Identification of cellular context sensitive regulatory variation in mouse genomes

Assessment of the functional consequences of disease-associated sequence variation at non-coding regulatory elements is complicated by their high degree of context sensitivity to both the local chromatin and nuclear environments. Allelic profiling of DNA accessibility across individuals has shown that only a select minority of sequence variation affects transcription factor (TF) occupancy, yet the low sequence diversity in human populations means that no experimental assessment is available for the majority of disease-associated variants. Here we describe high-resolution in vivo maps of allelic DNA accessibility in liver, kidney, lung and B cells from 5 increasingly diverged strains of F1 hybrid mice. The high density of heterozygous sites in these hybrids enables precise quantification of the effect size and cell-type specificity of hundreds of thousands of variants throughout the mouse genome. We show that functional variation delineates characteristic sensitivity profiles for hundreds of TF motifs, representing nearly all important TF families. We develop a compendium of TF-specific sensitivity profiles accounting for genomic context effects. Finally, we link these maps of allelic accessibility to allelic transcript levels in the same samples. This work provides a foundation for quantitative prediction of cell-type specific effects of non-coding variation on TF activity, which will dramatically facilitate both fine-mapping and systems-level analyses of common disease-associated variation in human genomes.