Genetics of Behavior

Genetics of Behavior • Models, methods, and phenotypes • Animal models • The nervous system • Aggression and brain metabolism • Mood disorders and schizophrenia • Social behavior Models, Methods and Phenotypes • Evidence of a genetic basis for some human behaviors – Pedigree analysis, family studies, adoption studies, twin studies • Likely that many genes are involved (polygenic); environment, too Proposed Models of Inheritance • Single gene – Simple inheritance; regular dominance rules apply – Examples of conditions with a behavioral component: Huntington’s Disease, LeschNyhan syndrome, fragile-X Proposed Models of Inheritance • Polygenic trait – Additive: two or more genes contribute equally in an additive manner to the phenotype – One or more genes have a major effect, one or more have a minor effect – Epistasis: an allele of one gene masks the expression of a second gene Twin Studies • If single gene model is proposed, analysis begins – Pedigree analysis, linkage studies (including DNA markers, recombinant technology) • If polygenic is more likely, twin studies – Twin studies have established genetic links: manic depression, schizophrenia, and behavioral traits • Sexual preference, alcoholism Twin Studies • Newer methods: – Study the children of twins to be sure there are heritable components – Couple with recombinant DNA techniques to search for behavior genes Phenotypes • Defining behavior phenotypes poses some difficulties • Mental illnesses – Some well defined by the American Psychiatric Association – Some very vague – Often descriptions ignore underlying biochemical basis of symptoms The Nervous System • Mutations can result in altered metabolic pathways, interfere in producing gene products • If in nervous system cell, can affect behavior – Examples: PKU – Alter brain structure: Huntington’s disease, Alzheimer disease, Charcot-Marie-Tooth disease – May be brain structure disorders: bipolar illness, schizophrenia Animal Studies • Open-field behavior in mice – A mouse in a new area will either explore actively or be very timid – Albino line is timid, very emotional in a new area – Normally pigmented line explores actively, not very emotional – Cross for several generations, and resulting albino offspring are timid, normally pigmented offspring are adventurous Advantages of Animal Studies • Can create true-breeding lines • Population size is easily controlled • Matings can be designated and easily controlled • Environmental conditions (food, water, sleep, etc.) can be maintained more easily Transgenic Animals • Use transgenic animals to study neurodegenerative disorders – Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington disease (HD) • First, must identify and isolate gene likely to be involved in a particular disorder • Animals often used: mice, Drosophila Single Gene: Nervous System • • • • • Huntington Disease Adult-onset neurodegenerative disorder Autosomal dominant inheritance Affects 1 in 10,000 Americans, Europeans Involves expansion in a trinucleotide repeat and shows anticipation Huntington Disease • Phenotype begins in midlife – Involuntary movements, jerky motions of arms, legs, torso • Progresses over time – Personality changes, agitated behavior, dementia • Gene located on short arm of chromosome 4 – Mutants have extra CAG trinucleotide repeats – Results in extra glutamines in gene product Huntington Disease • Mutation causes protein to become toxic • <35 repeats = no disease development • 35-39 repeats may or may not develop disease • 40-60 repeats will develop disease as adults • >60 repeats will develop disease before age 20 Huntington Disease • Anticipation associated with increase in the number of repeats passed on in successive generations – Paternal inheritance particularly likely to cause early onset • Damage to several parts of the brain – Cells fill with clusters of mutant proteins, degenerate and die – Involuntary movements, personality changes result Huntington Disease • Transgenic mice display human mutant phenotypes • Fetal nerve cell transplants being investigated as a treatment – Some evidence to suggest the cells may be able to survive and make necessary connections – Testing is promising, but not complete Language and Brain Development • KE family has speech/language disorder – Autosomal dominant trait • Mapped to long arm of chromosome 7 – FOXP2 (the SPCH1 region) has a nucleotide switch: G replaced with A – Changes amino acid in protein, rendering transcription factor ineffective • Mutation causes reduction in transcription factor during fetal development Single Gene: Aggression • In 1993, new form of X-linked mild mental retardation identified • Affected male phenotype: – Aggressive and violent behavior • Gene mapped to short arm of X chromosome – Gene