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Where Is the Abnormal Gene?—Genetic Linkage Analysis and Association Studies

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FIGURE 6–1. Genetic linkage and recombination. Depicted is a hypothetical family (circles: females; squares: males) transmitting an autosomal dominant disease. The disease locus A (containing either the defective allele a1 or its normal counterpart a2) lies close to a marker locus B (containing marker alleles b1 and b2). The mother is affected with the disease (shaded symbol) and is heterozygous at both the disease and the marker loci. The father is unaffected (open symbol) and is homozygous at both loci. Because the disease and marker loci are genetically linked (i.e., they lie near each other), crossing over rarely occurs between them. Most children who inherit the disease allele a1 also receive the b1 marker allele from their mother. Occasionally, a recombination event (i.e., "crossing over") occurs in the mother, and she transfers a chromosome bearing the b2 marker allele along with the disease allele (as occurred in the daughter labeled "recombinant"). The frequency of such recombinants increases as the distance between the disease and marker locus increases.

FIGURE 6–2. Schematic representation of a microsatellite marker. Note. Panel A. Autosomal homologous chromosome pairs from parents in a pedigree to be genotyped. Panel B. The DNA sequence on the long arm of the chromosome is examined in greater detail, revealing the variable repeating DNA sequence termed a microsatellite marker. For a dinucleotide repeat, each box represents two nucleotides (e.g., CA). Differing numbers of repeats of this dinucleotide are frequently found in different individuals. The example shows a father with four and three repeats and a mother with five and two repeats. (This is a simplification; most commonly there are 15–20 repeats.) Panel C. Using DNA primers (* and **), one of which is radiolabeled, and a heat-stable DNA polymerase, repetitive cycles of DNA denaturation and replication exponentially amplify (105-fold) the DNA sequence bound by the primers. This process is termed the polymerase chain reaction (PCR) and is shown for only one of the two chromosomes of the father. Because the length of the fragment amplified is bounded by the primers, which are attached to nonrepeating sequences outside the microsatellite region, the length of the product of this reaction from each chromosome will be determined by the number of repeats. Panel D. The amplified DNA fragments are separated on the basis of size by gel electrophoresis. Panel E. The presence of the bands is determined by autoradiography. Individuals have two bands that correspond to the lengths of the amplified fragments. Each band is a marker for this region of the long arm of its own chromosome. The inheritance of these fragments can then be followed through all members of a pedigree whose DNA is available for the PCR reaction. Genotypes for each of the members of the hypothetical pedigree are shown under the autoradiogram. If an autosomal dominant disease is depicted by solid symbols, allele 4 would be linked to the disorder in this pedigree. This linkage, if statistically significant, indicates that the microsatellite marker is located close to the disease gene.

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