Human Genetics

, Volume 122, Issue 6, pp 583–588 | Cite as

CFTR mutations and reproductive outcomes in a population isolate

Original Investigation


Multiple hypotheses have been proposed to explain the high incidence of cystic fibrosis in Caucasian populations. Most rely on a fitness advantage to carriers of CF mutations, either through increased resistance to infectious disease, such as cholera, or through increased fertility. In this study we tested the latter hypothesis in the Hutterites of South Dakota, a genetic isolate with a relatively high CF carrier frequency. Following a population-wide screen for the only two mutations present in the Hutterites (M1101K, ΔF508), we tested for associations between carrier status and measures of fertility. There was no evidence of nonrandom transmission of mutations (P = 0.409) or skewed sex ratios (P = 0.847) in children of carrier parents. Moreover, carrier status was not associated with overall fertility (P = 0.597 for carrier fathers and 0.694 for carrier mothers). Although carrier males’ sibship sizes were larger than carrier females’ sibship sizes (P = 0.049), this was not significant after accounting for multiple testing. Overall, our results suggest that if there is a fertility advantage among CF carriers, it is too small to be detected in our sample (85 carriers out of ∼950 screened), or the effects are confined to ΔF508 carriers, for which there are too few in our sample to test this specific hypothesis.



We thank Sean Boyle and Henry Ehrlich at Roche Molecular Systems (Alameda, CA, USA) for providing genotyping arrays, Gülüm Kosova for calculating heritabilities for the fertility traits used in this study, and Dan Nicolae, Lin Pan, and Mark Abney for statistical consultation and helpful discussions. This project was supported in part by NIH grants HD21244, HL56399, and HL66533 to C.O. and M01 RR00055 to the University of Chicago Clinical Research Center.


