Tracing the mutations in cystic fibrosis by means of closely linked DNA markers

Abstract

Three reports on the genetics of CF appear in this issue of The American Journal of Human Genetics. Fujiwara et al. (1989) describe a genealogical analysis showing that there are at least three CF carriers among the founders of the Hutterite population. Beaudet et al. (1989) present examples demonstrating that it is possible to apply linkage disequilibrium data in prenatal diagnosis and genetic counseling. Cutting et al. (1989) provide additional data supporting the hypothesis that the majority of CF mutations found in the Caucasian population arose from one single mutational event; they also show evidence suggesting that multiple mutant alleles exist in American blacks. Thus, the central theme of these articles appears to concern to origins of CF mutations. How many different CF mutations are there? The strong linkage disequilibrium and haplotype association detected between the CF gene and the closely linked marker loci have been taken to mean that a substantial fraction of the CF mutant genes in the population are descended from a single mutation. Had multiple mutations occurred in different haplotype backgrounds at equal frequency, the association would not have been detected. On the basis of data collected from British, Danish, Spanish, and Finnish CF families, it has been suggested that a single mutational event could account for > 85% of the CF chromosomes in the northern European population (Estivill et al. 1987a, 1987b). A similar proportion of haplotype distribution has been observed in the North American Caucasian population (Beaudet et al. 1988), a finding consistent with this population's European ancestry. However, when the same type of study was conducted with an Italian CF population, a significant proportion of CF patients were found to carry other DNA marker haplotypes (Estivill et al. 1988). Since these other CF-associated haplotypes could not be easily explained by recombination events, the latter investigators suggest that two mutations are responsible for most CF cases in southern Europe. At this point, it should be noted that the haplotype analysis in CF thus far assumed that only a single mutational event occurred on each defined DNA marker haplotype background. The possibility of other CF mutations in the same haplotype background and the possibility of recurrent mutations in other haplotype backgrounds have not been considered. It should also be noted that the analyses are based on closely linked markers whose precise distance to CF is not entirely certain. Thus, the CF haplotype analysis conducted so far is in distinct contrast to those for other genetic disorders.