title: Functional divergence of the brain-size regulating gene MCPH1 during primate evolution and the origin of humans.
abstract: BACKGROUND
  One of the key genes that regulate human brain size, MCPH1 has evolved under strong Darwinian positive selection during the evolution of primates. During this evolution, the divergence of MCPH1 protein sequences among primates may have caused functional changes that contribute to brain enlargement.
  
  
  RESULTS
  To test this hypothesis, we used co-immunoprecipitation and reporter gene assays to examine the activating and repressing effects of MCPH1 on a set of its down-stream genes and then compared the functional outcomes of a series of mutant MCPH1 proteins that carry mutations at the human- and great-ape-specific sites. The results demonstrate that the regulatory effects of human MCPH1 and rhesus macaque MCPH1 are different in three of eight down-stream genes tested (p73, cyclinE1 and p14ARF), suggesting a functional divergence of MCPH1 between human and non-human primates. Further analyses of the mutant MCPH1 proteins indicated that most of the human-specific mutations could change the regulatory effects on the down-stream genes. A similar result was also observed for one of the four great-ape-specific mutations.
  
  
  CONCLUSIONS
  Collectively, we propose that during primate evolution in general and human evolution in particular, the divergence of MCPH1 protein sequences under Darwinian positive selection led to functional modifications, providing a possible molecular mechanism of how MCPH1 contributed to brain enlargement during primate evolution and human origin.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Road, Kunming, Yunnan 650223, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lin
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qi
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000033:anatomy & histology*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D008253:Macaca mulatta / Q000235:genetics*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D010802:Phylogeny; D025941:Protein Interaction Mapping; D016415:Sequence Alignment; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D050687:E2F1 Transcription Factor; C460645:MCPH1 protein, human; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins