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The ENCODE Project was launched in 2003, as the first nearly complete human genome sequence was reported 2. At that time, our understanding of the human genome was limited. For example, although 5% of the genome was known to be under purifying selection in placental mammals 3, 4, our knowledge of specific elements, particularly with regards to non-protein coding genes and regulatory regions, was restricted to a few well-studied loci 2, 5.

ENCODE commenced as an ambitious effort to comprehensively annotate the elements in the human genome, such as genes, control elements, and transcript isoforms, and was later expanded to annotate the genomes of several model organisms. Mapping assays identified biochemical activities and thus candidate regulatory elements.