Chapter 062. Principles of Human Genetics (Part 27)

Genetic LinkageGenetic linkage refers to the fact that genes are physically connected, or linked, to one another along the chromosomes. Two fundamental principles are essential for understanding the concept of linkage: (1) when two genes are close together on a chromosome, they are usually transmitted together, unless a recombination event separates them (Figs. 62-3, 62-8); and (2) the odds of a crossover, or recombination event, between two linked genes is proportional to the distance that separates them. Thus, genes that are further apart are more likely to undergo a recombination event than genes that are very close together. The...
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Chapter 062. Principles of Human Genetics (Part 27) Chapter 062. Principles of Human Genetics (Part 27) Genetic Linkage Genetic linkage refers to the fact that genes are physically connected, orlinked, to one another along the chromosomes. Two fundamental principles areessential for understanding the concept of linkage: (1) when two genes are closetogether on a chromosome, they are usually transmitted together, unless arecombination event separates them (Figs. 62-3, 62-8); and (2) the odds of acrossover, or recombination event, between two linked genes is proportional to thedistance that separates them. Thus, genes that are further apart are more likely toundergo a recombination event than genes that are very close together. Thedetection of chromosomal loci that segregate with a disease by linkage can be usedto identify the gene responsible for the disease (positional cloning) and to predictthe odds of disease gene transmission in genetic counseling. Polymorphisms are essential for linkage studies because they provide ameans to distinguish the maternal and paternal chromosomes in an individual. Onaverage, 1 out of every 1000 bp varies from one person to the next. Although thisdegree of variation seems low (99.9% identical), it means that >3 million sequencedifferences exist between any two unrelated individuals and the probability thatthe sequence at such loci will differ on the two homologous chromosomes is high(often >70–90%). These sequence variations include VNTRs, short tandem repeats(STRs), and SNPs. Most STRs, also called polymorphic microsatellite markers,consist of di-, tri-, or tetranucleotide repeats that can be measured readily usingPCR (Fig. 62-12). Characterization of SNPs, using DNA chips, provides animportant new tool for comprehensive analyses of genetic variation, linkage, andassociation studies. Although these sequence variations usually have no apparentfunctional consequences, they provide much of the basis for variation in genetictraits. Figure 62-12 CAG repeat length and linkage analysis in multiple endocrineneoplasia (MEN) type 1. Upper panel. Detection of different alleles usingpolymorphic microsatellite markers. The example depicts a CAG trinucleotiderepeat. PCR with primers flanking the polymorphic region results in products ofvariable length, depending on the number of CAG repeats. After characterizationof the alleles in the parents, transmission of the paternal and maternal alleles canbe determined. Lower panel. Genotype analysis using microsatellite markers in afamily with MEN-1. Two microsatellite markers, A and B, are located in closeproximity to the MEN1 gene on chromosome 11q13. For each individual, the Aand B alleles have been determined. Based on this analysis, the genotype A3,B4 islinked to the disease because it occurs in the two affected individuals I-1 and II-1but not in unaffected siblings. Because the disease allele is linked to A3,B4 withinthe affected family, it is likely that the individual III-1 is a carrier of the mutatedMEN1 gene. Although III-5 also has the A3,B4 genotype, she has inherited theallele from her unaffected father (II-4), who is not related to the original family.The A3,B4 genotype is only associated with MEN-1 in the original family, but notin the general population. Therefore, individual III-5 is not at risk for developingthe disease. In order to identify a chromosomal locus that segregates with a disease, it isnecessary to characterize polymorphic DNA markers from affected and unaffectedindividuals of one or several pedigrees. One can then assess whether certainmarker alleles cosegregate with the disease. Markers that are closest to the diseasegene are less likely to undergo recombination events and therefore receive a higherlinkage score. Linkage is expressed as a lod (logarithm of odds) score—the ratioof the probability that the disease and marker loci are linked rather than unlinked.Lod scores of +3 (1000:1) are generally accepted as supporting linkage, whereas ascore of –2 is consistent with the absence of linkage. An example of the use of linkage analysis is shown in Fig. 62-12. In thiscase, the gene for the autosomal dominant disorder MEN-1 is known to be locatedon chromosome 11q13. Using positional cloning, the MEN1 gene was identifiedand shown to encode menin, a tumor suppressor. Affected individuals inherit amutant form of the MEN1 gene, predisposing them to certain types of tumors(parathyroid, pituitary, pancreatic islet) (Chap. 345). In the tissues that develop atumor, a second hit occurs in the normal copy of the MEN1 gene. This somaticmutation may be a point mutation, a microdeletion, or loss of a chromosomalfragment (detected as loss of het ...