Using zebrafish models to identify novel alleles affecting human behaviour- a proof of principle study using smoking as an example.

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• Dr Caroline Brennan, The School of Biological and Chemical Sciences, University of London
• Thursday 15 January 2015, 14:30-15:30
• Part II Room, Department of Genetics.

If you have a question about this talk, please contact Caroline Newnham.

Host: Boris Adryan

Background: Smoking is one of the leading preventable causes of adult mortality today and places a huge social and financial burden on society. One step toward the effective prevention and treatment for nicotine addiction would be to delineate genetic variants that mediate individual differences in sensitivity to the drug and responses to treatment. Although animal models cannot replicate all the complexities of human smoking, they can help with the identification of genetic factors influencing component behaviours such as reward sensitivity, amount smoked, persistent drug taking, and relapse. Recently we, and others, have established behavioural assays of drug seeking and impulse control in adult zebrafish and used these to demonstrate conservation of reward pathways including responses 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.

Objectives: To identify novel alleles affecting nicotine preference in zebrafish and smoking behaviour in humans.

Method/ Materials: We conducted a forward genetic screen of families of N-ethyl-N-nitrosourea (ENU) mutagenised zebrafish for nicotine-induced conditioned place preference to identify a novel mutation influencing nicotine preference. Subsequent focussed single nucleotide polymorphism analysis of the homologous region in cohorts of human patients was performed and subject to PLINK analysis to test for correlation with smoking behaviour. Quantitative polymerase chain reaction analysis was used to evaluate levels of expression of components of the dopaminergic and cholinergic signalling pathways in larval wildtype and mutant zebrafish.

Results: We identify loss of function mutations in the QM2 gene that lead to increased nicotine place preference in adult zebrafish. Analysis of the QM2 locus in humans identified 2 novel polymorphisms that predict smoking behaviour and response to treatment. Analysis of cholinergic receptor expression revealed an increase in expression of CHR Na5 with no other analysed gene expression affected.

Conclusion: Forward genetic screens of adult zebrafish behaviour can uncover target loci of direct relevance to complex human behaviour such as smoking. Analysis of molecular processes in fish give insight into possible mode of action of human variants and reveal targets for development of personalised therapies.

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