Alcohol and genetics: Is your child at risk?.
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Alcoholism or alcohol dependence is devastating. Genes that impact risk for this disorder can be inherited and passed on to one’s children. How genetic information is obtained, current genetic findings, and other important, influential factors will be discussed in this lecture.
A Single Gene Trait
From Simpson et al. (1997) Nature Genetics 16:19.
A Complex Trait
Gene x Environment Interaction
Gene x Gene Interaction or Epistasis
Adapted from Phillips et al. (2002) Genes Brain Behav 1:14.
“Although dolphins have long been celebrated for their high intelligence and for appearing to have a complex language, a team of researchers at the University of Florida reported Monday that these traits are markedly less evident on dry land.”
[the ONION, Feb 15, 2006]
Use of Animals to Identify Direct and Indirect Alcohol Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism
From Lovinger & Crabbe (2005) Nature Neurosci 8:1471.
to the Study of Genetics
Approaches used for Human and Animal Populations
•Twin & Adoption Studies • Haplotype Analyses
• Association Studies • Natural Mutations
• Family Linkage Studies • mRNA Differential Display
• Microarray Expression Profiling• QTL Mapping
• Association Genome Scanning
Unique Approaches used for Animal Populations
•Targeted Mutations • Random Mutagenesis
• Viral Gene Transfection • Selective Breeding
• Antisense Approaches • Inbred Strain Studies
• RNA interference • Chimera Analysis
• Genes that influence a quantitative trait may each have a small effect.
• A QTL identifies the location of a gene that influences a complex trait.
• QTL Mapping is a method for pinpointing chromosomal regions where trait-specific genes reside.
• Several QTL can work together to account for individual differences; their effects may “add up” or they may interact with each other.
The ultimate goal of QTL mapping and other genetic studies is to identify the influential genes (the quantitative trait genes or QTG) and determine what they do that heightens risk for alcoholism or affords protection.
2nd selectedgeneration3rd selectedgeneration
Voluntary Alcohol Consumption
Adapted from Phillips et al. (2005) Behav Neurosci 119:892.
Between the C57BL/6J (B6) and DBA/2J (D2) Mouse Strains
Investigated sequence: 1- 1850 bp, coding sequence: 1-1782 bp (594 AA.)
Polymorphism: C57BL/6J: 646:GAT, DBA/2J: 646:AAT
Legend: Pos: position, AA: amino acid, GlycoS: glycosylation site,GORP: secondary structure after
Garnier-Osguthorpe-Robson; AA: D=Asp; A=Ala; Y=Tyr; K=Lys; P=Pro; T=Thr; M=Met.
GORP: H=alpha helix; T=beta turn
Syntaxin Binding Protein 1 (Stxbp1) Allele Frequency in 4 Generations of Mice Bred for Low and High Alcohol Consumption
Alcohol intake in Rhesus Monkeys is Correlated with Serotonin Transporter Availability
Spearman\'s R=0.76, P=0.006
From Heinz et al (2003) Molec Psychiat 8:231.
GABRA1 (Gabra1), GABRA6 (Gabra6), GABRB2, and GABRG2 (Gabrg2)
CHRM2 – muscarinic cholinergic receptor
DRD2 – dopamine D2 receptor
GAL – the neuropeptide, galanin
OPRM1 – mu opioid receptor
hTAS2R16 – a taste receptor for bitter substances
This inebriometer was developed to measure ethanol-induced loss of postural control in Drosophila melanogaster.
From Singh & Heberlein (2000) Alcohol Clin Exp Res 24:1127.
cheapdate mutant – increased ethanol sensitivity.
hangover mutant– reduced ethanol tolerance.
lush mutant – reduced avoidance of ethanol.
slowpoke gene – BK channel gene; expression is increased by ethanol and induces ethanol tolerance.
Slo-1 mutant – BK channel gene; decreased sensitivity to ethanol’s effects on movement
– uncontrolled and escalated drinking
– adolescent to adult transitions