Linkage and mapping J 83 Two related concepts distinguished from linkage 1. Linkage disequilibrium is the tendency for certain alleles at twa linked loci to occur together more often than expected by chance. a. For example, if marker locus M with alleles Mt? and M is linked to disease locus Data genetic distance of 5 cM, and if itis found that the mutant allele at D oc- curs on the same chromosome as M® more often than expected within a certain population, linkage disequilibrium exists. b. Linkage disequilibrium is measured in a population, not in a family, and often varies in different populations. 2, Synteny is the occurrence of two loci together on the sa ieci may not be linked if they are so far apart that crossing over usually oc: tween them. DI Clinical applications of linkage 1. Linkage is clinically useful because it may pel a. Determination of the likely genotype of an individual at a disease gene locus on the basis of readily identifiable linked markers b. Determination of the pattern of inheritance or specific form of a disease that ex- hibits genetic heterogeneity (see Ill) c Gene mapping by defining the order and recombination distance between loci on a chromosome (see Il) ical uses of linkage {see also Chapter Prenatal diagnosis of genetic diseases, Carrier detection in autosomal or X-lin! muscular dystrophy c. Presymptomatic diagnosis of late-onset autosomal dominant diseases, such as fa- mulial breast cancer .ctors in genetically heterogeneous conditions or multi- d. Elucidation of genetic fat factorial diseases, such as insulin-dependent diabetes mellitus 3. The clinical use of linkage always requires obtaining information on other family members besides the one whose genotype is being determined. arker to provide information about a disease gene always in- bination may occur between the loci for the yme chromosome. Syntenic curs be- 6 Ill) include: such as phenylketonuria (PKU) iked recessive diseases, such as Duchenne 4. The use of a linked mi volves some uncertainty because recom marker and the disease. [ a GENE MAPPING is the assignment of genes to specific chromosome locations. More than 6000 genetic loci have been mapped to specific human chromosomes. Most of these loci are short tandem-repeat polymorphisms (STRPs) (see Chapter 418 1b (WI), f their extreme polymorphisin and ease of testing which are excellent markers because of hain reaction (PCR) {sec Chapter 6 | BJ. The total also includes more by polymerase cl than 450 genes. The average distance between mapped markers is less than 1 cM. Many additional loci are mapped each month as part of the Human Genome Project (see IV). ‘A. Several methods of gene mapping are available. The results of one method often com- plement those of another. 1, Family studies are used to demonstrate linkage between loci. If linkage between the loci can be shown to exist, both must reside on the same chromosome, The fre- quency of recombination between linked inarkers Is a measure of genetic distance and can be used to place them in linear order. 2. Somatic cell genetic methods are used to demonstrate synteny or to show that an un- mapped locus resides on a given chromosome. In general, somatic cell genetic meth- s involve the demonstration of loss of a given gene from cells that lack a specific