title: A dimorphic 4-bp repeat in the cystic fibrosis gene is in absolute linkage disequilibrium with the delta F508 mutation: implications for prenatal diagnosis and mutation origin.
abstract: The gene causing cystic fibrosis (CF) has been recently cloned, and the major mutation (delta F508) accounting for approximately 70% of CF chromosomes has been uncovered. We have identified at the 3' end of intron 6 in the CF gene a 4-bp tandem repeat (GATT) that exhibits interesting features. First, PCR screening of 103 normal individuals revealed that the repeat exists only in two polymorphic allelic forms, either as a hexamer or a heptamer. These two alleles are in Hardy-Weinberg equilibrium and predict a heterozygote frequency of 41% (p[seven repeats] = .71; q [six repeats] = .29). Second, the allele with six repeats was found linked to delta F508 on all 76 CF chromosomes investigated, demonstrating strong linkage disequilibrium and suggesting that delta F508 had originated on the gene bearing six repeats. Third, when the repeat alleles are linked to the DNA markers XV2c and KM19, extended haplotypes are generated. These new haplotypes become informative in situations in which prenatal diagnosis cannot be performed solely with XV2c and KM19. Since this repeat marker is located in the CF gene and would be very less likely to recombine with the gene, it can serve as a valuable DNA marker for haplotype analysis. A possible crossover, however, was identified between XV2c and KM19, transferring delta F508 to a different haplotype.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco 94143-0134.
authors.forename: F F
authors.initials: FF
authors.lastname: Chehab
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: E
authors.initials: E
authors.lastname: Louie
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: E
authors.initials: E
authors.lastname: Kawasaki
authors.forename: H
authors.initials: H
authors.lastname: Erlich
mesh_terms: D000483:Alleles; D001483:Base Sequence; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D005784:Gene Amplification; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D009154:Mutation; D011296:Prenatal Diagnosis; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D005819:Genetic Markers