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Human-specific gain of function in a developmental enhancer

Prabhakar, Shyam and Visel, Axel and Akiyama, Jennifer A. and Shoukry, Malak and Lewis, Keith D. and Holt, Amy and Plajzer-Frick, Ingrid and Morrison, Harris and FitzPatrick, David R. and Afzal, Veena and Pennacchio, Len A. and Rubin, Edward M. and Noonan, James P. (2008) Human-specific gain of function in a developmental enhancer. Science, 321 (5894). pp. 1346-1350. ISSN 0036-8075. http://resolver.caltech.edu/CaltechAUTHORS:20090427-080846213

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/science.1159974DOIUNSPECIFIED
http://www.sciencemag.org/cgi/content/abstract/321/5894/1346PublisherUNSPECIFIED
Additional Information:© 2008 American Association for the Advancement of Science. 2 May 2008; accepted 7 July 2008. We thank members of the Pennacchio and Rubin laboratories for critical comments on the manuscript. Research was done under Department of Energy Contract DE-AC02-05CH11231, University of California, E. O. Lawrence Berkeley National Laboratory, and supported by National Heart, Lung and Blood Institute grant HL066681 and National Human Genome Research Institute grant HG003988 (L.A.P.); the Agency for Science, Technology, and Research of Singapore (S.P.); an American Heart Association postdoctoral fellowship (A.V.); and NIH National Research Service Award fellowship 1-F32-GM074367 and the Department of Genetics, Yale University School of Medicine (J.P.N.).
Funders:
Funding AgencyGrant Number
Department of EnergyDE-AC02-05CH11231
National Heart, Lung and Blood InstituteHL066681
National Human Genome Research InstituteHG003988
Agency for Science, Technology, and Research of SingaporeUNSPECIFIED
American Heart Association postdoctoral fellowshipUNSPECIFIED
NIH National Research Service Award fellowship 1-F32-GM074367
Department of Genetics, Yale University School of MedicineUNSPECIFIED
Issue or Number:5894
Record Number:CaltechAUTHORS:20090427-080846213
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20090427-080846213
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14078
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Aug 2009 18:18
Last Modified:26 Dec 2012 10:58

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