Fig. 1

Promoters of all evolutionary histories are enriched for segregating variants within the human population. a Robustly expressed, CAGE defined promoters are identified in the human genome and categorised through whole genome alignment to mouse and outgroup species. Promoters whose orthologous sequence aligns between human and mouse are evaluated for conservation of promoter activity in 52 well matched tissue and cell samples, and 347 additional mouse derived sample types. Human promoters that correspond to alignment gaps in the mouse are resolved as either human lineage insertions or mouse lineage deletions by reference to genome alignment from outgroup species. Phylogenetic tree topology and branch lengths based on protein coding sequence four-fold degenerate sites as previously reported [16]. b–e Examples of human promoters with the four distinct classes of evolutionary history considered in this study. Counts of each evolutionary history promoter class in the human genome are given. Red histograms show the CAGE defined transcript 5′ end measures at the orthologous human and mouse loci. Annotated genes are shown below, where exons are indicated by boxes, introns by lines and chevrons to the right denote their transcriptional orientation. Blocks in the genome alignment sections below show aligning sequence where darker colours indicate higher sequence identity. Single and double lines are alignment gaps. f Human single-nucleotide polymorphisms (SNPs) are enriched around promoters from all evolutionary histories. Enrichments are calculated as the rolling average of 250 bp windows and normalised to the average for the window 2 kb to 4 kb upstream of the promoter (neutral-proxy region). The 95% confidence interval from bootstrap replicates is indicated by lighter volumes around each curve. The arrow below denotes the direction of transcription. g As for (f) but showing the spatial distribution of human insertion/deletion polymorphisms