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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

Comparison of human MECP2_e2 amino acid sequences with those from other primates. Top bar indicates different MECP2 regions with codon numbers delimiting each region. ID = interdomain. Numbers inside parentheses indicate the number of specimens analyzed. Ins* indicates an insertion between codons 357 and 358
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Fig2: Comparison of human MECP2_e2 amino acid sequences with those from other primates. Top bar indicates different MECP2 regions with codon numbers delimiting each region. ID = interdomain. Numbers inside parentheses indicate the number of specimens analyzed. Ins* indicates an insertion between codons 357 and 358

Mentions: Comparisons of the MECP2_e2 coding region of nonhuman primates revealed amino acid substitutions in 14 codons when compared with the human sequence (Fig. 2), and one in-frame insertion of a single serine codon, between codons 357 and 358 in A. paniscus, was identified. In terms of amino acid polarity, analysis of the substitutions identified three that occurred between nonpolar residues, followed by polar for nonpolar substitutions (n = 2), nonpolar for polar substitutions (n = 3), one negatively charged for another negatively charged substitution and substitution of one polar residue for another polar residue. We observed three different substitutions in three codons of the N-terminal region of MECP2_e2. Of these, E38D (substitution of a negatively charged residue by another negatively charged residue) occurred in all of the non-hominid primates. The exception to this was the Saguinus midas sequence, which shared the same residue to that of the human sequence. Our interpretation of these findings lends to the proposal that aspartate was the ancestral residue of codon 38 and that a D38E substitution must have occurred twice and independently in the phylogenetically distant lineages leading to the large hominoids and Saguinus. Another substitution was found in the N-terminal region of MECP2_e2 (S49P, which involves a nonpolar for a polar substitution); this was restricted to the Sapajus genus and was absent in all other taxa studied herein, including Cebus, a closely related genus. Two substitutions, T203V (in the interdomain) and V275A (in the TRD domain), were restricted to two species of Saimiri, and A277T (in the TRD domain) to Callicebus species. Three different substitutions were found in four species; these were in the interdomains or C-terminal regions (T196S, A358T and V380M) previously listed in RettBASE as being nonpathogenic in humans. Indeed, T196S and A358T are polymorphic variants and V380M is a variant with unknown effects. Finally, the O. garnettii alignment showed an isoleucine codon that matched the first methionine codon in the majority of the other primates, and that the first methionine codon in this species corresponded to codon five of human MECP2_e2.Fig. 2


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)

Comparison of human MECP2_e2 amino acid sequences with those from other primates. Top bar indicates different MECP2 regions with codon numbers delimiting each region. ID = interdomain. Numbers inside parentheses indicate the number of specimens analyzed. Ins* indicates an insertion between codons 357 and 358
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Comparison of human MECP2_e2 amino acid sequences with those from other primates. Top bar indicates different MECP2 regions with codon numbers delimiting each region. ID = interdomain. Numbers inside parentheses indicate the number of specimens analyzed. Ins* indicates an insertion between codons 357 and 358
Mentions: Comparisons of the MECP2_e2 coding region of nonhuman primates revealed amino acid substitutions in 14 codons when compared with the human sequence (Fig. 2), and one in-frame insertion of a single serine codon, between codons 357 and 358 in A. paniscus, was identified. In terms of amino acid polarity, analysis of the substitutions identified three that occurred between nonpolar residues, followed by polar for nonpolar substitutions (n = 2), nonpolar for polar substitutions (n = 3), one negatively charged for another negatively charged substitution and substitution of one polar residue for another polar residue. We observed three different substitutions in three codons of the N-terminal region of MECP2_e2. Of these, E38D (substitution of a negatively charged residue by another negatively charged residue) occurred in all of the non-hominid primates. The exception to this was the Saguinus midas sequence, which shared the same residue to that of the human sequence. Our interpretation of these findings lends to the proposal that aspartate was the ancestral residue of codon 38 and that a D38E substitution must have occurred twice and independently in the phylogenetically distant lineages leading to the large hominoids and Saguinus. Another substitution was found in the N-terminal region of MECP2_e2 (S49P, which involves a nonpolar for a polar substitution); this was restricted to the Sapajus genus and was absent in all other taxa studied herein, including Cebus, a closely related genus. Two substitutions, T203V (in the interdomain) and V275A (in the TRD domain), were restricted to two species of Saimiri, and A277T (in the TRD domain) to Callicebus species. Three different substitutions were found in four species; these were in the interdomains or C-terminal regions (T196S, A358T and V380M) previously listed in RettBASE as being nonpathogenic in humans. Indeed, T196S and A358T are polymorphic variants and V380M is a variant with unknown effects. Finally, the O. garnettii alignment showed an isoleucine codon that matched the first methionine codon in the majority of the other primates, and that the first methionine codon in this species corresponded to codon five of human MECP2_e2.Fig. 2

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