LONDON ¿ The genes that control the characteristics and qualities of the human personality have proved difficult to dissect. Perhaps so many different genes contribute to traits such as anxiety, depression, intelligence and memory that it will prove ever impossible to work out which genes have which effect.
A recent study published in the March issue of Nature Genetics suggests this view is unduly pessimistic. Researchers in Oxford have shown that it is possible to use an outbred strain of mice to identify genes responsible for quantitative behavioral traits. The method could be used to identify almost any genetic trait which results in continuous variation of a characteristic ¿ including, for example, height and weight.
Christopher Talbot, of the Institute of Molecular Medicine in Oxford, U.K., and colleagues, report their findings in a paper titled ¿High-resolution mapping of quantitative trait loci in outbred mice.¿
Jonathan Flint, Wellcome Trust Clinical Fellow at the Institute of Molecular Medicine, and senior author of the paper, told BioWorld International, ¿In this study, we showed that there is a gene which correlates with the trait known as emotionality in mice, and we narrowed the position of this gene down to an area containing a small number of genes, maybe only a few dozen. But the study is also important because it means that, for the first time, we have a general technique for identifying the genes that determine quantitative traits.¿
Flint said he could envisage applying the technique to the study of many different psychiatric conditions, which might make it possible to unravel the biological and metabolic mechanisms responsible for them. ¿It might be possible to develop mouse models that would allow you, using this technique, to correlate certain genes with conditions and behaviors such as depression, sensation-seeking, hyperactivity, low attention span and good or bad memory,¿ he said.
Flint and his colleagues proved four years ago that it was possible to detect the influence of single genes on behavioral traits. The behavioral trait they were interested in is called ¿emotionality,¿ which can be defined as the animals¿ susceptibility to anxiety. Emotionality can be measured quantitatively by putting the animal in a white box, and assessing two variables: the amount the animal moves around and the amount it defecates.
Flint said: ¿Some animals sit still in this environment and defecate a lot, while others run around and don¿t defecate very much. In general, these two measures are related to the animal¿s fearfulness, or timidity, and there is probably some relevance to human behavior here.¿
Four years ago, the researchers took two genetically identical mice and crossed them. They were able to show that mice which had inherited certain genes behaved differently in the experiments described from those which had not inherited these genes. ¿These experiments only told us which chromosome the gene influencing emotionality was on,¿ Flint said, ¿but they did not tell us exactly where it is, only that it was in an area comprising 5,000 or 10,000 other genes.¿
For the study reported in Nature Genetics, the team took a different approach. They used a population of mice which had been outbred for 58 generations, and for which the entire genealogy is known. This population was established 30 years ago, from crosses between eight inbred mouse strains.
After dividing the animals up into groups, according to which genetic markers were present in their genomes, Flint and his colleagues tested them for their degree of emotionality. ¿We found that there was a difference between groups, and were able to pinpoint the gene responsible to an area containing just 20 or so genes,¿ Flint said. Their method resulted in a 30-fold increase in map resolution over that provided by second-generation crossing of different inbred mice.
In their paper, the researchers conclude: ¿Our results demonstrate that the use of an outbred strain of mice allows mapping of quantitative trait loci at a resolution suitable for positional cloning strategies.¿ The use of outbred mice, they say, ¿provides a straightforward method to define a small interval in which to search for candidate genes influencing these and other quantitative traits.¿
Flint is now concentrating his efforts on finding the gene itself which is responsible for the variation in emotionality. He predicts that the search might take another two or three years. n