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Microsatellite haplotypes for cystic fibrosis: mutation frameworks and evolutionary tracers
1Departament de Genètica Molecular, Hospital Duran i Reynals, Barcelona, Catalunya, Spain.
Human Molecular Genetics
|July 1, 1993
Summary
This study analyzed cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Spanish families, revealing that common mutations like delta F508 originated tens of thousands of years ago in early European populations.
Area of Science:
- Genetics
- Molecular Biology
- Population Genetics
Background:
- The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene is crucial for understanding CF pathogenesis.
- Microsatellite markers within the CFTR gene provide insights into mutation origins and population history.
Purpose of the Study:
- To analyze associations between CFTR gene mutations and specific microsatellite haplotypes in Spanish CF families.
- To estimate the origin and evolutionary history of common CFTR mutations.
Main Methods:
- Analysis of 440 Spanish CF families with 22 different CF mutations.
- Haplotype analysis of 1,036 chromosomes using microsatellites IVS8CA, IVS17BTA, and IVS17BCA.
- Estimation of mutation rates and origins based on haplotype data.
Main Results:
- No new alleles were detected at CFTR microsatellites, with a mutation rate < 3.3 x 10(-4).
- The delta F508 mutation likely originated within the 23-31-13 haplotype at least 53,000 years ago.
- Other common mutations (G542X, N1303K) also show ancient origins (≥35,000 years ago).
- Strong associations were observed between specific mutations and haplotypes, with some mutation-bearing haplotypes absent in normal chromosomes.
Conclusions:
- Common CFTR mutations have ancient origins in European populations, predating the modern era.
- Microsatellite slippage and mispairing are key mechanisms for microsatellite allele generation.
- Specific CFTR mutation-haplotype associations are robust, aiding in genetic analysis and understanding CF evolution.