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Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Publisher Summary The isolation of chromatin assembled in vivo may bridge the gap between natural and artificial chromosomal material. This chapter describes a method for the isolation of genes from Saccharomyces cerevisiae in the form of chromatin in different transcriptional states. The method is an extension of the work of Gartenberg, who employed site-specific recombination in vivo and differential centrifugation to separate selected chromosomal regions from bulk chromatin. Affinity chromatography is used to purify the selected chromosomal regions to near homogeneity. The combination of differential centrifugation and tandem affinity purification permits the separation of a specific chromosomal locus from virtually all nucleic acids and most of the proteins present in the cell. After purification of PHO5 chromatin, PHO5 DNA is present in 20- to 30-fold excess over all other chromosomal DNA. The only nucleic acid detectable in the final eluate by agarose gel electrophoresis and ethidium bromide staining is PHO5 circle DNA. The purified material is free from chromatin-remodeling activities, nucleases, proteases, and topoisomerases. Using this approach, it is found that different transcriptional states of PHO5 chromatin are stable in vitro, conserving important structural and topological features of the PHO5 locus in vivo.