Chapter 5 Linkage and Mapping }. M. Friedman LINKAGE is the occurrence of two or more genetic loci in such close physical proxim- ity on a chromosome that they are more likely to assort (or segregate) together rather than independently during meiosis (Figure 5-1)f Linkage occurs because crossing over does not usually take place between loci that are close to each other. : 2 “A] Concepts of genetic linkage 1, Linkage refers to loci, not to alleles. a. For example, consider a genetic marker locus M that is linked to the locus for a dominantly inherited disease, D. If locus M has two allelic forms, M? and M?, then some families may carry the mutant D allele on the same chromosome as M?, and others may carry the mutant D allele on the same chromosome as M?. In either case, the allele at the marker locus and the D allele at the disease locus will usually be transmitted together at meiosis. b. The process of determining which allele at one locus is carried on the same chro= ingore as a given allele at another locus is called determining the phase of the linkage. ane serene i (1) Thus, if'a person is known to be heterozygous M'/M! at a marker locus and heterozygous D/d at a disease locus, two possibililies exist: The chromosome that carries the mutant allele at the disease locus may carry M"' at the marker locus, or it may carry MY, (2) Family studies are necessary to establish which of these two possibilities in fact exists. 2. The specific alleles present al linked loci in a given individual or family are irrele- vant as long as they are informative for testing, Measurement of genetic linkage can take place only in family studies. Meiosis, which is required to demonstrate linkage, occurs only during gametogenesis. Therefore, only fam ily members can be studied to determine if linkage of genes has occurred. 1. The unil used to express how close two linked genes are is the centimorgan, (cM), or percent recombination. : ‘a. Loci that are separated by crossing over in 1% of gametes are 1 cM apart. b. Loci that are 50 close that they are almost never separated by crossing over are linked at a genetic distance of 0 cM. c. Unlinked loci are separated by a genetic distance of 50 cM, because a given al- lele at one locus has @ 50% chance of being transmitted with either allele at an unlinked locus. 2. The usual statistical method of measuring linkage in family data is calculation of the lod score. a. Lod is an acronym for “logarithm of the odds.” The lod score is the logio of the odds in favor of finding the observed combination of alleles at the lact being stud- __ ied if they are linked at a given distance rather than heing unlinked. (b.\A lod score of +3 or greater at a recombination distance af less than 50 cM be- ~“1ween two locl is considered to be strang evidence of linkage (1000: 1 odils for linkage). ¢ ©, A lod score of -2 or less is considered strong avidence that there is no linkage (100: 1 odds against linkage). a