An integrated encyclopedia of DNA elements in the human genome

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research. The human genome sequence provides the underlying code for human biology. Despite intensive study, especially in identifying protein-coding genes, our understanding of the genome is far from complete, particularly with regard to non-coding RNAs, alternatively spliced transcripts and regulatory sequences. Systematic analyses of transcripts and regulatory information are essential for the identification of genes and regulatory regions, and are an important resource for the study of human biology and disease. Such analyses can also provide comprehensive views of the organization and variability of genes and regulatory information across cellular contexts, species and individuals. The Encyclopedia of DNA Elements (ENCODE) project aims to delineate all functional elements encoded in the human genome 1–3. Operationally, we define a functional element as a discrete genome segment that encodes a defined product (for example, protein or non-coding RNA) or displays a reproducible biochemical signature (for example, protein binding, or a specific chromatin structure). Comparative genomic studies suggest that 3–8% of bases are under purifying (negative) selection 4–8 and therefore may be functional, although other analyses have suggested much higher estimates 9–11. In a pilot phase covering 1% of the genome, the ENCODE project annotated 60% of mammalian evolutionarily constrained bases, but also identified many additional putative functional elements without evidence of constraint 2. The advent of more powerful DNA sequencing technologies now enables whole-genome and more precise analyses with a broad repertoire of functional assays. Here we describe the production and initial analysis of 1,640 data sets designed to annotate functional elements in the entire human genome. We integrate results from diverse experiments within …