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Human-Specific Gain of Function in a Developmental Enhancer
Shyam Prabhakar,1*Axel Visel,1Jennifer A. Akiyama,1Malak Shoukry,1Keith D. Lewis,1Amy Holt,1Ingrid Plajzer-Frick,1Harris Morrison,2David R. FitzPatrick,2Veena Afzal,1Len A. Pennacchio,1,3Edward M. Rubin,1,3James P. Noonan1
Changes in gene regulation are thought to have contributed tothe evolution of human development. However, in vivo evidencefor uniquely human developmental regulatory function has remainedelusive. In transgenic mice, a conserved noncoding sequence(HACNS1) that evolved extremely rapidly in humans acted as anenhancer of gene expression that has gained a strong limb expressiondomain relative to the orthologous elements from chimpanzeeand rhesus macaque. This gain of function was consistent acrosstwo developmental stages in the mouse and included the presumptiveanterior wrist and proximal thumb. In vivo analyses with syntheticenhancers, in which human-specific substitutions were introducedinto the chimpanzee enhancer sequence or reverted in the humanenhancer to the ancestral state, indicated that 13 substitutionsclustered in an 81–base pair module otherwise highly constrainedamong terrestrial vertebrates were sufficient to confer thehuman-specific limb expression domain.
1 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. 2 MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK. 3 United States Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA.
* Present address: Computational and Mathematical Biology, GenomeInstitute of Singapore 138672, Singapore.
Present address: Division of Biology, California Institute ofTechnology, Pasadena, CA 91125, USA.
Present address: Department of Genetics, Yale University Schoolof Medicine, New Haven, CT 06520, USA.
To whom correspondence should be addressed. E-mail: emrubin{at}lbl.gov (E.M.R.); james.noonan{at}yale.edu (J.P.N.)
The editors suggest the following Related Resources on Science sites:
In Science Magazine
TECHNICAL COMMENTS
Laurent Duret and Nicolas Galtier (6 February 2009) Science323 (5915), 714c.
[DOI: 10.1126/science.1165848] |Abstract »|Full Text »|PDF »
TECHNICAL COMMENTS
Shyam Prabhakar, Axel Visel, Jennifer A. Akiyama, Malak Shoukry, Keith D. Lewis, Amy Holt, Ingrid Plajzer-Frick, Harris Morrison, David R. FitzPatrick, Veena Afzal, Len A. Pennacchio, Edward M. Rubin, and James P. Noonan (6 February 2009) Science323 (5915), 714d.
[DOI: 10.1126/science.1166571] |Abstract »|Full Text »|PDF »
PERSPECTIVES
Gregory A. Wray and Courtney C. Babbitt (5 September 2008) Science321 (5894), 1300.
[DOI: 10.1126/science.1163568] |Summary »|Full Text »|PDF »
Response to Comment on "Human-Specific Gain of Function in a Developmental Enhancer".
S. Prabhakar, A. Visel, J. A. Akiyama, M. Shoukry, K. D. Lewis, A. Holt, I. Plajzer-Frick, H. Morrison, D. R. FitzPatrick, V. Afzal, et al. (2009)
Science
323, 714d
|Abstract »|Full Text »|PDF »
Present address: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. 
Present address: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. 
To whom correspondence should be addressed. E-mail: 
