Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins

Cell. 2016 Jan 14;164(1-2):45-56. doi: 10.1016/j.cell.2015.12.007. Epub 2016 Jan 7.


Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone-size differences in sticklebacks map to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor-plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Biological Evolution*
  • Enhancer Elements, Genetic
  • Evolution, Molecular*
  • Fish Proteins / genetics
  • Fish Proteins / metabolism
  • Fresh Water
  • Growth Differentiation Factor 6 / genetics*
  • Growth Differentiation Factor 6 / metabolism
  • Humans
  • Quantitative Trait Loci
  • Seawater
  • Skeleton / anatomy & histology
  • Skeleton / physiology*
  • Smegmamorpha / genetics
  • Smegmamorpha / physiology
  • Species Specificity
  • Vertebrates / classification
  • Vertebrates / genetics*
  • Vertebrates / growth & development
  • Vertebrates / metabolism


  • Fish Proteins
  • Growth Differentiation Factor 6