Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Abstract

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Genetic effects on gene expression across human tissues

“…We quantified the enrichment of trans -eVariants in promoter and enhancer regions using the same tissue-specific annotations from the Roadmap Epigenomics project 1,2 used for cis -eQTL analysis (Extended Data Table 4). trans -eVariants (10% FDR) were enriched in cell-type matched enhancers (median Fisher’s exact test, P ≤ 2.2 ×10 −3 ) but not strongly enriched for promoters (median P ≤ 0.22), compared to randomly selected variants matched by distance to nearest TSS, MAF and chromosome (Fig.…”

“…Recent large-scale studies have characterized the regulatory function of the genome across a diverse array of cell types, each from a small number of samples 1–3 . Measuring how gene regulation and expression vary across individuals has further expanded our understanding of the functions of healthy tissues and the molecular origins of complex traits and diseases 4–9 .…”

Aging by epigenetics—A consequence of chromatin damage?

“…Third, remarkably and paradoxically, formation of heterochromatin actually depends on a degree of transcription, which contributes to heterochromatinization through the RNAi pathway [4]. Consistent with this, recent genome-wide analyses have shown that virtually all DNA nucleotides of the human genome are, to some degree, transcribed into RNA [13][14][15]. Indeed, telomeric heterochromatin was recently shown to be transcribed [16,17].…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…Surprisingly, one of the ENCODE project accomplishments was to demonstrate that 80% of the genome is "associated with at least one biochemical function" (Maher, 2012). The ENCODE project passed through a pilot phase (Consortium et al, 2007), and currently is in the data production phase.…”