Figure 1. Turkish population haplotypes provide evidence of evolutionarily recent positive selection of FMF-associated pyrin mutations.

a, Extended linkage disequilibrium (LD) surrounding MEFV_p.V726A and MEFV_p.M694V, but not MEFV_p.E148Q, in 2,313 Turkish individuals. (LD depicted by the four-gamete rule with black boxes indicating pairs of markers for which the 4th (recombinant) gamete frequency is less than 0.003, Haploview). b, Extended haplotype homozygosity (EHH) of haplotypes bearing FMF mutations compared with haplotypes with the ancestral alleles determined in 4,626 Turkish haplotypes. c, Histograms of unstandardized iHS statistics of GWAS markers³⁷ with similar frequency and local recombination rate as each FMF mutation. Top panel, 1,570 markers similar to MEFV_p.V726A; middle panel, 2,677 markers similar to MEFV_p.M694V; bottom panel, 6,166 markers similar to MEFV_p.E148Q. The most extreme negative iHS values have the strongest evidence of recent positive selection. d, Representative trajectories from forward-time simulation of episodic selection. The depicted trajectories reflect a single run of the simulated evolutionary process. The plague pandemics are depicted by the hatched rectangles. The red curve depicts a representative trajectory for MEFV_p.M694V from one initial allelic copy 197 generations ago to an allele frequency of 2.1×10⁻³ at the beginning of the first plague pandemic and to a present-day allele frequency of 0.0313. The blue curve depicts a representative trajectory for MEFV_p.V726A from one initial allelic copy 163 generations ago to 1.6×10⁻³ at the beginning of the first plague pandemic and to a present-day allele frequency of 0.0197.