Summary
The prenatal diagnosis of cystic fibrosis is now routinely performed by using two probes tightly linked to the CF locus (XV2C and KM19). These probes have been shown to exhibit a strong linkage disequilibrium with the CF locus. Our data (103 families) have been pooled with other French data (237 families). They are consistent with the hypothesis of a unique ancestral mutation initially associated with a B (D1E2) restriction fragment length polymorphism (RFLP) haplotype, subsequently reassociated by cross-over with A, C or D haplotypes. Assuming such an hypothesis, the mutation is supposed to be 3000–6000 years old, depending on generation length and the true recombination ratio between the KM19 and CF loci. Up-to-date Spanish, Danish and Greek data are reported together with other previously published population data in order to discuss the geographic origin and age of the mutation in Europe. The action of selection in terms of heterozygote advantage and distorsion of segregation is discussed.
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References
Anderson CM, Allan J, Johansen PG (1967) Comments on the possible existence and nature of a heterozygote advantage in cystic fibrosis. Mod Probl Pediatr 10:381–387
Bartels I, Grzeschik K-H, Cooper DN, Schmidtke J (1986) Regional mapping of six DNA sequences on human chromosome 7. Am J Hum Genet 38:280–287
Beaudet AL, Bowcock A, Buchwald M, Cavalli-Sforza LL, Farrall M, King MC, Klinger K, Lalouel JM, Lathrop G, Naylor S, Ott J, Tsui LC, Wainwright B, Watkins P, White R, Williamson R (1986) Linkage of cystic fibrosis to two tightly linked DNA markers: joint report from a collaborative study. Am J Hum Genet 39:681–693
Beaudet AL, Feldman GL, Fernbach SD, Buffone GJ, O'Brien WE (1989) Linkage disequilibrium, cystic fibrosis, and genetic counselling. Am J Hum Genet 44:319–326
Cavalli-Sforza LL, Bodmer WF (1971) The genetics of human populations. Freeman, San Francisco
Crawfurd MD'A (1972) A genetic study, including evidence for heterosis, of cystic fibrosis of the pancreas. Heredity (Edinburgh) 29:126
Cutting GR, Antonarakis SE, Buetow KM, 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
Danks DM, Allan J, Anderson CM (1965) A genetic study of fibrocystic disease of the pancreas. Ann Hum Genet 28:323–356
Estivill X, Farrall M, Scambler PJ, Bell GM, Hawley KMF, Lench NJ, Bates GP, Kruyer HC, Frederick PA, Stanier P, Watson EK, Williamson R, Wainwright B (1987a) A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. Nature 326:840–845
Estivill X, Scambler PJ, Wainwright BJ, Hawley K, Frederick P, Schwartz M, Baiget M, Kere J, Williamson R, Farral M (1987b) Patterns of polymorphism and linkage disequilibrium for cystic fibrosis. Genomics 1:257–263
Estivill X, Farrall M, Williamson R, Ferrari M, Seia M, Giunta AM, Novelli G, Potenza L, Dallapicolla B, Borgo G, Gasparini P, Pignati PF, De Benedetti L, Vitale E, Devoto M, Romeo G (1988) Linkage disequilibrium between cystic fibrosis and linked DNA polymorphisms in Italian families: a collaborative study. Am J Hum Genet 43:23–28
Farrall M, Watson E, Bates G, Bell G, Bell J, Davies KA, Estivill X, Kruyer H, Law HY, Lench N, Lissens W, Simon P, Scambler P, Stanier P, Vassart G, Worrall C, Williamson R, Wainwright BJ (1986) Further data supporting linkage between cystic fibrosis and the met oncogene and haplotype analysis with met and pJ3. 11. Am J Hum Genet 39:713–719
Farrall M, Wainwright BJ, Feldman GL, Beaudet A, Sretenovic Z, Halley D, Simon M, Dickerman L, Devoto M, Romeo G, Kaplan JC, Kitzis A, Williamson R (1988) Recombinations between IRP and cystic fibrosis. Am J Hum Genet 43:471–475
Gedschold J, Kropf S, Szibor R, Berger M (1987) Cystic fibrosis — a single locus disease? Results of the population genetics study. Hum Genet 75:277–280