  1. Abney M, McPeek MS, Ober C (2000) Estimation of variance components of quantitative traits in inbred populations. Am J Hum Genet 66:629–650PubMedCrossRefGoogle Scholar
  2. Bourgain C, Abney M, Schneider D, Ober C, McPeek MS (2004) Testing for Hardy–Weinberg equilibrium in samples with related individuals. Genetics 168:2349–2361PubMedCrossRefGoogle Scholar
  3. Chen X, Levine L, Kwok PY (1999) Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 9:492–498PubMedGoogle Scholar
  4. Cystic Fibrosis Genetic Analysis Consortium (1994) Population variation of common cystic fibrosis mutations. Human Mutation 4:167–177Google Scholar
  5. Cystic Fibrosis Genetic Analysis Consortium (2006) Cystic Fibrosis Mutation Database, vol 2006.
  6. Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ (1992) Processing of mutant cystic-fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358:761–764PubMedCrossRefGoogle Scholar
  7. Eaton JW, Mayer AJ (1953) The social biology of very high fertility among the Hutterites; the demography of a unique population. Hum Biol 25:206–264PubMedGoogle Scholar
  8. Gedschold J, Szibor R, Kropf S, Berger M (1988) Different numbers of maternal and paternal siblings of cystic-fibrosis patients. Hum Genet 80:399–400PubMedCrossRefGoogle Scholar
  9. Gregory RJ, Cheng SH, Rich DP, Marshall J, Paul S, Hehir K, Ostedgaard L, Klinger KW, Welsh MJ, Smith AE (1990) Expression and characterization of the cystic-fibrosis transmembrane conductance regulator. Nature 347:382–386PubMedCrossRefGoogle Scholar
  10. Hostetler JA (1974) Hutterite society. Johns Hopkins University Press, BaltimoreGoogle Scholar
  11. Hostetler JA (1985) History and relevance of the Hutterite population for genetic studies. Am J Med Genet 22:453–462PubMedCrossRefGoogle Scholar
  12. Jorde LB, Lathrop GM (1988) A test of the heterozygote-advantage hypothesis in cystic-fibrosis carriers. Am J Hum Genet 42:808–815PubMedGoogle Scholar
  13. Kitzis A, Chomel JC, Kaplan JC, Giraud G, Labbe A, Dastugue B, Dumur V, Farriaux JP, Roussel P, Williamson R, Feingold J (1988) Unusual segregation of cystic-fibrosis allele to males. Nature 333:215PubMedCrossRefGoogle Scholar
  14. Maruyama T, Nei M (1981) Genetic variability maintained by mutation and overdominant selection in finite populations. Genetics 98:441–459PubMedGoogle Scholar
  15. Ober CL, Martin AO, Simpson JL, Hauck WW, Amos DB, Kostyu DD, Fotino M, Allen FH Jr (1983) Shared HLA antigens and reproductive performance among Hutterites. Am J Hum Genet 35:994–1004PubMedGoogle Scholar
  16. Ober C, Bombard A, Dhaliwal R, Elias S, Fagan J, Laffler TG, Martin AO, Rosinsky B (1987) Studies of cystic-fibrosis in Hutterite families by using linked DNA probes. Am J Hum Genet 41:1145–1151PubMedGoogle Scholar
  17. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S (1997) HLA and mate choice in humans. Am J Hum Genet 61:497–504PubMedCrossRefGoogle Scholar
  18. Ober C, Hyslop T, Elias S, Weitkamp LR, Hauck WW (1998) Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study. Hum Reprod 13:33–38PubMedCrossRefGoogle Scholar
  19. Ober C, Hyslop T, Hauck WW (1999) Inbreeding effects on fertility in humans: evidence for reproductive compensation. Am J Hum Genet 64:225–231PubMedCrossRefGoogle Scholar
  20. Ober C, Tsalenko A, Parry R, Cox NJ (2000) A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet 67:1154–1162PubMedCrossRefGoogle Scholar
  21. Ober C, Abney M, McPeek MS (2001) The genetic dissection of complex traits in a founder population. Am J Hum Genet 69:1068–1079PubMedCrossRefGoogle Scholar
  22. Ober C, Aldrich CL, Chervoneva I, Billstrand C, Rahimov F, Gray HL, Hyslop T (2003) Variation in the HLA-G promoter region influences miscarriage rates. Am J Hum Genet 72:1425–1435PubMedCrossRefGoogle Scholar
  23. O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266PubMedCrossRefGoogle Scholar
  24. Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn SS, Banting G, Ratcliff R, Evans MJ, Colledge WH (1998) Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393:79–82PubMedCrossRefGoogle Scholar
  25. Pluzhnikov A, Nolan DK, Tan Z, McPeek MS, Ober C (2007) Correlation of intergenerational family sizes suggests a genetic component of reproductive fitness. Am J Hum Genet 81:165–169PubMedCrossRefGoogle Scholar
  26. Pritchard DJ (1991) Cystic-fibrosis allele frequency, sex-ratio anomalies and fertility—a new theory for the dissemination of mutant alleles. Hum Genet 87:671–676PubMedCrossRefGoogle Scholar
  27. Quinton PM (1983) Chloride impermeability in cystic-fibrosis. Nature 301:421–422PubMedCrossRefGoogle Scholar
  28. Sheps MC (1965) An analysis of reproductive patterns in an American isolate. Popul Stud 19:65–80CrossRefGoogle Scholar
  29. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516PubMedGoogle Scholar
  30. Stuhrmann M, Dork T, Fruhwirth M, Golla A, Skawran B, Antonin W, Ebhardt M, Loos A, Ellemunter H, Schmidtke J (1997) Detection of 100% of the CFTR mutations in 63 CF families from Tyrol. Clin Genet 52:240–246PubMedCrossRefGoogle Scholar
  31. Tenkate LP, Temeerman GJ, Buys CHCM, Halley DJJ, Oostra B (1988) Cystic-fibrosis allele segregation. Nature 334:20CrossRefGoogle Scholar
  32. Tummler B, Aschendorf A, Darnedde T, Hundrieser J (1988) Segregation of cystic-fibrosis allele. Nature 334:110PubMedCrossRefGoogle Scholar
  33. van de Vosse E, Ali S, de Visser AW, Surjadi C, Widjaja S, Vollaard AM, van Dissel JT (2005) Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR). Hum Genet 118:138–140PubMedCrossRefGoogle Scholar
  34. Wang X, Myers A, Saiki RK, Cutting GR (2002) Development and evaluation of a PCR-based, line probe assay for the detection of 58 alleles in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clin Chem 48:1121–1123PubMedGoogle Scholar
  35. Weiss LA, Abney M, Cook EH Jr, Ober C (2005) Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet 76:33–41PubMedCrossRefGoogle Scholar
  36. Welsh MJ, Ramsey BW, Accurso F, Cutting GR (2001) Cystic fibrosis. In: Scriver CL, Beaudet AL, Valle D, Sly WS (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 5121–5188Google Scholar
  37. Wright SW, Morton NE (1968) Genetic studies on cystic fibrosis in Hawaii. Am J Hum Genet 20:157–169PubMedGoogle Scholar
  38. Zielenski J, Tsui LC (1995) Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 29:777–807PubMedCrossRefGoogle Scholar
  39. 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 10:214–228PubMedCrossRefGoogle Scholar
  40. Zielenski J, Fujiwara TM, Markiewicz D, Paradis AJ, Anacleto AI, Richards B, Schwartz RH, Klinger KW, Tsui LC, Morgan K (1993) Identification of the M1101k mutation in the cystic-fibrosis transmembrane conductance regulator (Cftr) gene and complete detection of cystic-fibrosis mutations in the Hutterite population. Am J Hum Genet 52:609–615PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Department of Human GeneticsThe University of ChicagoChicagoUSA
  2. 2.Department of GeneticsUniversity of CambridgeCambridgeUK

Personalised recommendations