ABCMdb

PMID: 9012419

Slatkin M, Rannala B
Estimating the age of alleles by use of intraallelic variability.
Am J Hum Genet. 1997 Feb;60(2):447-58., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Gly542* The method is applied to two alleles at the cystic fibrosis (CFTR) locus, AF508 and G542X, for which intraallelic variability at three intronic microsatellite loci has been examined. Login to comment 6 ABCC7 p.Gly542* Our results indicate that G542X is somewhat older than AF508. Although absolute estimates depend on the mutation rates at the microsatellite loci, our results support the hypothesis that AF508 arose <500 generations (- 10,000 years) ago. Login to comment 46 ABCC7 p.Gly542* Finally, we apply this method to estimate the ages of two alleles of the cystic fibrosis (CF) locus, AF508 and G542X. Login to comment 79 ABCC7 p.Gly542* Figure 2c shows 1 as a function of t1 with parameters appropriate for a second allele of cystic fibrosis, G542X. Login to comment 80 ABCC7 p.Gly542* Figure 2c shows 1 as a function of t1 with parameters appropriate for a second allele of cystic fibrosis, G542X. Login to comment 83 ABCC7 p.Gly542* Solely on the basis of on the observed frequencies of the two alleles, AF508 then appears to be somewhat older than G542X. Login to comment 84 ABCC7 p.Gly542* ABCC7 p.Gly542* The estimated population frequency of AF508 is higher than that of G542X, and this conclusion agrees with the general view that more frequent alleles are likely to be older. Login to comment 85 ABCC7 p.Gly542* The estimated population frequency of AF508 is higher than that of G542X, and this conclusion agrees with the general view that more frequent alleles are likely to be older. Login to comment 91 ABCC7 p.Gly542* With mutation rate g, the number of segregating sites within the allelic class, S is a Poisson distributed random variable with mean pT, where T is the total length of the intraallelic gene genealogy (see, -8 -8.25 -8.5 -8.75 _9 -9.25 -9.5 -9.75 a 2000 2200 2400 2600 2800 3000 -5 -5.25 -5.5 -5.75 e -6 -6.25 -6.5 -6.75 1200 1400 1600 1800 2000 tl 350 400 450 500 550 600 650 tl Figure 2 Log-likelihood (1) of the observed number of copies of the AF508 and G542X mutations of the CF gene as a function of the time of origin of each mutation (tj) measured in units of generations. Login to comment 92 ABCC7 p.Gly542* With mutation rate g, the number of segregating sites within the allelic class, S is a Poisson distributed random variable with mean pT, where T is the total length of the intraallelic gene genealogy (see, -8 -8.25 -8.5 -8.75 _9 -9.25 -9.5 -9.75 a 2000 2200 2400 2600 2800 3000 -5 -5.25 -5.5 -5.75 e -6 -6.25 -6.5 -6.75 1200 1400 1600 1800 2000 tl 350 400 450 500 550 600 650 tl Figure 2 Log-likelihood (1) of the observed number of copies of the AF508 and G542X mutations of the CF gene as a function of the time of origin of each mutation (tj) measured in units of generations. Login to comment 96 ABCC7 p.Gly542* Panel c shows I as a function of t1 for the G542X allele with 4 = 0.005, N = 3 X 108, and f = 0.00014. Login to comment 97 ABCC7 p.Gly542* Panel c shows I as a function of t1 for the G542X allele with 4 = 0.005, N = 3 X 108, and f = 0.00014. Login to comment 98 ABCC7 p.Gly542* Panel d shows I as a function of t1 for the G542X allele with 4 = 0.02 and the other parameters as given above. Login to comment 99 ABCC7 p.Gly542* Panel d shows I as a function of t1 for the G542X allele with 4 = 0.02 and the other parameters as given above. Login to comment 223 ABCC7 p.Gly542* We can apply our method to another mutation of CFTR, G542X, a nonsense mutation in exon 11, that has been assessed by Casals et al. Login to comment 224 ABCC7 p.Gly542* We can apply our method to another mutation of CFTR, G542X, a nonsense mutation in exon 11, that has been assessed by Casals et al. Login to comment 229 ABCC7 p.Gly542* The frequency of G542X is much smaller than AF508, making up 8% of the CF alleles found in a survey of Spain. Login to comment 230 ABCC7 p.Gly542* The frequency of G542X varies with location in Spain (Casals et al. 1993), but for the purposes of our analysis we will assume a frequency of .03 x .08 = .0024 in a random sample of the Spanish population. Login to comment 231 ABCC7 p.Gly542* The frequency of G542X varies with location in Spain (Casals et al. 1993), but for the purposes of our analysis we will assume a frequency of .03 x .08 = .0024 in a random sample of the Spanish population. Login to comment 233 ABCC7 p.Gly542* (1993) suggest the geographic distribution supports the introduction of G542X from North Africa between 2,000 and 3,000 years ago, which implies that the appropriate population for analysis may be much larger. Login to comment 234 ABCC7 p.Gly542* (1993) suggest the geographic distribution supports the introduction of G542X from North Africa between 2,000 and 3,000 years ago, which implies that the appropriate population for analysis may be much larger. Login to comment 236 ABCC7 p.Gly542* Figure 4 shows the likelihood curves for four combinations of parameter values for G542X. Login to comment 237 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* These figures, and others not shown, indicate that G542X is somewhat -70 -75 -80 -85 -90 -95 e e - - --L- -13 -14 -15 -16 -17 e a -14r -16 -18 -20 -22 -24 0 100 200 300 400 b 0 50 100 150 200 50 100 150 200 250 tl tl Figure 4 Log-likelihood (1) of the observed number of copies (i = 62) and segregating sites (S = 5) for the G542X allele of CF. Login to comment 238 ABCC7 p.Gly542* ABCC7 p.Gly542* These figures, and others not shown, indicate that G542X is somewhat -70 -75 -80 -85 -90 -95 e e - - - -L- -13 -14 -15 -16 -17 e a -14r -16 -18 -20 -22 -24 0 100 200 300 400 b 0 50 100 150 200 50 100 150 200 250 tl tl Figure 4 Log-likelihood (1) of the observed number of copies (i = 62) and segregating sites (S = 5) for the G542X allele of CF. Login to comment 246 ABCC7 p.Gly542* older than AF508. Although many fewer copies were examined for the G542X allele, the relative amount of intraallelic variability is slightly larger than that found for the AF508 allele. Login to comment 247 ABCC7 p.Gly542* ABCC7 p.Gly542* The ratio of estimated ages depends on the values of unknown parameters, but, if we assume the same value of 4 for both alleles, then G542X appears to be -1.5-3 times older than AF508. Login to comment 248 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* If we assume that the value of 4 for G542X is lower than for AF508, reflecting the possibility that AF508 may have a heterozygote advantage that G542X lacks, then the ratio of the ages would be even greater. Login to comment 249 ABCC7 p.Gly542* ABCC7 p.Gly542* If we assume that the value of 4 for G542X is lower than for AF508, reflecting the possibility that AF508 may have a heterozygote advantage that G542X lacks, then the ratio of the ages would be even greater. Login to comment 250 ABCC7 p.Gly542* Because G542X is in much lower frequency than AF508, (8) implies that it is younger. Login to comment 251 ABCC7 p.Gly542* Because G542X is in much lower frequency than AF508, (8) implies that it is younger. Login to comment