Gilbert F, Falk C, Li Z, Faulkner L, Seiler S (1988) Cystic fibrosis: disequilibrium and implications for counseling. Am J Hum Genet 43:A84–0334
Jorde LB, Lathrop GM (1988) A test of the heterozygote advantage hypothesis in cystic fibrosis. Am J Hum Genet 42:808–815
Kerem B, Rommens JM, Buchanan JA, Marchiewicz D, Cox TK, Chakravarty A, Buchwald M, Tsui L-C (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080
Knudson AG, Wayne I, Hallett Y (1967) On the selective advantage of cystic fibrosis heterozygotes. Am J Hum Genet 19:388–392
Krawczak M, Konecki DS, Schmidtke J, Dück M, Engel W, Nützenadel W, Trefz FK (1988) Allelic association of the cystic fibrosis locus DNA markers, XV2C and KM19, in 55 German families. Hum Genet 80:78–80
Lathrop GM, Farrall M, O'Connell P, Wainwright P, Leppert M, Nakamura Y, Lench N, Kruyer H, Dean M, Park M, Vande Voude G, Lalouel JM, Williamson R, White R (1988) Refined linkage map of chromosome 7 in the region of the cystic fibrosis gene. Am J Hum Genet 42:38–44
Meindl RS (1987) Hypothesis: a selective advantage for cystic fibrosis heterozygotes. Am J Phys Anthropol 74:39–45
Mornet E, Simon-Bouy B, Serre JL, Estivill X, Farrall M, Williamson R, Boué J, Boué A (1988) Genetic differences between cystic fibrosis with and without meconium ileus. Lancet I:376–378
Mornet E, Simon-Bouy B, Serre JL, Muller F, Taillandier A, Fernandez M, Boué J, Boué A (1989) Genetic heterogeneity between two clinical forms of cystic fibrosis evidenced by familial analysis and linked DNA probes. Clin Genet 35:81–87
Riordan JR, Rommens JM, Kerem B, Alon N, Rozmael R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi MC, Collins FS, Tsui L-C (1989) Identification of the cystic fibrosis gene: cloning and characterisation of complementary DNA. Science 245:1066–1073
Robertson MT (1989) Prolactin, human nutrition and evolution, and the relation to cystic fibrosis. Med Hypotheses 29:87–99
Schaap T, Cohen MM (1976) A proposed model for the inheritance of cystic fibrosis. In: Mangos JA, Talamo C (eds) Cystic fibrosis: projections into the future. Stratton Intercontinental, New York, pp 291–303
Schmidtke J, Krawczak M, Schwartz M, Alkan M, Bonduelle M, Bühler E, Chenke M, Darnedde T, Domagk J, Engel W, Frey D, Fryburg K, Halley D, Hundrieser J, Ladanyi L, Libaers I, Lissens W, Mächler M, Malik NJ, Morreau J, Neubauer V, Oostra B, Pape B, Poncin JE, Schinzel A, Simon P, Trefz FK, Tümmler B, Vassart G, Voss R (1987) Linkage relationships and allelic associations of the cystic fibrosis locus and four marker loci. Hum Genet 76:337–343
Vidaud M, Kitzis A, Ferec C, Bozon D, Dumur V, Giraud G, David F, Pascal O, Auvinet M, Morel Y, Andre J, Chomel JC, Saleun JP, Farriaux JP, Roussel P, Labbe A, Dastugue B, Lucotte G, Monnier N, Foucaud P, Goossens M, Feingold J, Kaplan JC (1989) Confirmation of linkage disequilibrium between haplotype B(XV-2c,allele 1; KM19,allele 2) and cystic fibrosis allele in the French population. Hum Genet 81:183–184
Weber J, Aulehla-Scholz C, Kaiser R, Eigel A, Neugebauer M, Horst J, Olek K (1989) Cystic fibrosis: typing 89 German families with linked DNA probes. Hum Genet 81:54–56
White R, Leppert M, O'Connell P, Nakamura Y, Woodward S, Hoff M, Herbst J, Dean M, Vande Voude G, Lathrop GM, Lalouel JM (1986) Further data on cystic fibrosis: the Utah study. Am J Hum Genet 39:694–698
Wright SW, Morton NE (1968) Genetic studies on cystic fibrosis in Hawaï. Am J Hum Genet 20:157–169
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Serre, J.L., Simon-Bouy, B., Mornet, E. et al. Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics. Hum Genet 84, 449–454 (1990). https://doi.org/10.1007/BF00195818
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DOI: https://doi.org/10.1007/BF00195818