Quantitative Trait Loci Mapping

Alcohol's complex impact on behavior is demonstrated by studies that attempt to relate problems associated with alcohol abuse, such as dependence on alcohol or tolerance to its effects, to the biological and molecular mechanisms underlying those effects. Alcoholism(1) has been described as a polygenic disorder, that is, one that is influenced by many genes located in different areas, or loci, of a person's or animal's DNA (McCleam et al. 1991; Goldman 1993). The genetically influenced characteristics, or traits, thought to underlie responses to alcohol (e.g., sensitivity to its effects) are called quantitative traits, and many genes influence the overall characteristic, each to a certain extent. Thus, within a population, a quantitative trait differs in the degree to which individuals possess it (e.g., height) rather than in the kind of trait they possess (e.g., eye color). Accordingly, a section of DNA thought to contribute to a quantitative trait is called a quantitative trait locus (QTL). Susceptibility to cancer is another example of quantitative traits that are determined by the combined contributions of several QTLs. Quantitative traits are said to be continuously distributed in population, because individuals exhibit them to different degrees. Because of this distribution, quantitative traits are much more difficult to study than qualitative traits, such as eye color or blood type, which are determined by a single locus and which therefore are distributed discretely. One way to study the contributions of individual QTLs to a quantitative trait such as sensitivity to alcohol is for researchers first to locate in the genome (i.e., an organism's entire genetic material) the genetic information that encodes these traits. A technique for finding this information is called QTL mapping. After a QTL has been identified, the gene can be isolated and its functions studied in more detail. Thus, QTL analysis provides a means of locating and measuring the effects of a single QTL on trait, or phenotype.(2) This article provides a brief overview of the methods involved in QTL mapping. It also discusses the advantages and limitations of QTL analysis and includes several examples demonstrating the application of the technique. MAPPING THE GENOME A QTL is a small section of DNA on a chromosome thought to influence a specific trait. Scientists search different areas of the genome for locations (i.e., loci) they can associate with the trait. The gene included in each QTL exists in more than one form, or allele, and can differ between individuals in a population. One person can carry two different alleles of a gene, one inherited from the mother and one from the father. The effect of one QTL is often fairly small. Thus, the collective impact of many genes located at several QTLs provides the genetic influence on different behavioral and physical phenotypes, such as those related to alcohol abuse (figure 1).(All figures omitted) For technical reasons, QTL mapping for alcohol-related traits is more commonly performed in animal models than in humans; however, because of the common evolutionary history of all mammals, large regions of our genomes have a common identity. This method is therefore a potentially rich source of information about the genes associated with alcohol abuse in humans (Copeland et al. 1993). Genetic Markers To identify the location of QTLs, researchers determine the degree to which a phenotype, such as a person's initial sensitivity to alcohol's effects, is associated with a known genetic marker. These markers are DNA segments known to occupy particular places on the chromosomes.(3) Each marker is polymorphic -- that is, it exists in several different variants that can distinguish individuals or strains of laboratory animals from one another (for a further discussion of genetic markers, see the article by Anthenelli and Tabakoff, pp. 176-181). The association of a genetic marker with a certain trait allows researchers to estimate both the location of a QTL and the magnitude of its contribution to the trait (Tanksley 1993). …