Heterogeneity in the extent of linkage disequilibrium among exonic, intronic, non-coding RNA and intergenic chromosome regions

Whole-genome sequence data enable construction of high-resolution linkage disequilibrium (LD) maps revealing the LD structure of functional elements within genic and subgenic sequences. The Malecot-Morton model defines LD map distances in linkage disequilibrium units (LDUs), analogous to the centimorgan scale of linkage maps. For whole-genome sequence-derived LD maps, we introduce the ratio of corresponding map lengths kilobases/LDU to describe the extent of LD within genome components. The extent of LD is highly variable across the genome ranging from ~38 kb for intergenic sequences to ~858 kb for centromeric regions. LD is ~16% more extensive in genic, compared with intergenic sequences, reflecting relatively increased selection and/or reduced recombination in genes. The LD profile across 18,268 autosomal genes reveals reduced extent of LD, consistent with elevated recombination, in exonic regions near the 5' end of genes but more extensive LD, compared with intronic sequences, across more centrally located exons. Genes classified as essential and genes linked to Mendelian phenotypes show more extensive LD compared with genes associated with complex traits, perhaps reflecting differences in selective pressure. Significant differences between exonic, intronic and intergenic components demonstrate that fine-scale LD structure provides important insights into genome function, which cannot be revealed by LD analysis of much lower resolution array-based genotyping and conventional linkage maps.