A Caltech Library Service

Defining functional DNA elements in the human genome

Kellis, Manolis and Wold, Barbara J. and Marinov, Georgi K. (2014) Defining functional DNA elements in the human genome. Proceedings of the National Academy of Sciences of the United States of America, 111 (17). pp. 6131-6138. ISSN 0027-8424. PMCID PMC4035993.

PDF - Published Version
See Usage Policy.

PDF - Supplemental Material
See Usage Policy.


Use this Persistent URL to link to this item:


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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle Information
Wold, Barbara J.0000-0003-3235-8130
Marinov, Georgi K.0000-0003-1822-7273
Additional Information:© 2014 National Academy of Sciences. Freely available online through the PNAS open access option. Edited by Robert Haselkorn, University of Chicago, Chicago, IL, and approved January 29, 2014 (received for review October 16, 2013). M.K., B.W., M.P.S., B.E.B., and R.C.H. contributed equally to this work. A.K., G.K.M., and L.D.W. contributed equally to this work. Author contributions: M.K., B.W., M.P.S., B.E.B., and R.C.H. designed research; M.K., B.W., M.P.S., B.E.B., A.K., G.K.M., L.D.W., and R.C.H. performed research; A.K., G.K.M., and L.D.W. contributed computational analysis and tools; M.K., B.W., M.P.S., B.E.B., E.B., G.E.C., J.D., I.D., L.L.E., P.J.F., E.A.F., M.G., M.C.G., D.M.G., T.R.G., E.D.G., R.G., T.H., J.K., J.D.L., R.M.M., M.J.P., B.R., J.A.S., Z.W., K.P.W., and R.C.H. contributed to manuscript discussions and ideas; and M.K., B.W., M.P.S., B.E.B., and R.C.H. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Data deposition: In addition to data already released via the ENCODE Data Coordinating Center, the erythroblast DNase-seq data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, (accession nos. GSE55579, GSM1339559, and GSM1339560). Authored by members of the ENCODE Consortium. This article contains supporting information online at
Issue or Number:17
PubMed Central ID:PMC4035993
Record Number:CaltechAUTHORS:20140528-111716378
Persistent URL:
Official Citation:Kellis, M., Wold, B., Snyder, M. P., Bernstein, B. E., Kundaje, A., Marinov, G. K., . . . Hardison, R. C. (2014). Defining functional DNA elements in the human genome. Proceedings of the National Academy of Sciences, 111(17), 6131-6138. doi: 10.1073/pnas.1318948111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45939
Deposited By: Jason Perez
Deposited On:28 May 2014 18:51
Last Modified:03 Oct 2019 06:38

Repository Staff Only: item control page