e frequency of mating between two individuals suffering from different genetic disorders is extremely small.The only way forward for a human genetic map was to base it on polymorphic markers which were not necessarily related to disease or genes. As long as the markers showed mendalian segregation and were polymorphic enough so that recombinants could be scored in a reasonable percentage of meiosis, a human genetic map could be obtained. The problem here was that, until recently, suitable polymorphic markers were just not available. Classical human genetic markers consisted of protein polymorphisms, notably blood group and serum protein markers, which are both rare and not very informative (see box 11.1). By 1981, only very partial human linkage maps had been obtained, and then only in the case of a few chromosomes.It was therefore the identification of DNA-based polymorphisms transformed human genetic mapping. Unlike cliassical markers, DNA-based polymorphisms were not simply confined to the 3% of the DNA that was expressed (genes): they were also available in noncoding DNA. Since the latter was not so strongly conserved in evolution, changes in the DNA are comparatively frequent. The realisation that DNA polymorphisms could be abundant called for a radical revision of thinking, and the early 1980’s saw serious discussion of the possibility of constructing a complete human genetic map for the first time (Botstein et al., 1980). Moreover, DNA markers have the advantage that they can be typed by the same technique, with their chromosomal location beind determined by using FISH or radiation hybrid mapping (sections 10.1 and 10.2), allowing DNA-based genetic maps to be cross-referenced to physical maps. This avoids the fustrating situation that arose when the long sought cystic fibrosis gene (CFTR) was first mapped. Linkage was established to a protein polymorphism of the enzyme paraoxonase, but the chromosomal location of the paraox...
