title: Genetic comparisons yield insight into the evolution of enamel thickness during human evolution.
abstract: Enamel thickness varies substantially among extant hominoids and is a key trait with significance for interpreting dietary adaptation, life history trajectory, and phylogenetic relationships. There is a strong link in humans between enamel formation and mutations in the exons of the four genes that code for the enamel matrix proteins and the associated protease. The evolution of thick enamel in humans may have included changes in the regulation of these genes during tooth development. The cis-regulatory region in the 5' flank (upstream non-coding region) of MMP20, which codes for enamelysin, the predominant protease active during enamel secretion, has previously been shown to be under strong positive selection in the lineages leading to both humans and chimpanzees. Here we examine evidence for positive selection in the 5' flank and 3' flank of AMELX, AMBN, ENAM, and MMP20. We contrast the human sequence changes with other hominoids (chimpanzees, gorillas, orangutans, gibbons) and rhesus macaques (outgroup), a sample comprising a range of enamel thickness. We find no evidence for positive selection in the protein-coding regions of any of these genes. In contrast, we find strong evidence for positive selection in the 5' flank region of MMP20 and ENAM along the lineage leading to humans, and in both the 5' flank and 3' flank regions of MMP20 along the lineage leading to chimpanzees. We also identify putative transcription factor binding sites overlapping some of the species-specific nucleotide sites and we refine which sections of the up- and downstream putative regulatory regions are most likely to harbor important changes. These non-coding changes and their potential for differential regulation by transcription factors known to regulate tooth development may offer insight into the mechanisms that allow for rapid evolutionary changes in enamel thickness across closely-related species, and contribute to our understanding of the enamel phenotype in hominoids.
authors.affiliation: North Carolina Museum of Natural Sciences, Nature Research Center, Raleigh, NC 27601, USA; Department of Biology, North Carolina Central University, Durham, NC 27707, USA; Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA; Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Horvath
authors.affiliation: Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA.
authors.forename: Gowri L
authors.initials: GL
authors.lastname: Ramachandran
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fedrigo
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Nielsen
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA; Department of Biology, Duke University, Durham, NC 27708, USA.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Babbitt
authors.affiliation: Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: St Clair
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Pfefferle
authors.affiliation: Institute for Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Jernvall
authors.affiliation: Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA; Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA; Department of Biology, Duke University, Durham, NC 27708, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wray
authors.affiliation: Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA. Electronic address: cw19@duke.edu.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wall
mesh_terms: D000818:Animals; D001483:Base Sequence; D003743:Dental Enamel / Q000033:anatomy & histology*; D003746:Dental Enamel Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015186:Hominidae / Q000033:anatomy & histology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016674:Hylobatidae / Q000033:anatomy & histology* / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta / Q000033:anatomy & histology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D053519:Matrix Metalloproteinase 20 / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D012641:Selection, Genetic; D016415:Sequence Alignment
chemical_list: D003746:Dental Enamel Proteins; D016326:Extracellular Matrix Proteins; D053519:Matrix Metalloproteinase 20
keywords: AMBN; AMELX; ENAM; MMP20; Primate comparative genomics