title: The identification and functional implications of human-specific "fixed" amino acid substitutions in the glutamate receptor family.
abstract: BACKGROUND
  The glutamate receptors (GluRs) play a vital role in the mediation of excitatory synaptic transmission in the central nervous system. To clarify the evolutionary dynamics and mechanisms of the GluR genes in the lineage leading to humans, we determined the complete sequences of the coding regions and splice sites of 26 chimpanzee GluR genes.
  
  
  RESULTS
  We found that all of the reading frames and splice sites of these genes reported in humans were completely conserved in chimpanzees, suggesting that there were no gross structural changes in humans after their divergence from the human-chimpanzee common ancestor. We observed low KA/KS ratios in both humans and chimpanzees, and we found no evidence of accelerated evolution. We identified 30 human-specific "fixed" amino acid substitutions in the GluR genes by analyzing 80 human samples of seven different populations worldwide. Grantham's distance analysis showed that GRIN2C and GRIN3A are the most and the second most diverged GluR genes between humans and chimpanzees. However, most of the substitutions are non-radical and are not clustered in any particular region. Protein motif analysis assigned 11 out of these 30 substitutions to functional regions. Two out of these 11 substitutions, D71G in GRIN3A and R727H in GRIN3B, caused differences in the functional assignments of these genes between humans and other apes.
  
  
  CONCLUSIONS
  We conclude that the GluR genes did not undergo drastic changes such as accelerated evolution in the human lineage after the divergence of chimpanzees. However, there remains a possibility that two human-specific "fixed" amino acid substitutions, D71G in GRIN3A and R727H in GRIN3B, are related to human-specific brain function.
authors.affiliation: Division of Human Moelcular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. hug4@psu.edu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Goto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Watanabe
authors.forename: Naozumi
authors.initials: N
authors.lastname: Araragi
authors.forename: Rui
authors.initials: R
authors.lastname: Kageyama
authors.forename: Kunika
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kuroki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyoda
authors.forename: Masahira
authors.initials: M
authors.lastname: Hattori
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakaki
authors.forename: Asao
authors.initials: A
authors.lastname: Fujiyama
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fukumaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shibata
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D055028:Comparative Genomic Hybridization; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D005810:Multigene Family; D016366:Open Reading Frames; D002679:Pan troglodytes / Q000235:genetics*; D022821:RNA Splice Sites; D017470:Receptors, Glutamate / Q000235:genetics*; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D022821:RNA Splice Sites; D017470:Receptors, Glutamate