Extensive Linkage Disequilibrium, a Common 16.7-Kilobase Deletion, and Evidence of Balancing Selection in the Human Protocadherin . Cluster

Regions of extensive linkage disequilibrium (LD) appear to be a common feature of the human genome. However, the mechanisms that maintain these regions are unknown. In an effort to understand whether gene density contributes to LD, we determined the degree of promoter sequence variation in a large tandem-arrayed gene family, the human protocadherin . cluster, on chromosome 5. These genes are expressed at synaptic junctions in the developing brain and the adult brain and may be involved in the determination of synaptic complexity. We sequenced the promoters of all 13 . protocadherin genes in 96 European Americans and identified polymorphisms in the promoters .1, .3, .4, .5, .7, .9, .11, and .13. In these promoters, 11 common SNPs are in extensive LD, forming two 48-kb haplotypes of equal frequency, in this population, that extend from the .1 through .7 genes. We sequenced these promoters in East Asians and African Americans, and we estimated haplotype frequencies and calculated LD statistics for all three populations. Our results indicate that, although extensive LD is an ancient feature of the . cluster, it has eroded over time. SNPs 3. of .7 are involved in ancestral recombination events in all populations, and overall .-cluster LD is reduced in African Americans. We obtained significant positive values for Tajima's D test for all . promoter SNPs in Europeans (D=3.03) and East Asians (D=2.64), indicating an excess of intermediate-frequency variants, which is a signature of balancing selection. We also discovered a 16.7-kb deletion that truncates the .8 gene and completely removes the .9 and .10 genes. This deletion appears in unaffected individuals from multiple populations, suggesting that a reduction in protocadherin gene number is not obviously deleterious.