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Science 5 September 2008:
Vol. 321. no. 5894, pp. 1346 - 1350
DOI: 10.1126/science.1159974
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Reports

Human-Specific Gain of Function in a Developmental Enhancer

Shyam Prabhakar,1* Axel Visel,1 Jennifer A. Akiyama,1 Malak Shoukry,1 Keith D. Lewis,1{dagger} Amy Holt,1 Ingrid Plajzer-Frick,1 Harris Morrison,2 David R. FitzPatrick,2 Veena Afzal,1 Len A. Pennacchio,1,3 Edward M. Rubin,1,3{ddagger} James P. Noonan1{ddagger}§

Changes in gene regulation are thought to have contributed to the evolution of human development. However, in vivo evidence for uniquely human developmental regulatory function has remained elusive. In transgenic mice, a conserved noncoding sequence (HACNS1) that evolved extremely rapidly in humans acted as an enhancer of gene expression that has gained a strong limb expression domain relative to the orthologous elements from chimpanzee and rhesus macaque. This gain of function was consistent across two developmental stages in the mouse and included the presumptive anterior wrist and proximal thumb. In vivo analyses with synthetic enhancers, in which human-specific substitutions were introduced into the chimpanzee enhancer sequence or reverted in the human enhancer to the ancestral state, indicated that 13 substitutions clustered in an 81–base pair module otherwise highly constrained among terrestrial vertebrates were sufficient to confer the human-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, Genome Institute of Singapore 138672, Singapore.

{dagger} 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.

{ddagger} To whom correspondence should be addressed. E-mail: emrubin{at}lbl.gov (E.M.R.); james.noonan{at}yale.edu (J.P.N.)

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Upper-Limb Evolution and Development.
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J. Bone Joint Surg. Am. 91, 26-30
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A. J. Bonham, T. Neumann, M. Tirrell, and N. O. Reich (2009)
Nucleic Acids Res.
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Comment on "Human-Specific Gain of Function in a Developmental Enhancer".
L. Duret and N. Galtier (2009)
Science 323, 714c
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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
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Science. ISSN 0036-8075 (print), 1095-9203 (online)