Article

Human-specific gain of function in a developmental enhancer.

Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Science (impact factor: 31.2). 10/2008; 321(5894):1346-50. DOI:10.1126/science.1159974
Source: PubMed

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.

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Keywords

13 substitutions
 
ancestral state
 
chimpanzee enhancer sequence
 
developmental stages
 
enhancer
 
HACNS1
 
human development
 
human enhancer
 
human-specific limb expression domain
 
human-specific substitutions
 
presumptive anterior wrist
 
proximal thumb
 
rhesus macaque
 
strong limb expression domain
 
synthetic enhancers
 
transgenic mice
 
uniquely human developmental regulatory function