Worldwide genetic analysis of the CFTR region

Mutations at the cystic fibrosis transmembrane conductance regulator gene ( CFTR) cause cystic fibrosis, the most prevalent severe genetic disorder in individuals of European descent. We have analyzed normal allele and haploty pe variation at four short tandem repeat polymorphisms (STRPs) and two sing le-nucleotide polymorphisms (SNPs) in CFTR in 18 worldwide population sampl es, comprising a total of 1,944 chromosomes. The rooted phylogeny of the SN P haplotypes was established by typing ape samples. STRP variation within S NP haplotype backgrounds was highest in most ancestral haplotypes-although, when STRP allele sizes were taken into account, differences among haplotyp es became smaller. Haplotype background determines STRP diversity to a grea ter extent than populations do, which indicates that haplotype backgrounds are older than populations. Heterogeneity among STRPs can be understood as the outcome of differences in mutation rate and pattern. STRP sites had hig her heterozygosities in Africans, although, when whole haplotypes were cons idered, no significant differences remained. Linkage disequilibrium (LD) sh ows a complex pattern not easily related to physical distance. The analysis of the fraction of possible different haplotypes not found may circumvent some of the methodological difficulties of LD measure. LD analysis showed a positive correlation with locus polymorphism, which could partly explain t he unusual pattern of similar LD between Africans and non-Africans. The low values found in non-Africans may imply that the size of the modern human p opulation that emerged "Out of Africa" may be larger than what previous LD studies suggested.