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MECP2, a gene associated with Rett syndrome in humans, shows conserved coding regions, independent Alu insertions, and a novel transcript across primate evolution.

Viana MC, Menezes AN, Moreira MA, Pissinatti A, Seuánez HN - BMC Genet. (2015)

Bottom Line: Conversely, we found 48 sites under negative selection in different regions, 23 of which were consistently found by three different algorithms.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.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.

View Article: PubMed Central - PubMed

Affiliation: Genetics Division, Instituto Nacional de Câncer, Rua André Cavalcanti 37, 4th floor, 20231-050, Rio de Janeiro, RJ, Brazil. mcarolviana@gmail.com.

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.

No MeSH data available.


Related in: MedlinePlus

MECP2 structure showing exons (E) and introns (In). The figure shows transcripts resulting from alternative splicing with 1,734 and 10,241 nucleotides (nt). Transcripts from different regions of exon 4 are indicated as 4a and 4b. Translation of mature mRNA molecules results in proteins of 498 and 486 amino acids (aa), MECP2_e1 and MECP2_e2, respectively
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Fig1: MECP2 structure showing exons (E) and introns (In). The figure shows transcripts resulting from alternative splicing with 1,734 and 10,241 nucleotides (nt). Transcripts from different regions of exon 4 are indicated as 4a and 4b. Translation of mature mRNA molecules results in proteins of 498 and 486 amino acids (aa), MECP2_e1 and MECP2_e2, respectively

Mentions: Through alternative splicing (Fig. 1), two mRNAs of different sizes are normally transcribed resulting in the following two isoforms: MECP2_e1, with a start codon in exon 1 and containing exon 1, 3 and 4 transcripts, and MECP2_e2, with a start codon in exon 2 and containing exon 1, 2, 3 and 4 transcripts. MECP2_e1 encodes a protein of 498 amino acids and MECP2_e2 a protein of 486 amino acids [17, 18]. MECP2_e1 is the major isoform found in the brain and throughout development [4, 19, 20]. MECP2_e1 has more relevance to the RTT phenotype [21], a finding also supported by studies on MeCP2-e1 deficient mice that developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity at 7 to 31 weeks prior to death [22]. Conversely, selective deletion of MeCP2_e2 did not result in RTT-associated neurological phenotypes, but resulted in a survival disadvantage for embryos carrying a MeCP2_e2 allele of maternal origin. A specific requirement for MeCP2_e2 function was found in extraembryonic tissue, where selective loss of MeCP2_e2 resulted in placental defects [23].Fig. 1


MECP2, a gene associated with Rett syndrome in humans, shows conserved coding regions, independent Alu insertions, and a novel transcript across primate evolution.

Viana MC, Menezes AN, Moreira MA, Pissinatti A, Seuánez HN - BMC Genet. (2015)

MECP2 structure showing exons (E) and introns (In). The figure shows transcripts resulting from alternative splicing with 1,734 and 10,241 nucleotides (nt). Transcripts from different regions of exon 4 are indicated as 4a and 4b. Translation of mature mRNA molecules results in proteins of 498 and 486 amino acids (aa), MECP2_e1 and MECP2_e2, respectively
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4493987&req=5

Fig1: MECP2 structure showing exons (E) and introns (In). The figure shows transcripts resulting from alternative splicing with 1,734 and 10,241 nucleotides (nt). Transcripts from different regions of exon 4 are indicated as 4a and 4b. Translation of mature mRNA molecules results in proteins of 498 and 486 amino acids (aa), MECP2_e1 and MECP2_e2, respectively
Mentions: Through alternative splicing (Fig. 1), two mRNAs of different sizes are normally transcribed resulting in the following two isoforms: MECP2_e1, with a start codon in exon 1 and containing exon 1, 3 and 4 transcripts, and MECP2_e2, with a start codon in exon 2 and containing exon 1, 2, 3 and 4 transcripts. MECP2_e1 encodes a protein of 498 amino acids and MECP2_e2 a protein of 486 amino acids [17, 18]. MECP2_e1 is the major isoform found in the brain and throughout development [4, 19, 20]. MECP2_e1 has more relevance to the RTT phenotype [21], a finding also supported by studies on MeCP2-e1 deficient mice that developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity at 7 to 31 weeks prior to death [22]. Conversely, selective deletion of MeCP2_e2 did not result in RTT-associated neurological phenotypes, but resulted in a survival disadvantage for embryos carrying a MeCP2_e2 allele of maternal origin. A specific requirement for MeCP2_e2 function was found in extraembryonic tissue, where selective loss of MeCP2_e2 resulted in placental defects [23].Fig. 1

Bottom Line: Conversely, we found 48 sites under negative selection in different regions, 23 of which were consistently found by three different algorithms.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.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.

View Article: PubMed Central - PubMed

Affiliation: Genetics Division, Instituto Nacional de Câncer, Rua André Cavalcanti 37, 4th floor, 20231-050, Rio de Janeiro, RJ, Brazil. mcarolviana@gmail.com.

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.

No MeSH data available.


Related in: MedlinePlus