Researchers at Queen Mary University of London have shown that zebrafish can provide genetic clues to smoking, a complex human behaviour.
By studying genetically-altered zebrafish they were able to pinpoint a human gene, Slit3, involved in nicotine addiction and also discover the ways in which it may act.
While zebrafish have been used extensively in genetic research, they’ve been used only in developmental models, such as identifying genes associated with disease, rather than to predict genes involved in a complex cognitive behaviour such as smoking.
Although smoking has long been known to have a genetic element, relatively little has been known about the genes involved since it has been difficult to identify them from human studies alone.
In a study published in eLife journal, the researchers tested families of genetically altered zebrafish for nicotine preference. When one family showed a much stronger nicotine preference compared to the others, the researchers identified all the mutations in the family, eventually narrowing down to a mutation in the Slit3 gene linked to the behaviour.
To see if the same gene affected nicotine preference in people, the researchers looked for association between variants in the human Slit3 gene and smoking behaviour, such as decreased or increased desire to smoke and how easy it was to quit, in groups of people in the UK and Finland. They found 3 variants in the human Slit3 gene that were significantly linked to smoking activity.
To then learn more about how the Slit3 gene might be working, the researchers tested both mutant and wild type fish for sensitivity to a dopaminergic drug. In humans this drug affects the startle reflex – our physical reaction to a sudden loud noise – that is linked to addictions, including nicotine addiction. When tested with the startle reaction, the mutant fish showed decreased sensitivity to the drug. After testing various different receptors that might be involved in the reduced drug sensitivity, the researchers found that only one receptor was implicated – the serotonin receptor 5HT 1AA.
Caroline Brennan, Professor of Molecular Genetics at Queen Mary University of London, led the research. She explained: “This gives us a hypothesis for how the Slit3 gene works in humans. It is somehow altering the level of serotonin receptors present; and the differences in the levels are presumably then influencing sensitivity to nicotine addiction.”
Professor Brennan added: “As well as finding out more about the genes involved in nicotine addiction, most importantly, we’ve found an easier way of finding these genes in the future. Although zebrafish are a ‘lower’ organism, they have a similar genetic structure to humans and share 70% of genes with us. 84% of genes known to be associated with human disease have a zebrafish counterpart; and while there has been scepticism regarding their usefulness in terms of human cognition, we have shown that they can give insight into the genetics of that as well.”
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Notes to editors:
Identification of Slit3 as a locus affecting nicotine in zebrafish and human smoking behaviour” is published by eLife. DOI: 10.7554/eLife.51295
About Queen Mary University of London
At Queen Mary University of London, we believe that a diversity of ideas helps us achieve the previously unthinkable. In 1785, Sir William Blizard established England’s first medical school, The London Hospital Medical College, to improve the health of east London’s inhabitants. Together with St Bartholomew’s Medical College, founded by John Abernethy in 1843 to help those living in the City of London, these two historic institutions are the bedrock of Barts and The London School of Medicine and Dentistry. Today, Barts and The London continues to uphold this commitment to pioneering medical education and research. Being firmly embedded within our east London community, and with an approach that is driven by the specific health needs of our diverse population, is what makes Barts and The London truly distinctive. Our local community offer to us a window to the world, ensuring that our ground-breaking research in cancer, cardiovascular and inflammatory diseases, and population health not only dramatically improves the outcomes for patients in London, but also has a far-reaching global impact. This is just one of the many ways in which Queen Mary is continuing to push the boundaries of teaching, research and clinical practice, and helping us to achieve the previously unthinkable.
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The research was funded by the US National Institutes of Health, the UK Medical Research Council, and the National Institute for Health Research (NIHR).
The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation. https:/
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