Vollger, M. R.; Swanson, E. G.; Neph, S. J.; Ranchalis, J.; Munson, K. M.; Ho, C.-H.; Sedeno-Cortes, A. E.; Fondrie, W. E.; Bohaczuk, S. C.; Mao, Y.; Parmalee, N. L.; Mallory, B. J.; Harvey, W. T.; Kwon, Y.; Garcia, G. H.; Hoekzema, K.; Meyer, J. G.; Cicek, M.; Eichler, E. E.; Noble, W. S.; Witten, D. M.; Bennett, J. T.; Ray, J. P.; Stergachis, A. B.

Most human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We demonstrate that Fiber-seq Inferred Regulatory Elements (FIREs) enable the accurate quantification of chromatin accessibility across the 6 Gbp diploid human genome with single-molecule and single-nucleotide precision. We find that cells can harbor >1,000 regulatory elements with haplotype-selective chromatin accessibility (HSCA) and show that these elements preferentially localize to genomic loci containing the most human genetic diversity, with the human leukocyte antigen (HLA) locus showing the largest amount of HSCA genome-wide in immune cells. Furthermore, we uncover HSCA elements with sequence non-deterministic chromatin accessibility, representing likely somatic epimutations, and show that productive transcription from the inactive X chromosome is buttressed by clustered promoter-proximal elements that escape X chromosome inactivation.