Microsatellite haplotypes for cystic fibrosis

Mutation frameworks and evolutionary tracers

Nuria Morral, Virginia Nunes, Teresa Casals, Miguel Chillón, Javier Giménez, Jaume Bertranpetit, Xavier Estivill

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Highly informative intragenic microsatellite markers within the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene allow the analysis of associations between specific mutations and haplotypes. We have analysed 440 Spanish CF families carrying 22 different CF mutations and have established haplotypes in 1,036 chromosomes for microsatellites IVS8CA, IVS17BTA and IVS17BCA. No new alleles were detected at the three CFTR microsatellites, in more than 3,000 meiosis analysed (estimated mutation rate of less than 3.3 × 10-4). The evolution of 16 haplotypes associated with the most common CF mutation, ΔF508, and the low mutation rate at these microsatellite loci suggest that ΔF508 originated within the 23-31-13 haplotype at least 53,000 years ago, very early in the history of the European population. The number of haplotype changes seen for two other common mutations, G542X (haplotype 23-33-13) and N1303K (23-31-13), suggests that they originated at least 35,000 years ago. Microsatellite allele variability associated with ΔF508, G542X and N1303K demonstrates that slippage and mispairing is the main mechanism generating microsatellite alleles. In spite of the haplotype variability detected for these 3 common mutations, the association between haplotype and mutations is very strong. Mutations 1609delCA, 3667del4, ΔI507 and G551D are all associated with haplotype 16-7-17, which has a frequency of 14.5% in normal chromosomes. 5 haplotypes bearing specific CF mutations were not found in normal chromosomes. Haplotype 16-46-13 is strongly associated with CF mutations E92K and 3601-111G→C. About 23% of CF chromosomes with unknown mutations show significant linkage disequilibrium for microsatellite haplotypes. The strong association between haplotypes and mutations allows the development of frameworks of practical use in diagnosis and in the identification of as yet unknown mutations.

Original languageEnglish (US)
Pages (from-to)1015-1022
Number of pages8
JournalHuman Molecular Genetics
Volume2
Issue number7
StatePublished - Jul 1993
Externally publishedYes

Fingerprint

Microsatellites
Fibrosis
Haplotype
Chromosomes
Cystic Fibrosis
Microsatellite Repeats
Haplotypes
Mutation
Bearings (structural)
Chromosome
Genes
Alleles
Mutation Rate
Conductance
Framework
Cystic fibrosis
Evolutionary
Regulator
Cystic Fibrosis Transmembrane Conductance Regulator
Linkage Disequilibrium

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Molecular Biology
  • Genetics(clinical)

Cite this

Morral, N., Nunes, V., Casals, T., Chillón, M., Giménez, J., Bertranpetit, J., & Estivill, X. (1993). Microsatellite haplotypes for cystic fibrosis: Mutation frameworks and evolutionary tracers. Human Molecular Genetics, 2(7), 1015-1022.

Microsatellite haplotypes for cystic fibrosis : Mutation frameworks and evolutionary tracers. / Morral, Nuria; Nunes, Virginia; Casals, Teresa; Chillón, Miguel; Giménez, Javier; Bertranpetit, Jaume; Estivill, Xavier.

In: Human Molecular Genetics, Vol. 2, No. 7, 07.1993, p. 1015-1022.

Research output: Contribution to journalArticle

Morral, N, Nunes, V, Casals, T, Chillón, M, Giménez, J, Bertranpetit, J & Estivill, X 1993, 'Microsatellite haplotypes for cystic fibrosis: Mutation frameworks and evolutionary tracers', Human Molecular Genetics, vol. 2, no. 7, pp. 1015-1022.
Morral N, Nunes V, Casals T, Chillón M, Giménez J, Bertranpetit J et al. Microsatellite haplotypes for cystic fibrosis: Mutation frameworks and evolutionary tracers. Human Molecular Genetics. 1993 Jul;2(7):1015-1022.
Morral, Nuria ; Nunes, Virginia ; Casals, Teresa ; Chillón, Miguel ; Giménez, Javier ; Bertranpetit, Jaume ; Estivill, Xavier. / Microsatellite haplotypes for cystic fibrosis : Mutation frameworks and evolutionary tracers. In: Human Molecular Genetics. 1993 ; Vol. 2, No. 7. pp. 1015-1022.
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