title: Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute; Stanford University School of Medicine, Department of Developmental Biology, 279 Campus Drive, Beckman Center B300, Stanford, CA 94305, USA.
authors.forename: Vahan B
authors.initials: VB
authors.lastname: Indjeian
authors.affiliation: Stanford University School of Medicine, Department of Developmental Biology, 279 Campus Drive, Beckman Center B300, Stanford, CA 94305, USA.
authors.forename: Garrett A
authors.initials: GA
authors.lastname: Kingman
authors.affiliation: Stanford University School of Medicine, Department of Developmental Biology, 279 Campus Drive, Beckman Center B300, Stanford, CA 94305, USA.
authors.forename: Felicity C
authors.initials: FC
authors.lastname: Jones
authors.affiliation: Howard Hughes Medical Institute; Stanford University School of Medicine, Department of Developmental Biology, 279 Campus Drive, Beckman Center B300, Stanford, CA 94305, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Guenther
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Grimwood
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schmutz
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Howard Hughes Medical Institute; Stanford University School of Medicine, Department of Developmental Biology, 279 Campus Drive, Beckman Center B300, Stanford, CA 94305, USA. Electronic address: kingsley@stanford.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Kingsley
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D005075:Biological Evolution; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D029941:Fish Proteins / Q000235:genetics / Q000378:metabolism; D005618:Fresh Water; D055431:Growth Differentiation Factor 6 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D040641:Quantitative Trait Loci; D012623:Seawater; D012863:Skeleton / Q000033:anatomy & histology / Q000502:physiology*; D023701:Smegmamorpha / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D014714:Vertebrates / Q000145:classification / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: D029941:Fish Proteins; D055431:Growth Differentiation Factor 6