ABSTRACT
4.1 Small Area Gene Mapping by Linkage Disequilibrium
In human pedigree analysis, the gene cannot be pinpointed to a very small area, say less than 1 cM. The reason is that when the recombination fraction is very small, crossover can seldom be observed in a few generations. One way that we may be able to increase the sample size is to jump from families (or siblings) to subpopulation. For example, suppose a group of people has been settled in one geographic area for 600 years, and suppose the disease originated from a single mutation 600 years ago. Moreover, at the time of mutation, a certain marker was very close to the disease gene, say 0.1 cM (100 kbp) away. Then, after 600 years, or approximately 20 generations, the same marker should still be linked to the mutant gene because of the small (0.001) crossover probability. Any pedigree is unlikely to trace back 20 generations, but the linkage between the disease and this particular marker can still be seen from the population in this area. If one allele from a marker locus appears more often in affected individuals than in unaffected individuals, then we may suspect that this marker is related, and perhaps very close, to the disease gene. Table 4.1.1 gives the frequency tables for four markers and cystic fibrosis (CF, see a description of this disease in Example 2.2.3) patients and their controls (from Estivill et al., 1987).
