title: Functional test of PCDHB11, the most human-specific neuronal surface protein.
abstract: BACKGROUND
  Brain-expressed proteins that have undergone functional change during human evolution may contribute to human cognitive capacities, and may also leave us vulnerable to specifically human diseases, such as schizophrenia, autism or Alzheimer's disease. In order to search systematically for those proteins that have changed the most during human evolution and that might contribute to brain function and pathology, all proteins with orthologs in chimpanzee, orangutan and rhesus macaque and annotated as being expressed on the surface of cells in the human central nervous system were ordered by the number of human-specific amino acid differences that are fixed in modern populations.
  
  
  RESULTS
  PCDHB11, a beta-protocadherin homologous to murine cell adhesion proteins, stood out with 12 substitutions and maintained its lead after normalizing for protein size and applying weights for amino acid exchange probabilities. Human PCDHB11 was found to cause homophilic cell adhesion, but at lower levels than shown for other clustered protocadherins. Homophilic adhesion caused by a PCDHB11 with reversion of human-specific changes was as low as for modern human PCDHB11; while neither human nor reverted PCDHB11 adhered to controls, they did adhere to each other. A loss of function in PCDHB11 is unlikely because intra-human variability did not increase relative to the other human beta-protocadherins.
  
  
  CONCLUSIONS
  The brain-expressed protein with the highest number of human-specific substitutions is PCDHB11. In spite of its fast evolution and low intra-human variability, cell-based tests on the only proposed function for PCDHB11 did not indicate a functional change.
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Guilherme Braga
authors.initials: GB
authors.lastname: de Freitas
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Rafaella Araújo
authors.initials: RA
authors.lastname: Gonçalves
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. gralle@bioqmed.ufrj.br.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gralle
mesh_terms: D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000473:pathology / Q000502:physiology*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003584:Cytological Techniques; D019143:Evolution, Molecular; D006801:Humans; D020014:K562 Cells; D008253:Macaca mulatta / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D002679:Pan troglodytes / Q000235:genetics; D057080:Pongo abelii / Q000235:genetics; D000091363:Protocadherins
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; C000610245:PCDHB11 protein, human; D000091363:Protocadherins
keywords: Clustered protocadherins; Gene ontology; Human evolution; Neutral evolution