Can a place of origin of the main cystic fibrosis mutations be identified?

Abstract

The genetic background of the mutations that most often cause cystic fibrosis (CF) is different from that of non-CF chromosomes in populations of European origin. It is not known whether these haplotype backgrounds could be found at high frequencies in populations in which CF is, at present, not common; such populations would be candidates for the place of origin of CF mutations. An analysis of haplotypes of CF transmembrane conductance regulator, together with their variation in specific CF chromosomes, in a worldwide survey of normal chromosomes shows (1) a very low frequency or absence of the most common CF haplotypes in all populations analyzed and (2) a strong genetic variability and divergence, among various populations, of the chromosomes that carry disease-causing mutations. The depth of the gene genealogy associated with disease-causing mutations may be greater than that of the evolutionary process that gave rise to present-day human populations. The concept of "population of origin" lacks either spatial or temporal meaning for mutations that are likely to have been present in Europeans before the ethnogenesis of present populations; subsequent population processes may have erased the traces of their geographic origin.

Figure 1

Polymorphisms in the CFTR region (IVS1CA, IVS6aGATT, IVS8CA, T854, IVS17bTA, and TUB20), and location of the five most common CF mutations (ΔF508, G542X, N1303K, G551D, and W1282X). CFTR exons are numbered 1–24.

Figure 2

Distribution of 17 populations analyzed. Population names (sample sizes [no. of chromosomes]) are as follows: ADY = Adygei (106); BAS = Basques (222); BIA = Biaka Pygmies (138); CAT = Catalans (176); CHI = Han Chinese (124); DRU = Druze (126); FIN = Finns (70); JPN = Japanese (96); KAZ = Kazakhs (80); MAY = Maya (106); MBU = Mbuti Pygmies (78); RUS = Russians (96); SAH = Saharawi (118); SUR = Surui (94); TAN = Tanzanians (80); YAK = Yakut (102); YEM = Yemenites (86). Further information on these population samples can be found in the Allele Frequency Database and in a report by Mateu et al. (2001).

Figure 3

Maximum-likelihood tree of allele frequencies of five loci (IVS6aGATT, IVS8CA, T854, IVS17bTA and TUB20) among normal chromosomes, from worldwide populations, and among CF chromosomes (ΔF508, G542X, N1303K, G551D and W1282X chromosomes). The inset shows an enlarged maximum-likelihood tree of allele frequencies of two loci (IVS8CA and IVS17bTA) among ΔF508 chromosomes in different European populations (Fbas = Basque; Fbri = British; Fbul = Bulgarian; Fcze = Czech; Fden = Danish; Ffin = Finnish; Ffra = French; Fger = German; Fhun = Hungarian; Fire = Irish; Fita = Italian; Fslo = Slovakian; Fspa = Spanish; Fswe = Swedish). Bars show the scale in genetic-distance units. Several trees have been built, using either other methods (e.g., Nei-Kimura distance and the neighbor-joining algorithm) or different sets of chromosomes. In all cases, results are similar.