-Barenaked Ladies – “Alcohol”

Alcoholism is a disease with major world health implications. There are over 15 million people in the U.S. suffering from alcoholism resulting in over 100,000 deaths a year and health care costs approaching 200 billion dollars. In Britain there are an estimated 36,000 hospital admissions a year that are directly related to alcohol and the public health cost in Australia is similar in scale to that in the USA. There is certainly a genetic component to alcoholism, but inheritance of the disease is complex and complicated by environmental factors. Alcoholism is thus a difficult disease to detect at an early stage and to treat. Isolating the genetic components – the genes that predispose a person to alcoholism – is also a complex process, but could prove valuable for detection and treatment.

For most genetic diseasez, scientists rely on animal models for the disease in which they are interested in studying. This is generally because one can neither selectively breed humans to establish inheritance patterns nor use experimental treatments. For diseases, like alcoholism, that have an environmental component there is a limit to how much control scientists can have over their subjects’ environments. Animal models allow researchers latitude for these and other genetic manipulations. The two species most commonly used for the study of alcoholism are mice and fruit flies (Drosophila). The latter may seem a strange choice but offer a number of advantages to geneticists. They are small and it is easy to rear thousands of flies in a small space. Their genome has been sequence and they have served as a model organism for the study of inheritance for over a century. Two-thirds of human disease genes have orthologues (versions) in Drosophila. Importantly for the study of alcohol abuse – flies get drunk.

A new study published in the latest issue Genome Biology exploits some of these advantages in a search for some of the genes that may be involved in alcoholism. The authors of this paper, a group from North Carolina State University, use whole genome expression analysis to identify candidate genes that affect alcohol sensitivity. The advantage that Drosophila provides in this study is in the experimental set-up. The NC State researchers established two artificially selected populations over 35 generations, one sensitive to alcohol and one resistant. This type of artificial selection involves selecting inidividuals that exhibit the trait of interest and breeding them together. The scale of these populations is only possible in an organism that requires little space and has a short generation time – like the humble fruit fly.

Using these two artificially selected populations, the researchers then looked for genes that varied in their expression level using a technique that allows each Drosophila gene to be analyzed. Gene expression refers to the production of an enzyme, a functional protein, from a gene, a stretch of DNA. Not surprisingly, considering the number of generations of selection, there were thousands of genes that were expressed at a different level in the two populations. Most of these changes, however, were modest and they focused on a few dozen genes with at least a two-fold change in the level of expression.

The most impressive thing about this paper is that they carry their research one step further. One of the main problems with whole genome transcriptional profiling by microarray is that the accuracy of the results is often questionable. This group confirms their microarray results by measuring alcohol sensitivity in mutants of each of the genes that were expressed differently in the two selected populations. Using these functional tests, mutants in 73% or 32 of the candidate genes were found to have effects on alcohol sensitivity. Of these, only three have been previously identified and 23 have human orthologues.

I try to avoid getting to much into the technical aspects of research in my Science Tuesday posts, but couldn’t resist this week. To establish whether or not flies are sensitive or resistant to alcohol they are placed in an inebriometer (really) and then subjected to a battery of locomoter tests including how high they can climb before falling and how long they remain mobile immediately after an overdose of alcohol. They also measure how often the flies fight after exposure to alcohol – not sure how flies fight. But if these types of tests sound fun to you, well… I don’t like to judge.

Basic conclusions are that there are a number of genes that may play a role in alcoholism in humans that have not been studied. There is no real pattern to be found in the type of genes affected – they play roles in a number of cellular processes. There were a surprising number of genes involved in sensitivity to odors that were differentially expressed in alcohol sensitive flies. However, the most exciting conclusions here is that this type of artificial selection experiment can provide researchers with dozens of candidate genes in humans to explore when studying complex genetic diseases.

There are a few flaws with these experiments. The researchers themselves point out that this study only really looks at one developmental time point, so it’s providing a picture of changes in gene expression at one time in the flies’ life cycle. Additionally, there may be changes in gene expression that are regulated by means other than transcriptional control. However, the biggest issue is that while flies can get drunk, they do not demonstrate the addictive propensity of human alcoholics. Thus, this study provides little information about the disease’s most deadly aspect. Most of the readers of this post have probably had a night in which they indulged a bit heavily – but only about 5% of you have felt the compulsion to carry on the next day. The current study provides a lot of genetic information about how the body, and by extension the brain, deals with an excess of alcohol. But it provides no information about the real issue in the disease of alcoholism, that next day syndrome – the addiction.

Image Credits:

Flies in a glass

Microarray

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