Genetic strategies to detect genes involved in alcoholism and alcohol-related traits.

(A) A set of human chromosomes as seen under a microscope, containing 22 chromosome pairs (ordered according to size) and 2 sex chromosomes. In this case, the chromosomes were obtained from a male, as indicated by the presence of an X and a Y chromosome. (B) The structure of DNA. The DNA molecule is composed of two strands of building blocks that interact with each other. Each building block contains a chemical group called a base. There are four bases, adenine (A), cytosine (C), guanine (G), and thymine (T), in a sequence of paired bases. The base A on one strand always pairs with T on the opposite strand, and G always pairs with C. The sequence of these bases encodes the genetic information. (C) Micro-satellite and single-nucleotide polymorphism (SNP) markers. Microsatellite markers are short sequences of two to four bases (in this example, the bases T and A) that are repeated several times. The number of repeats differs among individuals, creating many different versions (i.e., alleles) of the marker for genetic analyses. For SNP markers, only a single base differs between individuals (in this case, the base T is changed to a C); thus, there are only two possible alleles of the SNP.

Determination of identity by descent (IBD). For each nuclear family of two siblings and their parents, the illustration shows the genetic makeup of a marker with four variants (i.e., alleles). In the left panel, both siblings have inherited allele 1. However, the brother inherited allele 1 from the mother whereas his sister inherited allele 1 from the father. Therefore, they have no shared alleles (IBD = 0). In the middle panel, both siblings inherited allele 1 from the father (IBD = 1). In the right panel, both siblings inherited allele 2 from their father and allele 3 from their mother (IBD = 2). Siblings who are similar for a trait that is determined by a gene located close to the marker would be expected to share more alleles (i.e., have a higher IBD number) than siblings who are dissimilar for the trait.NOTE: Squares represent males and circles represent females.

(A) Design of case control studies. These analyses compare the frequencies of alleles in a population of unrelated cases (e.g., alcoholics) and a population of control subjects (e.g., nonalcoholics). In the example shown here, a marker with three different alleles is assessed. The analysis shows that allele 1 occurs in 80 percent of the cases but only 20 percent of the control subjects. This finding suggests that allele 1 may be associated with disease susceptibility (e.g., susceptibility to alcoholism). (B) The transmission disequilibrium test (TDT) tests the hypothesis that a particular marker allele is more frequently transmitted to affected offspring from heterozygous parents. Again, a marker with three alleles is shown. In each of the three trios shown here, the father is heterozygous, carrying allele 2 and either allele 1 or allele 3. The mothers are either homozygous and therefore can transmit only one allele to their offspring (and are thus not informative for the TDT test) or heterozygous. Because in all three cases shown here the affected offspring carry allele 2 from the father, that allele is likely to be associated with the disorder. Information from many trios is tabulated to evaluate the statistical significance of the TDT test.NOTE: Squares represent males and circles represent females.

Schematic illustration of the F2 breeding design used in genetic analyses, and the generation of recombinant inbred (RI) lines. For the F2 design, animals from the F2 generation are studied both for the trait under investigation and for their genetic makeup (i.e., genotype). Repeated inbreeding of the F2 animals results in the development of multiple RI lines. These lines differ in the composition of the genetic material inherited from the progenitors. However, all animals within an RI line are genetically identical.

Development of a congenic line in which a quantitative trait locus (QTL) from the donor line is being bred into the recipient line. The blue and white areas represent genetic material inherited from the two progenitors. The F1 offspring of a cross between donor and recipient carries approximately 50 percent of the genetic material from each parent. By repeatedly breeding the F1 animals and their offspring with the recipient line, the proportion of genetic material from the donor line becomes progressively less until only the QTL under investigation remains from the donor line.