynaptic neuron) Axon Synapse Direction of action potential

  17. Transmission of information between neurons involves neurotransmitters.

  18. Cloninger’s Basic Personality Dimensions • Novelty seeking • Avoidance of harm • Reward dependence • Persistence. • Self-directedness (accept yourself) • Cooperativeness (accept others) • Self-transcendence (feel part of nature)

  19. Test: Temperament and Character Inventory

  20. Australian Twin Study Earlier Twin Studies showed additive genetic effects accounted for 48% of the variance in Self-transcendence scores for men and women alike. http://genepi.qimr.edu.au/staff/nick_pdf/CV361.pdf

  21. The tridimensional personality questionnaire (TPQ) • Designed to measure aspects of temperament: • Novelty Seeking • Harm Avoidance • Reward Dependence • Persistence

  22. TPQ example Novelty Seeking questions • True / False • I often try new things just for fun or thrills, even if most people think it is a waste of time. (T) • I often do things based on how I feel at the moment without thinking about how they were done in the past. (T) • I am much more controlled than most people. (F)

  23. Novelty-Seeking Gene • Recreational drugs like cocaine, nicotine and alcohol may work through the brain's dopamine system. • In Parkinson's disease, the dopamine-producing cells of the brain gradually degenerate. Parkinson’s patients are unusually low in novelty-seeking behavior. • The dopamine system has been suggested by Cloninger to play a role in impulsive, extravagant behavior.

  24. Novelty-Seeking Gene • High score on the Novelty Seeking scale: • impulsive, exploratory, fickle, excitable, quick-tempered, extravagant • Low score on the Novelty Seeking scale: • reflective, rigid, loyal, stoic, slow-tempered, frugal

  25. Novelty-Seeking Gene • Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. • Richard Ebstein et al., 1996 • Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. • Jonathan Benjamin, et al., 1996 • Dean Hamer lab, NIH

  26. Novelty-Seeking Gene • Studies have shown that the number of exon III repeats can affect the affinity of ligand (proteins or drugs) that bind to the receptor. • D4DR is expressed in limbic areas involved in cognition and emotion.

  27. Novelty-Seeking Gene • Research on animals, as well as extensive studies of human twins of both the identical and fraternal variety, indicate that about half of novelty-seeking behavior is attributable to genes, the other half to as-yet ill-defined environmental circumstances. • The D4 dopamine receptor may account for perhaps 10 % of the difference in novelty-seeking behavior between persons.

  28. Novelty-Seeking Gene • Some studies have failed to replicate the initial findings. • The Dopamine D4 Receptor Gene and Novelty Seeking • Anil K. Malhorta, M.D., and David Goldman, M.D. • Finnish Population

  29. Novelty-Seeking Gene • Were the early results just due to chance results in small or unusual populations, and not a real effect of D4DR, or not representative of the general population? • Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR and COMT val/met variants. • A. Strobel et al. 2003 • (Same group as prior report)

  30. Novelty-Seeking Gene • Benjamin et al. had found: • Novelty Seeking scores are higher in the presence of the DRD4 exon III 7-repeat allele in the absence of the short (s) allele of the serotonin transporter gene promoter-linked polymorphic region (5-HTTLPR) and in the presence of the val/met genotype of the COMT gene.

  31. Novelty-Seeking Gene • Benjamin suggested "that failure to replicate associations between personality factors and some genes may be partially due to the presence of additional modifying common polymorphisms".

  32. Novelty-Seeking Gene • Strobel et al. decided to see if this effect explained their failure to find an association in their German population. • Genotyped 5-HTTLPR and COMT val/met in their prior subjects.

  33. Hypothesis • In the group defined by 5-HTTLPR 1/1 genotype and COMT val/val genotype, individuals with the DRD4 exon III 7-repeat allele would have higher Novelty Seeking scores than those without the repeat.

