LETTER
Reply to Brunet and Doolittle: Both selected
effect and causal role elements can influence
human biology and disease
02139; bBroad Institute, Cambridge, MA
02139; cDivision of Biology and Biological
Engineering, California Institute of
Technology, Pasadena, CA 91125;
d
Department of Genetics, Stanford
University, Stanford, CA 94305; eHarvard
Medical School and fMassachusetts General
Hospital, Boston, MA 02114; gEuropean
Molecular Biology Laboratory, European
Bioinformatics Institute, Hinxton, Cambridge
CB10 1SD, United Kingdom; hMedical
Genetics, Duke University, Durham, NC
27708; iProgram in Systems Biology,
University of Massachusetts Medical
School, Worcester, MA 01605; jNational
Human Genome Research Institute, National
Manolis Kellisa,b,1, Barbara Woldc,
Institutes of Health, Bethesda, MD 20892;
Michael P. Snyderd, Bradley E.
Bernsteinb,e,f, Anshul Kundajea,b,d, Georgi kBiochemistry and Molecular Biology,
K. Marinovc, Lucas D. Warda,b, Ewan
University of Southern California, Los Angeles,
Birneyg, Gregory E. Crawfordh, Job
CA 90089; lProgram in Computational Biology
Dekkeri, Ian Dunham g, Laura L. Elnitski j, and Bioinformatics, Yale University, New
Peggy J. Farnhamk, Elise A. Feingold j,
Haven, CT 06520; mMarketing Your Science,
Mark Gersteinl, Morgan C. Giddingsm,
LLC, Boise, ID 83702; nDepartment of
David M. Gilbertn, Thomas R. Gingeraso,
Biological Science, Florida State University,
Eric D. Green j, Roderic Guigo p, Tim
q
r
s
Tallahassee, FL 32306; oFunctional Genomics
Hubbard , Jim Kent , Jason D. Lieb ,
Group, Cold Spring Harbor Laboratory, Cold
Richard M. Myerst, Michael J. Pazin j,
Spring Harbor, NY 11724; pBioinformatics
Bing Renu, John Stamatoyannopoulosv,
i
s
and Genomics Program, Center for Genome
Zhiping Weng , Kevin P. White ,
Regulation, E-08003 Barcelona, Catalonia,
and Ross C. Hardisonw,1
a
Spain; qMedical and Molecular Genetics,
Computer Science and Artificial
Intelligence Laboratory, Massachusetts
King’s College London and Wellcome Trust
Institute of Technology, Cambridge, MA
Sanger Institute, Hinxton, Cambridge CB10
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We agree with Brunet and Doolittle (1) on
the utility of distinguishing the evolutionarily
selected effects (SE) of some genomic elements from the causal roles (CR) of other
elements that lack signatures of selection
(1–4). DNA sequences identified by biochemical approaches include both SE and
CR elements, and genetic variation in both
has been implicated in human traits and disease susceptibility. We thus view the Encyclopedia of DNA Elements (ENCODE) catalog
and similar data resources as important foundations for understanding the DNA elements
and molecular mechanisms underlying human biology and disease.
E3366 | PNAS | August 19, 2014 | vol. 111 | no. 33
1SD, United Kingdom; rBiomolecular
Engineering, University of California, Santa
Cruz, CA 95064; sDepartment of Human
Genetics, University of Chicago, Chicago,
IL 60637; tHudsonAlpha Institute for
Biotechnology, Huntsville, AL 35806; uLudwig
Institute for Cancer Research, University of
California, San Diego, La Jolla, CA 92093;
v
Genome Sciences and Medicine, University
of Washington, Seattle, WA 98195; and
w
Biochemistry and Molecular Biology, The
Pennsylvania State University, University
Park, PA 16802
1 Brunet TDP, Doolittle WF (2014) Getting “function” right. Proc
Natl Acad Sci USA 111:E3365.
2 Kellis M, et al. (2014) Defining functional DNA elements
in the human genome. Proc Natl Acad Sci USA 111(17):
6131–6138.
3 Germain PL, Ratti E, Boem F (2014) Junk or functional DNA?
ENCODE and the function controversy. Biol Philos, 10.1007/s10539014-9441-3.
4 Doolittle WF, Brunet TDP, Linquist S, Gregory TR (2014)
Distinguishing between “function” and “effect” in genome biology.
Genome Biol Evol 6(5):1234–1237.
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; M.K., B.W., M.P.S., B.E.B., A.K.,
G.K.M., L.D.W., and R.C.H. analyzed data; and M.K., B.W., M.P.S.,
B.E.B., A.K., G.K.M., L.D.W., 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.S., Z.W., K.P.W., and R.C.H. wrote the paper.
The authors declare no conflict of interest.
1
To whom correspondence may be addressed. Email: manoli@mit.
edu or rch8@psu.edu.
www.pnas.org/cgi/doi/10.1073/pnas.1410434111
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