Polymorphism of the h allele and the population frequency of sporadic nonfunctional alleles.

BACKGROUND: Current polymerase chain reaction-based strategies for phenotype prediction often fail when sporadic nonfunctional alleles are encountered. The population frequency of such mutations was not known for any gene under low selection pressure and may be best examined in blood groups systems lacking prevalent nonfunctional alleles. The frequency of the very rare Bombay blood group (Oh, genotype hh sese) was recently determined in a systematic survey of more than 600,000 white individuals. STUDY DESIGN AND METHODS: With this survey used in conjunction with additional blood samples, the population frequency of nonfunctional alleles of the gene encoding the alpha (1,2)fucosyltransferase (H or FUT1) was determined.
RESULTS: Seven different h alleles were found in five unrelated individuals, three of whom were homozygous for unique alleles. There was no prevalent h allele. Five missense and one frameshift mutations were observed, that were the presumptive causes of the null phenotype; the coding sequence of one h allele was identical to the H sequence. The average inbreeding factor alpha was 0.00116. The frequency of nonfunctional alleles at the H gene locus was calculated as 1 in 347 in a large white population (95% CI: 1:185-1:824).
CONCLUSION: The Bombay blood group phenotype in white is due to diverse, sporadic, nonfunctional alleles without any prevalent allele. Assuming similar rates of nonfunctional alleles in glycosyltransferase genes like ABO, current genotyping strategies may fail as often as once in about 300 individuals of blood group O. Sporadic neutral alleles may also pose a serious obstacle for population-wide screening of many disease-associated genes.