title: Human-specific gain of function in a developmental enhancer.
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.
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Akiyama
authors.forename: Malak
authors.initials: M
authors.lastname: Shoukry
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lewis
authors.forename: Amy
authors.initials: A
authors.lastname: Holt
authors.forename: Ingrid
authors.initials: I
authors.lastname: Plajzer-Frick
authors.forename: Harris
authors.initials: H
authors.lastname: Morrison
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
authors.forename: Veena
authors.initials: V
authors.lastname: Afzal
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.forename: James P
authors.initials: JP
authors.lastname: Noonan
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019521:Body Patterning / Q000235:genetics*; D017124:Conserved Sequence; D047108:Embryonic Development; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005121:Extremities / Q000196:embryology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D018878:Limb Buds / Q000196:embryology / Q000378:metabolism; D008253:Macaca mulatta / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D051764:PAX9 Transcription Factor / Q000378:metabolism; D002679:Pan troglodytes / Q000235:genetics; D012641:Selection, Genetic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051764:PAX9 Transcription Factor; D014157:Transcription Factors
references.citation: Nat Rev Genet. 2007 Mar;8(3):206-16
references.pmid: 17304246
references.citation: Nature. 2006 Nov 23;444(7118):499-502
references.pmid: 17086198
references.citation: Oncogene. 2004 Apr 8;23(15):2727-31
references.pmid: 15048087
references.citation: Science. 2003 Oct 17;302(5644):413
references.pmid: 14563999
references.citation: Dev Biol. 1995 Aug;170(2):701-16
references.pmid: 7649395
references.citation: Science. 2002 Apr 19;296(5567):541-5
references.pmid: 11964482
references.citation: Nat Genet. 2007 Jan;39(1):31-40
references.pmid: 17159977
references.citation: J Biol Chem. 2002 Dec 13;277(50):48965-75
references.pmid: 12388557
references.citation: Genome Res. 2002 Jun;12(6):996-1006
references.pmid: 12045153
references.citation: Trends Genet. 2007 Jun;23(6):273-7
references.pmid: 17418442
references.citation: Nature. 2003 Apr 24;422(6934):849-57
references.pmid: 12712196
references.citation: Genes Dev. 1998 Sep 1;12(17):2735-47
references.pmid: 9732271
references.citation: Science. 1975 Apr 11;188(4184):107-16
references.pmid: 1090005
references.citation: Development. 1989 Apr;105(4):707-14
references.pmid: 2557196
references.citation: BMC Evol Biol. 2008 Jan 23;8:17
references.pmid: 18215302
references.citation: Genome Res. 2005 Aug;15(8):1034-50
references.pmid: 16024819
references.citation: Genome Res. 2004 Apr;14(4):708-15
references.pmid: 15060014
references.citation: Nat Genet. 2008 Feb;40(2):158-60
references.pmid: 18176564
references.citation: Genome Biol. 2007;8(6):R118
references.pmid: 17578567
references.citation: Development. 1997 Aug;124(15):2923-34
references.pmid: 9247335
references.citation: Science. 2006 Nov 3;314(5800):786
references.pmid: 17082449
references.citation: PLoS Biol. 2005 Dec;3(12):e387
references.pmid: 16274263
references.citation: Nat Rev Genet. 2004 Jun;5(6):456-65
references.pmid: 15153998
references.citation: Nat Genet. 1995 Jun;10(2):224-8
references.pmid: 7663520
references.citation: Nature. 2006 Sep 14;443(7108):167-72
references.pmid: 16915236
references.citation: PLoS Genet. 2006 Oct 13;2(10):e168
references.pmid: 17040131