446 HUMAN MUTATION 28(5), 441^450, 2007 FIGURE 1. Distributions of allelic frequency classes (left panels) of frequencies of haplotypes [Middleton et al., 1993] and haplotype allelic classes (right) in CDC25A, CX3CR1, and GSRM3. Bars represent the observed values; lines represent theoretical distributions. The occupancy of allelic frequency classes corresponds to counts of sites represented by i new alleles in a sample of n chromosomes (i 51, 2, 3,y, n^1). Here, the theoretical curve (solid line) corresponds to the distribution calculated from the equation [Fan et al., 2002; Fu,1997] Si (i) 5 Y/i, using Y/p (Table 1) as the estimator of Y.The theoretical distribution (solid line) of haplotype frequencies expected given k observed haplotypes (Table 1) is according to Ewens [1972]. Haplotype names are arbitrary and correspond to their names in our database. In the case of haplotype allelic classes, regrouping haplotypes sharing the same number of mutations from the ancestral haplotype, their theoretical occupancy was obtained by coalescent simulation under the standard model, assuming constant population size without (solid line) and with (dotted line) recombination, at 10-fold the genomic average in the case of segments where crossovers were detected. not in the Hardy-Weinberg equilibrium (w2 5 17.9, po4 10 5; w2 5 15.3, po0.0001; w2 5 8.3, po0.005, in the world sample, and w2 5 11.5, po0.0009; w2 5 10.6, po0.005; w2 5 9.6, po0.005, in the non-African sample, respectively). Note that no other sites, with low or high Fst, showed any departure from the HWE, suggesting that this represents a specific effect of the CX3CR1 locus. Therefore, the Hardy-Weinberg disequilibrium together with high Fsts can be taken as evidence for evolutionary forces other than random drift acting upon this locus. On the other side, the Fst distribution, there are sites with zero or near zero Fsts. If the data are informative, this might suggest the effect of evolutionary forces countering random drift in order to maintain allele frequencies at similar levels across populations (e.g., BTN3A2; Table 1). We note that the average per site Fst for all polymorphisms examined in this study was 4.6%, which is less than the corresponding values of 10 to 15% reported in the literature for a variety of genetic markers [Bowcock et al., 1991; Jorde et al., 2000; Akey et al., 2002]. This difference can be at least partly accounted for by the ascertainment bias and high average per site heterozygosity of the classical, early RFLP as well as Alu markers [Bowcock et al., 1991; Jorde et al., 2000]. Here, in contrast, all polymorphic sites are considered, including those of low minor allele frequency [Ronald and Akey, 2005]. However, a similarly Human Mutation DOI 10.1002/humu obtained (resequencing) set of 297 polymorphisms from the expressed sequence tags [Fan et al., 2002] shows twice as high an average Fst when compared with our data (9.2712.7% for the total sample and 6.5710.4% when Africans were excluded). Yet the shape of the Fst distribution is virtually identical in both data sets (Supplementary Fig. S3), raising the question whether the low average Fst observed here reflects its overall depression upstream of the protein-coding genes or only represents an artifact of a particular configuration of our population samples. Haplotype Allelic Classes and the Prevalence of Major Haplotypes In our data, we found two opposite variation patterns at the level of haplotypes (see haplotype networks in Supplementary Fig. S1 and the list of haplotypes in Supplementary Table S3). The first pattern is characterized by the dominant presence of the ancestral haplotype (all of whose alleles are ancestral), whereas the second includes loci where the ancestral haplotype is absent or is present only at residual frequencies. These two opposite diversity profiles can be contrasted during analysis of all segments together. In Figure 2A, we show the histogram of the ancestral haplotype frequencies in our sample of 28 segments, counting loci with no ancestral haplotype and the number of those with the ancestral