Human-specific gain of function in a developmental enhancer.
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.
Prabhakar
Shyam
S
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Visel
Axel
A
Akiyama
Jennifer A
JA
Shoukry
Malak
M
Lewis
Keith D
KD
Holt
Amy
A
Plajzer-Frick
Ingrid
I
Morrison
Harris
H
Fitzpatrick
David R
DR
Afzal
Veena
V
Pennacchio
Len A
LA
Rubin
Edward M
EM
Noonan
James P
JP
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
D051764:PAX9 Transcription Factor; D014157:Transcription Factors
Nat Rev Genet. 2007 Mar;8(3):206-16
17304246
Nature. 2006 Nov 23;444(7118):499-502
17086198
Oncogene. 2004 Apr 8;23(15):2727-31
15048087
Science. 2003 Oct 17;302(5644):413
14563999
Dev Biol. 1995 Aug;170(2):701-16
7649395
Science. 2002 Apr 19;296(5567):541-5
11964482
Nat Genet. 2007 Jan;39(1):31-40
17159977
J Biol Chem. 2002 Dec 13;277(50):48965-75
12388557
Genome Res. 2002 Jun;12(6):996-1006
12045153
Trends Genet. 2007 Jun;23(6):273-7
17418442
Nature. 2003 Apr 24;422(6934):849-57
12712196
Genes Dev. 1998 Sep 1;12(17):2735-47
9732271
Science. 1975 Apr 11;188(4184):107-16
1090005
Development. 1989 Apr;105(4):707-14
2557196
BMC Evol Biol. 2008 Jan 23;8:17
18215302
Genome Res. 2005 Aug;15(8):1034-50
16024819
Genome Res. 2004 Apr;14(4):708-15
15060014
Nat Genet. 2008 Feb;40(2):158-60
18176564
Genome Biol. 2007;8(6):R118
17578567
Development. 1997 Aug;124(15):2923-34
9247335
Science. 2006 Nov 3;314(5800):786
17082449
PLoS Biol. 2005 Dec;3(12):e387
16274263
Nat Rev Genet. 2004 Jun;5(6):456-65
15153998
Nat Genet. 1995 Jun;10(2):224-8
7663520
Nature. 2006 Sep 14;443(7108):167-72
16915236
PLoS Genet. 2006 Oct 13;2(10):e168
17040131