in the region encodes an enzyme that breaks down neurotransmitters Single Gene: Aggression • If neurotransmitter not broken down quickly, nervous system function altered • The mutation causes the enzyme to be nonfunctional, allowing neurotransmitter to build up • Further work necessary Some Single Gene Mistakes • Bipolar disorder – Initially determined to be on chromosome 11 – Individuals indentified that had a normal chromosome 11 AND bipolar disorder • Schizophrenia – Initially determined to be on chromosome 5 – Eventually determined to be largely coincidental Mood Disorders • Moods: sustained emotions • Affects: short-term expressions of emotions • Affective disorders: – Prolonged periods of depression (unipolar) – Cycles of depression and mania (bipolar) • Schizophrenia: profound – Psychotic symptoms, delusions, thought disorders, hallucinations Mood Disorders • Lifetime risk of developing an identifiable mood disorder is 8-9% (in US) • Depression is most common – Weight loss, insomnia, poor concentration, irritability, anxiety, lack of interest • 1% of population has bipolar illness – Periods of manic activity alternate with depression – Linked to genetics: family, twin, and adoption studies Genetics of Bipolar Illness • Concordance – Monozygotic twins (MZ): 60% – Dizygotic twins (DZ): 14% • Adoption studies and family studies indicate a link, too • Because MZ twin concordance is not 100%, some environmental influence, too • Likely polygenic Genetics of Schizophrenia • Affects about 1% of population • Usually appears in late adolescence, early 20s • No single distinguishing feature and causes no characteristic brain pathology • Features: – Psychotic symptoms, disorders of thought, perceptual disorders (hallucinations), behavioral changes, withdrawal from reality Genetics of Schizophrenia • Influence of both genetics and environment • Relatives of schizophrenics have 15% chance of developing disorder • Concordance for narrow definition: – MZ twins: 46%; DZ twins: 14% – MZ twins raised apart show same concordance as MZ twins raised together • Concordance for broad definition: – MZ twins: 100%; first order family risk: 45% Genomics • DNA microarrays used to measure expression level of several thousand genes simultaneously • Defects in myelin sheath plays a role in schizophrenia • Researchers looked for differences in myelination genes between schizophrenics and non-schizophrenics Social Behavior: Tourette Syndrome • Tourette syndrome characterized by motor and behavioral disorders – Outbursts of profane or vulgar language, parrotlike repetition of words; can progress • 10% of affected individuals have family history of condition – Family members of affected individuals are at greater risk than the general population • Males affected more frequently • Identifying genes difficult Social Behavior: Alzheimers (AD) • Progressive and fatal neurodegenerative disease • Affects 2% of population (developed countries) • 10% of US population over 65 has AD; 50% of those over 80 have AD • Symptoms: – Loss of memory; progressive dementia; disturbances of speech, motor activity, and recognition Social Behavior: Alzheimers (AD) • Brain lesions accompany progression • Caused by a protein fragment that accumulates outside cells – Amyloid beta-protein – Aggregates into senile plaques • Plaques cause degeneration and death of nearby neurons • Less than 50% of cases can be linked to genetics Social Behavior: Alzheimers (AD) • Gene for amyloid beta-protein on long arm of chromosome 21 – Mutations responsible for early-onset AD; autosomal dominant inheritance • Mutations in genes on chromosome 14 and 1 identified as possible contributors – Other chromosomes, mitochondrial DNA also potential contributors Social Behavior: Alcoholism • 10% of adults who drink are classified as alcoholics – 4:1 men to women – Likely a genetically influenced, multifactorial disorder • Genetic evidence: – In mice, alcohol preference can be selected for; greater risk of alcoholism in sons, brothers of alcoholics; 55% concordance for MZ twins, 28% for DZ twins; adopted sons more like biological fathers than adoptive fathers Social Behavior: Alcoholism • Likely inheritance is likely polygenic • Single gene models have been difficult to verify • However, determining the influence of a particular gene in a multigene system is also extremely difficult Social Behavior: Sexual Orientation • Concordance: – MZ twins: 52% – DZ twins: 22% – Unrelated siblings (adopted): 11% • Sexual orientation has a strong genetic component – Likely involves many genes and several environmental influences Summary • Almost all studies of complex behaviors provide only indirect evidence for the role of specific genes • Most behaviors involve multiple genes interacting and environmental influences