  34. Results • Found a significant difference between those with and without the 7-repeat allele, p = 0.035 after accounting for differences in the other polymorphisms. • The study shows that the failure to detect an effect (due to D4DR polymorphisms) could be explained by the presence of additional modifying common polymorphisms. • Inclusion of additional genetic variations may help resolve some of the inconsistencies in human gene-personality/behavior correlation studies. • http://www.nature.com/mp/journal/v8/n10/pdf/4001367a.pdf • Review Article of many studies

  35. Criminal Behavior/Violence • Classic nature versus nurture arguments • 1993 study of a Dutch family describes one long family history of " a syndrome of borderline mental retardation and abnormal behavior"

  36. Co-segregation of mental retardation, aggressive behavior and a mutation in monoamine oxidase type A gene (MAOA). * - males known to have the mutated MAOA allele. Δ - males known to have the normal MAOA allele

  37. Monoamine oxidase type A gene • Familial defect? • Single nucleotide substitution in the enzyme monoamine oxidase A (MAOA) • renders the enzyme non-functional • MAOA is a key enzyme • required to breakdown several neurotransmitters • dopamine, serotonin and noradrenaline. • behavioral defects not unexpected • What if one inherits a slight mental impairment that interferes with a persons ability to cope with frustrating situations -resulting in violence?

  38. Genetic and Environmental Effects • Role of Genotype in the Cycle of Violence in Maltreated Children • Avshalom Caspi et al. 2002 • wanted to identify gene variants that, given specific environmental triggers, predispose individuals to anti-social behavior • Low MAOA activity in abused boys led to criminal behavior • Low MAOA by itself was normal • High MAOA in abused boys had less criminal behavior observed, but more than unabused.

  39. Genetic control of human behavior • Supported by pedigree analysis • Family studies • Twin and adoption studies • Identification of susceptibility genes • Identification of single gene mutations • Most behaviors are complex • Many genes contribute to the expression of the trait • Behavioral traits are not easily measured • Subjective rather than objective measurements

  40. If Personality Runs in Families, so too does Mental Illness • Prior to 1966, schizophrenia was thought to be related to environmental conditions and poor parenting • 1966 - key study showed Infants put up for adoption by schizophrenic mothers showed the same rate of schizophrenia expected for being raised by a schizophrenic mother

  41. Disease Prevalence % Alzheimer disease 4.0 Anxiety 8.0 Phobias 2.5 Post-traumatic stress disorder 1.8 Generalized anxiety disorder 1.5 Obsessive compulsive disorder 1.2 Panic disorder 1.0 Attention deficit hyperactivity disorder 2.0 Autism 0.1 Drug addiction 4.0 Eating disorders 3.0 Mood disorders 7.0 Major depression 6.0 Bipolar disorder 1.0 Schizophrenia 1.3

  42. Single Gene Mutations and Abnormal Behavior • PKU: phenylketonuria • Leads to severe metal retardation • Single gene defect - major behavioral mutation • Avoid Phenylalanine in diet- screening for infants to detect • Lesch-Nyhan Syndrome • X-linked recessive trait • affects 1 in 100,000 males • inborn error of metabolism • lack the enzyme hypoxanthine-guanine phosphoribosyltransferase  • High level of uric acid in the blood and urine • Strong tendency for self-mutilation • Symptoms fully develop by ages 2-4 • Most die before age 20

  43. Huntington's Disease • Autosomal dominant disease • Late onset - mid-adult • First observed characteristic • Involuntary muscle movements of arms, legs, torso • Later - personality changes, agitated behavior and dementia • Associated with expanding CAG triplet repeats • Disease runs a 10-15 yr course of progressively worsening condition • Autopsy show severe loss of brain areas • Gene product - Huntingtin • House keeping neuron protein

  44. Normal brain Huntington’s diseased brain

  45. Relationships of genetic defects and abnormal behavior • PKU and Lesch-Nyhan • build up toxic chemicals that neurons are very sensitive to. • Huntington's • slow progressive death of neurons •  MAOA • aggressive behavior gene • a single gene mutation • an inborn error of metabolism • persons are basically functional - but have improper control of behavior when stressed by fear, anger, frustration

  46. Eating disorders are a behavioral trait • Anorexia nervosa • psychological perception of obesity and intentional starvation • Bulimia • psychological perception of obesity and intentional vomiting • Muscle dysmorphia • results from steroid consumption to develop enlarged musculature

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