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SUMMARY:Using zebrafish models to identify novel alleles affecting human b
 ehaviour- a proof of principle study using smoking as an example.  - Dr Ca
 roline Brennan\, The School of Biological and Chemical Sciences\, Universi
 ty of London 
DTSTART:20150115T143000Z
DTEND:20150115T153000Z
UID:TALK56509@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:Background: Smoking is one of the leading preventable causes o
 f adult mortality today and places a huge social and financial burden on s
 ociety. One step toward the effective prevention and treatment for nicotin
 e addiction would be to delineate genetic variants that mediate individual
  differences in sensitivity to the drug and responses to treatment.  Altho
 ugh animal models cannot replicate all the complexities of human smoking\,
  they can help with the identification of genetic factors influencing comp
 onent behaviours such as reward sensitivity\, amount smoked\, persistent d
 rug taking\, and relapse. Recently we\, and others\, have established beha
 vioural assays of drug seeking and impulse control in adult zebrafish and 
 used these to demonstrate conservation of reward pathways including respon
 ses to nicotine in fish as in mammals. These studies raise the possibility
  of using mutagenesis screens in fish to identify genes affecting complex 
 behaviours such as nicotine preference\, which is one aspect of smoking\, 
 in humans.\n\nObjectives: To identify novel alleles affecting nicotine pre
 ference in zebrafish and smoking behaviour in humans.\n\nMethod/ Materials
 : We conducted a forward genetic screen of families of N-ethyl-N-nitrosour
 ea (ENU) mutagenised zebrafish for nicotine-induced conditioned place pref
 erence to identify a novel mutation influencing nicotine preference.   Sub
 sequent focussed single nucleotide polymorphism analysis of the homologous
  region in cohorts of human patients was performed and subject to PLINK an
 alysis to test for correlation with smoking behaviour. Quantitative polyme
 rase chain reaction analysis was used to evaluate levels of expression of 
 components of the dopaminergic and cholinergic signalling pathways in larv
 al wildtype and mutant zebrafish.\n\nResults: We identify loss of function
  mutations in the QM2 gene that lead to increased nicotine place preferenc
 e in adult zebrafish.  Analysis of the QM2 locus in humans identified 2 no
 vel polymorphisms that predict smoking behaviour and response to treatment
 . Analysis of cholinergic receptor expression revealed an increase in expr
 ession of CHRNa5 with no other analysed gene expression affected.\n\nConcl
 usion: Forward genetic screens of adult zebrafish behaviour can uncover ta
 rget loci of direct relevance to complex human behaviour such as smoking. 
  Analysis of molecular processes in fish give insight into possible mode o
 f action of human variants and reveal targets for development of personali
 sed therapies.\n
LOCATION:Part II Room\, Department of Genetics
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