Summary
A total of 75 non-ΔF508 chromosomes from 59 German cystic fibrosis patients was screened for mutations in exon 11 of the cystic fibrosis (CFTR) gene. These Caucasian patients were found to possess an identical haplotype background for two common mutations (G551D, R553X) constistent with their being identical by descent. However, a different R553X associated haplotype found in American black patients was suggestive of recurrent mutation, a postulate supported by the location of the R553X alteration in a hypermutable CpG dinucleotide. Likelihood estimates for recurrent mutation and identity by descent were compared and strongly supported the hypothesis of recurrent R553X mutation. The ability to distinguish between these two alternatives provides an indication of whether or not the search for mutations should be restricted to chromosomes with similar haplotypes.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bal J, Stuhrmann M, Schloesser M, Schmidtke J, Reiss J (in press) A cystic fibrosis patient homozygous for the nonsense mutation R553X. J Med Genet
Bartels I, Grzeschik K-H, Cooper DN, Schmidtke J (1986) Regional mapping of six cloned DNA sequences on human chromosome 7. Am J Hum Genet 38:280–287
Bodmer WF, Cavalli-Sforza LL (1976) Genetics, evolution, and man. Freeman, San Francisco
Boat TF, Welsh MJ, Beaudet AL (1989) Cystic fibrosis. In: Scriver CL, Beaudet AL, Sly WS, Valle D (eds) Metabolic basis of inherited disease. McGraw Hill, New York, pp 2649–2680
Cooper DN, Clayton JF (1988) DNA polymorphism and the study of disease associations. Hum Genet 78:299–312
Cooper DN, Krawczak M (1989) Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum Genet 83:181–188
Cooper DN, Krawczak M (1990) The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 85:55–74
Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155
Cutting GR, Antonorakis SE, Buetow KH, Kasch LM, Rosenstein BJ, Kazazian HH Jr (1989) Analysis of DNA polymorphism haplotypes linked to the cystic fibrosis locus in North American black and Caucasian families supports the existence of multiple mutations of the cystic fibrosis gene. Am J Hum Genet 44:307–318
Cutting GR, Kasch LM, Rosenstein BJ, Zielenski J, Tsui LC, Antonarakis SE, Kazazian HH Jr (1990) A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature 346:366–369
Cystic Fibrosis Genetic Analysis Consortium (1990) Worldwide survey of the ΔF508 mutation — report from the Cystic Fibrosis Genetic Analysis Consortium. Am J Hum Genet: 354–359
Drumm ML, Pope HA, Cliff WH, Rommens JM, Marvin SA, Tsui LC, Collins FS, Frizell RA, Wilson JM (1990) Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell 62:1227–1233
European Working Group on CF Genetics (1990) Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. Hum Genet 85:436–445
Estivill X, Farrall M, Scambler PFJ, Bell G, Hawley KMF, Lench N, Bates GP, Kreyer HL, Frederick PA, Stanier P, Watson EK, Williamson R, Wainwright BJ (1987) A candidate for the cystic fibrosis locus is isolated by selection for methylation freeislands. Nature 326:840–845
Estivill X, Gasparini P, Novelli G, Casals T, Nunes V, Gallano P, Savoia A, Ruzzo A, Dallapiccola B (1989) Linkage disequilibrium for DNA haplotypes near the cystic fibrosis locus in two South European populations. Hum Genet 83:175–178
Feldman GL, Williamson R, Beaudet AL, O'Brien WE (1988) Prenatal diagnosis of cystic fibrosis by DNA amplification for detection of KM-19 polymorphism. Lancet II:102
Huth A, Estivill X, Grade K, Billwitz H, Speer A, Rosenthal A, Williamson R, Ramsay M, Coutelle C (1989) Polymerase chain reaction for detection of the pMP6d-9/MspI RFLP, a marker closely linked to the cystic fibrosis mutation. Nucleic Acids Res 17:7118
Kasai K, Nakamura Y, White R (1990) Amplification of a variable number of tandem repeats (VNTR) locus (pMCT118) by the polymerase chain reaction (PCR) and its application to forensic science. J Forensic Sci 35:1196–1200
Kerem BS, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080
Kogan SC, Doherty M, Gitschier J (1987) An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A. N Engl J Med 317:985–990
Krawczak M, Konecki DS, Schmidtke J, Dück M, Engel W, Nützenadel W, Trefz FK (1988) Allelic association of the cystic fibrosis locus and two DNA markers, XV2c and KM19, in 55 German families. Hum Genet 80:78–80
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Northrup H, Rosenbloom C, O'Brien WE, Beaudet AL (1989) Additional polymorphism for D7S8 linked to cystic fibrosis including detection by DNA amplification. Nucleic Acids Res 17:1784
Pattinson JK, Millar DS, Grundy CB, Wieland K, Mibashan RS, Martinowitz U, McVey J, Tan-Un K, Vidaud M, Goossens M, Sampietro M, Mannucci PM, Krawczak M, Reiss J, Zoll B, Whitmore D, Bradshaw A, Wensley R, Ajani A, Mitchell V, Rizza C, Maia R, Winter P, Mayne EE, Kakkar VV, Tuddenham EGD, Cooper DN (1990) The molecular genetic analysis of haemophilia A; a directed-search strategy for the detection of point mutations in the human factor VIII gene. Blood 76:2242–2248
Poustka AM, Lehrach H, Williamson R, Bates G (1988) A long-range restriction map encompassing the cystic fibrosis locus and its closely linked genetic markers. Genomics 2:337–345
Reis A, Bremer S, Schlösser M, Dück M, Böhm I, Hundrieser J, Macek M, Stuhrmann M, Wagner M, Posselt HG, Wahn U, Reiss J, Trefz F, Tümmler B, Krawczak M, Schmidtke J (1990) Distribution patterns of the deltaF508 mutation in the CFTR gene on CF-linked marker haplotypes in the German population. Hum Genet 85:421–422
Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh M (1990) Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 347:358–363
Riordan JR, Rommens JM, Kerem BS, Alon N, Rozmahel R, Grzelezak Z, Zielenski J, Lok S, Plavsic N, Chou JC, Drumm MC, Iannuzzi MC, Collins FL, Tsui LC (1989) Identification of the cystic fibrosis gene: cloning and characterisation of complementary DNA. Science 245:1066–1073
Rommens JM, Iannuzzi MC, Kerem BS, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JC, Kennedy D, Hideka N, Zsiga M, Buchwald M, Riordan JR, Tsui LC, Collins FS (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245:1059–1065
Rosenbloom CL, Kerem BS, Rommens JM, Tsui LC, Wainwright B, Williamson R, O'Brien WE, Beaudet AL (1989) DNA amplification for detection of the XV-2c polymorphism linked to cystic fibrosis. Nucleic Acids Res 17:7117
Wagner M, Schlösser M, Reiss J (1990) Direct gene diagnosis of cystic fibrosis by allele-specific polymerase chain reactions. Mol Biol Med 7:359–364
Zielenski J, Rozmahel R, Bozon D, Kerem BS, Grzelczak Z, Riordan JR, Rommens J, Tsui LC (1991) Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics 10:214–228
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Reiss, J., Cooper, D.N., Bal, J. et al. Discrimination between recurrent mutation and identity by descent: application to point mutations in exon 11 of the cystic fibrosis (CFTR) gene. Hum Genet 87, 457–461 (1991). https://doi.org/10.1007/BF00197168
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00197168