The use of intraallelic variability for testing neutrality and estimating population growth rate

To better understand the forces affecting individual alleles, we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci (the intraallelic variability). We model three types of intraallelic variability: (a) the number of nonrecombinants at a linked biallelic marker locus, (b) the length of a conserved haplotype, and (c) the number of mutations at a linked marker locus. If the population growth rate is known, the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency. If the population growth rate is unknown but neutrality can be assumed, the joint distribution provides the likelihood of the growth rate and leads to a maximum-likelihood estimate. We apply the method to data from published data sets for four loci in humans. We conclude that the Delta 32 allele at CCR5 and a disease-associated allele at MLH1 arose recently and have been subject to strong selection. Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be similar to0.027 per generation with a support interval of (0.017-0.037). Four of the relatively common alleles at CFTR also appear to be neutral but Delta F508 appears to be significantly advantageous to heterozygous carriers.