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Defining functional DNA elements in the human genome

Manolis Kellis, Barbara Wold, Michael P. Snyder, Bradley E. Bernstein, Anshul Kundaje, Georgi K. Marinov, Lucas D. Ward, Ewan Birney, Gregory E. Crawford, Job Dekker, Ian Dunham, Laura L. Elnitski, Peggy J. Farnham, Elise A. Feingold, Mark Gerstein, Morgan C. Giddings, David M. Gilbert, Thomas R. Gingeras, Eric D. Green, Roderic Guigo, Tim Hubbard, Jim Kent, Jason D. Lieb, Richard M. Myers, Michael J. Pazin, Bing Ren, John A. Stamatoyannopoulos, Zhiping Weng, Kevin P. White, and Ross C. Hardison
PNAS April 29, 2014 111 (17) 6131-6138; first published April 21, 2014; https://doi.org/10.1073/pnas.1318948111
Manolis Kellis
aComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139;
bBroad Institute, Cambridge, MA 02139;
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  • For correspondence: manoli@mit.edu rch8@psu.edu
Barbara Wold
cDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;
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Michael P. Snyder
dDepartment of Genetics, Stanford University, Stanford, CA 94305;
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Bradley E. Bernstein
bBroad Institute, Cambridge, MA 02139;
eHarvard Medical School and
fMassachusetts General Hospital, Boston, MA 02114;
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Anshul Kundaje
aComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139;
bBroad Institute, Cambridge, MA 02139;
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Georgi K. Marinov
cDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;
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Lucas D. Ward
aComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139;
bBroad Institute, Cambridge, MA 02139;
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Ewan Birney
gEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom;
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Gregory E. Crawford
hMedical Genetics, Duke University, Durham, NC 27708;
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Job Dekker
iProgram in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605;
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Ian Dunham
gEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom;
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Laura L. Elnitski
jNational Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
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Peggy J. Farnham
kBiochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90089;
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Elise A. Feingold
jNational Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
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Mark Gerstein
lProgram in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520;
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Morgan C. Giddings
mMarketing Your Science, LLC, Boise, ID 83702;
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David M. Gilbert
nDepartment of Biological Science, Florida State University, Tallahassee, FL 32306;
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Thomas R. Gingeras
oFunctional Genomics Group, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
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Eric D. Green
jNational Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
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Roderic Guigo
pBioinformatics and Genomics Program, Center for Genome Regulation, E-08003 Barcelona, Catalonia, Spain;
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Tim Hubbard
qMedical and Molecular Genetics, King's College London and Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SD, United Kingdom;
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Jim Kent
rBiomolecular Engineering, University of California, Santa Cruz, CA 95064;
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Jason D. Lieb
sLewis Sigler Institute, Princeton University, Princeton, NJ 08544;
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Richard M. Myers
tHudsonAlpha Institute for Biotechnology, Huntsville, AL 35806;
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Michael J. Pazin
jNational Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
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Bing Ren
uLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093;
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John A. Stamatoyannopoulos
vGenome Sciences and Medicine, University of Washington, Seattle, WA 98195;
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Zhiping Weng
iProgram in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605;
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Kevin P. White
wHuman Genetics, University of Chicago, Chicago, IL 60637; and
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Ross C. Hardison
xBiochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802
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  • For correspondence: manoli@mit.edu rch8@psu.edu
  1. Edited by Robert Haselkorn, University of Chicago, Chicago, IL, and approved January 29, 2014 (received for review October 16, 2013)

This article has a Letter. Please see:

  • Getting “function” right - August 08, 2014

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  • Both SE and CR elements can impact human disease
    - Aug 08, 2014
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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.

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: manoli{at}mit.edu or rch8{at}psu.edu.
  • ↵2M.K., B.W., M.P.S., B.E.B., and R.C.H. contributed equally to this work.

  • ↵3A.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, www.ncbi.nlm.nih.gov/geo (accession nos. GSE55579, GSM1339559, and GSM1339560).

  • Authored by members of the ENCODE Consortium.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318948111/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Defining functional DNA elements
Manolis Kellis, Barbara Wold, Michael P. Snyder, Bradley E. Bernstein, Anshul Kundaje, Georgi K. Marinov, Lucas D. Ward, Ewan Birney, Gregory E. Crawford, Job Dekker, Ian Dunham, Laura L. Elnitski, Peggy J. Farnham, Elise A. Feingold, Mark Gerstein, Morgan C. Giddings, David M. Gilbert, Thomas R. Gingeras, Eric D. Green, Roderic Guigo, Tim Hubbard, Jim Kent, Jason D. Lieb, Richard M. Myers, Michael J. Pazin, Bing Ren, John A. Stamatoyannopoulos, Zhiping Weng, Kevin P. White, Ross C. Hardison
Proceedings of the National Academy of Sciences Apr 2014, 111 (17) 6131-6138; DOI: 10.1073/pnas.1318948111

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Defining functional DNA elements
Manolis Kellis, Barbara Wold, Michael P. Snyder, Bradley E. Bernstein, Anshul Kundaje, Georgi K. Marinov, Lucas D. Ward, Ewan Birney, Gregory E. Crawford, Job Dekker, Ian Dunham, Laura L. Elnitski, Peggy J. Farnham, Elise A. Feingold, Mark Gerstein, Morgan C. Giddings, David M. Gilbert, Thomas R. Gingeras, Eric D. Green, Roderic Guigo, Tim Hubbard, Jim Kent, Jason D. Lieb, Richard M. Myers, Michael J. Pazin, Bing Ren, John A. Stamatoyannopoulos, Zhiping Weng, Kevin P. White, Ross C. Hardison
Proceedings of the National Academy of Sciences Apr 2014, 111 (17) 6131-6138; DOI: 10.1073/pnas.1318948111
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Proceedings of the National Academy of Sciences: 111 (17)
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  • Biological Sciences
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  • Article
    • Abstract
    • Quest to Identify Functional Elements in the Human Genome
    • What Fraction of the Human Genome Is Functional?
    • Reconciling Genetic, Evolutionary, and Biochemical Estimates
    • Functional Genomic Elements and Human Disease
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