title: Defining functional DNA elements in the human genome.
abstract: With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.forename: Barbara
authors.initials: B
authors.lastname: Wold
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: Anshul
authors.initials: A
authors.lastname: Kundaje
authors.forename: Georgi K
authors.initials: GK
authors.lastname: Marinov
authors.forename: Lucas D
authors.initials: LD
authors.lastname: Ward
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.forename: Laura L
authors.initials: LL
authors.lastname: Elnitski
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Farnham
authors.forename: Elise A
authors.initials: EA
authors.lastname: Feingold
authors.forename: Mark
authors.initials: M
authors.lastname: Gerstein
authors.forename: Morgan C
authors.initials: MC
authors.lastname: Giddings
authors.forename: David M
authors.initials: DM
authors.lastname: Gilbert
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gingeras
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigo
authors.forename: Tim
authors.initials: T
authors.lastname: Hubbard
authors.forename: Jim
authors.initials: J
authors.lastname: Kent
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pazin
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
authors.forename: Ross C
authors.initials: RC
authors.lastname: Hardison
mesh_terms: D005075:Biological Evolution; D004247:DNA / Q000235:genetics*; D004194:Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012984:Software
chemical_list: D004247:DNA
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