title: MECP2, a gene associated with Rett syndrome in humans, shows conserved coding regions, independent Alu insertions, and a novel transcript across primate evolution.
abstract: BACKGROUND
  The methyl-CpG Binding Protein two gene (MECP2) encodes a multifunctional protein comprising two isoforms involved in nuclear organization and regulation of splicing and mRNA template activity. This gene is normally expressed in all tissues, with a higher expression level in the brain during neuronal maturation. Loss of MECP2 function is the primary cause of Rett syndrome (RTT) in humans, a dominant, X-linked disorder dramatically affecting neural and motor development.
  
  
  RESULTS
  We investigated the molecular evolution of MECP2 in several primate taxa including 36 species in 16 genera of neotropical (platyrrhine) primates. The coding region of the MECP2_e2 isoform showed a high level of evolutionary conservation among humans and other primates, with amino acid substitutions in 14 codons and one in-frame insertion of a single serine codon, between codons 357 and 358, in Ateles paniscus. Most substitutions occurred in noncritical regions of MECP2 and the majority of the algorithms used for analyzing selection did not provide evidence of positive selection. Conversely, we found 48 sites under negative selection in different regions, 23 of which were consistently found by three different algorithms. Similar to an inverted Alu insert found previously in a lesser ape at a parallel location, one Alu insertion of approximately 300 bp in Cebus and Sapajus was found in intron 3. Phylogenetic reconstruction of the intron 3 data provided a topology that was coincident with the consensus arrangement of the primate taxa. RNAseq data in the neotropical primate Callimico goeldii revealed a novel transcript consisting of a noncontinuous region of the human-homologous intron 2 in this species; this transcript accounted for two putative polypeptides.
  
  
  CONCLUSIONS
  Despite the remarkable evolutionary conservation of MECP2, one in-frame codon insertion was observed in A. paniscus, and one region of intron 3 was affected by a trans-specific Alu retrotransposition in two neotropical primate genera. Moreover, identification of novel MECP2 transcripts in Callimico suggests that part of a homologous human intronic region might be expressed, and that the potential open reading frame in this region might be a subject of interest in RTT patients who carry an apparently normal MECP2 sequence.
authors.affiliation: Genetics Division, Instituto Nacional de Câncer, Rua André Cavalcanti 37, 4th floor, 20231-050, Rio de Janeiro, RJ, Brazil. mcarolviana@gmail.com.
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Viana
authors.affiliation: Genetics Division, Instituto Nacional de Câncer, Rua André Cavalcanti 37, 4th floor, 20231-050, Rio de Janeiro, RJ, Brazil. albertmenezes@me.com.
authors.forename: Albert Nobre
authors.initials: AN
authors.lastname: Menezes
authors.affiliation: Genetics Division, Instituto Nacional de Câncer, Rua André Cavalcanti 37, 4th floor, 20231-050, Rio de Janeiro, RJ, Brazil. miguelm@inca.gov.br.
authors.forename: Miguel Angelo M
authors.initials: MA
authors.lastname: Moreira
authors.affiliation: Centro de Primatologia do Rio de Janeiro, Rio de Janeiro, Brazil. pissinatticprj@terra.com.br.
authors.forename: Alcides
authors.initials: A
authors.lastname: Pissinatti
authors.affiliation: Genetics Division, Instituto Nacional de Câncer, Rua André Cavalcanti 37, 4th floor, 20231-050, Rio de Janeiro, RJ, Brazil. hseuanez@inca.gov.br.|Department of Genetics, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. hseuanez@inca.gov.br.
authors.forename: Héctor N
authors.initials: HN
authors.lastname: Seuánez
mesh_terms: D017398:Alternative Splicing; D020087:Alu Elements; D019943:Amino Acid Substitution; D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D003062:Codon; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005091:Exons; D005786:Gene Expression Regulation; D023061:Gene Order; D056426:Genetic Loci; D006801:Humans; D007438:Introns; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D016366:Open Reading Frames; D010802:Phylogeny; D015518:Rett Syndrome / Q000235:genetics*; D012641:Selection, Genetic; D014158:Transcription, Genetic
chemical_list: D003062:Codon; D051783:Methyl-CpG-Binding Protein 2