Abstract
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.
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References
Abney M, McPeek MS, Ober C (2000) Estimation of variance components of quantitative traits in inbred populations. Am J Hum Genet 66:629–650
Bourgain C, Abney M, Schneider D, Ober C, McPeek MS (2004) Testing for Hardy–Weinberg equilibrium in samples with related individuals. Genetics 168:2349–2361
Chen X, Levine L, Kwok PY (1999) Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 9:492–498
Cystic Fibrosis Genetic Analysis Consortium (1994) Population variation of common cystic fibrosis mutations. Human Mutation 4:167–177
Cystic Fibrosis Genetic Analysis Consortium (2006) Cystic Fibrosis Mutation Database, vol 2006. http://www.genet.sickkids.on.ca/cftr/app
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 358:761–764
Eaton JW, Mayer AJ (1953) The social biology of very high fertility among the Hutterites; the demography of a unique population. Hum Biol 25:206–264
Gedschold J, Szibor R, Kropf S, Berger M (1988) Different numbers of maternal and paternal siblings of cystic-fibrosis patients. Hum Genet 80:399–400
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 347:382–386
Hostetler JA (1974) Hutterite society. Johns Hopkins University Press, Baltimore
Hostetler JA (1985) History and relevance of the Hutterite population for genetic studies. Am J Med Genet 22:453–462
Jorde LB, Lathrop GM (1988) A test of the heterozygote-advantage hypothesis in cystic-fibrosis carriers. Am J Hum Genet 42:808–815
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 333:215
Maruyama T, Nei M (1981) Genetic variability maintained by mutation and overdominant selection in finite populations. Genetics 98:441–459
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 35:994–1004
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 41:1145–1151
Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S (1997) HLA and mate choice in humans. Am J Hum Genet 61:497–504
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 13:33–38
Ober C, Hyslop T, Hauck WW (1999) Inbreeding effects on fertility in humans: evidence for reproductive compensation. Am J Hum Genet 64:225–231
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 67:1154–1162
Ober C, Abney M, McPeek MS (2001) The genetic dissection of complex traits in a founder population. Am J Hum Genet 69:1068–1079
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 72:1425–1435
O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266
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 393:79–82
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 81:165–169
Pritchard DJ (1991) Cystic-fibrosis allele frequency, sex-ratio anomalies and fertility—a new theory for the dissemination of mutant alleles. Hum Genet 87:671–676
Quinton PM (1983) Chloride impermeability in cystic-fibrosis. Nature 301:421–422
Sheps MC (1965) An analysis of reproductive patterns in an American isolate. Popul Stud 19:65–80
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 52:506–516
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 52:240–246
Tenkate LP, Temeerman GJ, Buys CHCM, Halley DJJ, Oostra B (1988) Cystic-fibrosis allele segregation. Nature 334:20
Tummler B, Aschendorf A, Darnedde T, Hundrieser J (1988) Segregation of cystic-fibrosis allele. Nature 334:110
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 118:138–140
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 48:1121–1123
Weiss LA, Abney M, Cook EH Jr, Ober C (2005) Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet 76:33–41
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 5121–5188
Wright SW, Morton NE (1968) Genetic studies on cystic fibrosis in Hawaii. Am J Hum Genet 20:157–169
Zielenski J, Tsui LC (1995) Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 29:777–807
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
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 52:609–615
Acknowledgments
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.
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Gallego Romero, I., Ober, C. CFTR mutations and reproductive outcomes in a population isolate. Hum Genet 122, 583–588 (2008). https://doi.org/10.1007/s00439-007-0432-1
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DOI: https://doi.org/10.1007/s00439-007-0432-1