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Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development.

Chowanadisai W - PLoS ONE (2014)

Bottom Line: The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes.ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell.Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, University of California Davis, Davis, California, United States of America.

ABSTRACT
The zinc transporter ZIP12, which is encoded by the gene slc39a12, has previously been shown to be important for neuronal differentiation in mouse Neuro-2a neuroblastoma cells and primary mouse neurons and necessary for neurulation during Xenopus tropicalis embryogenesis. However, relatively little is known about the biochemical properties, cellular regulation, or the physiological role of this gene. The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12. Ortholog detection of slc39a12 was conducted with reciprocal BLAST hits with the amino acid sequence of human ZIP12 in comparison to the human paralog ZIP4 and conserved local synteny between genomes. ZIP12 is present in the genomes of almost all vertebrates examined, from humans and other mammals to most teleost fish. However, ZIP12 appears to be absent from the zebrafish genome. The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes. Splice variation, due to the inclusion or exclusion of a conserved exon, is present in humans, rats, and cows and likely has biological significance. ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell. These findings highlight multiple aspects of ZIP12 at the biochemical, cellular, and physiological levels with likely biological significance. ZIP12 appears to have conserved function as a zinc uptake transporter in vertebrate nervous system development. Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

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Phylogenetic alignment and nucleotide sequences of slc39a12 show conservation across vertebrates.Human slc39a12 gene structure is indicated. Multiz phylogenetic alignment of slc39a12 orthologs in 16 vertebrate genomes show conservation in exons and some extra-exonic regions. Primate and vertebrate exonic and intronic regions of conservation are indicated by peaks following analysis by PhyloP and PhastCons. Scale bar at top indicates 50 kb.
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pone-0111535-g002: Phylogenetic alignment and nucleotide sequences of slc39a12 show conservation across vertebrates.Human slc39a12 gene structure is indicated. Multiz phylogenetic alignment of slc39a12 orthologs in 16 vertebrate genomes show conservation in exons and some extra-exonic regions. Primate and vertebrate exonic and intronic regions of conservation are indicated by peaks following analysis by PhyloP and PhastCons. Scale bar at top indicates 50 kb.

Mentions: The human slc39a12 gene spans 13 exons across 91.4 kilobases (kb) on chromosome 10p12.33 (Figure 1, Figure 2). Orthologs to the human slc39a12 gene (Table 1) were identified by combinations of Homologene searches, reciprocal BLAST hits [40], and local synteny preservation [41]. Identified orthologs of ZIP12 shared amino acid identities with the human ZIP12 that correlated with the relatedness of the organisms to humans, ranging from 86 to 99 percent for non-human primates to 48 to 50 percent in fish (Table 1). In contrast, the amino acid identities of the ZIP12 orthologs to human ZIP4 ranged between 31 to 40 percent without any correlation to relatedness with humans (Table 1). Because there are many common elements between members of the SLC39 gene family, particularly between ZIP12 and ZIP4 [9], [42], it can be difficult to distinguish orthologs of ZIP12 from SLC39 paralogs solely based upon sequence similarity such as BLAST. Local synteny between ortholog candidates is extremely useful in confirming reciprocal BLAST hits [41], especially in cases of gene families with large numbers of paralogs, such as the case with the solute carrier (SLC) gene families [43], [44]. In general, synteny was observed across vertebrates (Figure 3, Figure S1), but possible disruptions of the syntenic block in more distant organisms corresponded with reduced relatedness to humans, possibly due to genomic rearrangements during evolution [45]. As with the case with most orthologous genes in vertebrates [46], the coding exon structure of slc39a12, including number of exons and exon size, is conserved across humans, mice, and Xenopus tropicalis (data not shown). An alignment of human ZIP12 with other related ZIP genes (Figure S2) and with other ZIP12 orthologs (Figure S3) shows that many C-terminus elements are conserved, especially those predicted to encode the transmembrane helices and zinc transport function, such as the HEXPHEGD motif that is present in the LIV-1 subfamily of ZIP transporters [47]–[49]. The phylogenetic tree (Figure 4) indicates that the relatedness of ZIP12 across different organisms is highly correlated with the relatedness of the whole genomes across organisms [50]–[52].


Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development.

Chowanadisai W - PLoS ONE (2014)

Phylogenetic alignment and nucleotide sequences of slc39a12 show conservation across vertebrates.Human slc39a12 gene structure is indicated. Multiz phylogenetic alignment of slc39a12 orthologs in 16 vertebrate genomes show conservation in exons and some extra-exonic regions. Primate and vertebrate exonic and intronic regions of conservation are indicated by peaks following analysis by PhyloP and PhastCons. Scale bar at top indicates 50 kb.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222902&req=5

pone-0111535-g002: Phylogenetic alignment and nucleotide sequences of slc39a12 show conservation across vertebrates.Human slc39a12 gene structure is indicated. Multiz phylogenetic alignment of slc39a12 orthologs in 16 vertebrate genomes show conservation in exons and some extra-exonic regions. Primate and vertebrate exonic and intronic regions of conservation are indicated by peaks following analysis by PhyloP and PhastCons. Scale bar at top indicates 50 kb.
Mentions: The human slc39a12 gene spans 13 exons across 91.4 kilobases (kb) on chromosome 10p12.33 (Figure 1, Figure 2). Orthologs to the human slc39a12 gene (Table 1) were identified by combinations of Homologene searches, reciprocal BLAST hits [40], and local synteny preservation [41]. Identified orthologs of ZIP12 shared amino acid identities with the human ZIP12 that correlated with the relatedness of the organisms to humans, ranging from 86 to 99 percent for non-human primates to 48 to 50 percent in fish (Table 1). In contrast, the amino acid identities of the ZIP12 orthologs to human ZIP4 ranged between 31 to 40 percent without any correlation to relatedness with humans (Table 1). Because there are many common elements between members of the SLC39 gene family, particularly between ZIP12 and ZIP4 [9], [42], it can be difficult to distinguish orthologs of ZIP12 from SLC39 paralogs solely based upon sequence similarity such as BLAST. Local synteny between ortholog candidates is extremely useful in confirming reciprocal BLAST hits [41], especially in cases of gene families with large numbers of paralogs, such as the case with the solute carrier (SLC) gene families [43], [44]. In general, synteny was observed across vertebrates (Figure 3, Figure S1), but possible disruptions of the syntenic block in more distant organisms corresponded with reduced relatedness to humans, possibly due to genomic rearrangements during evolution [45]. As with the case with most orthologous genes in vertebrates [46], the coding exon structure of slc39a12, including number of exons and exon size, is conserved across humans, mice, and Xenopus tropicalis (data not shown). An alignment of human ZIP12 with other related ZIP genes (Figure S2) and with other ZIP12 orthologs (Figure S3) shows that many C-terminus elements are conserved, especially those predicted to encode the transmembrane helices and zinc transport function, such as the HEXPHEGD motif that is present in the LIV-1 subfamily of ZIP transporters [47]–[49]. The phylogenetic tree (Figure 4) indicates that the relatedness of ZIP12 across different organisms is highly correlated with the relatedness of the whole genomes across organisms [50]–[52].

Bottom Line: The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes.ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell.Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, University of California Davis, Davis, California, United States of America.

ABSTRACT
The zinc transporter ZIP12, which is encoded by the gene slc39a12, has previously been shown to be important for neuronal differentiation in mouse Neuro-2a neuroblastoma cells and primary mouse neurons and necessary for neurulation during Xenopus tropicalis embryogenesis. However, relatively little is known about the biochemical properties, cellular regulation, or the physiological role of this gene. The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12. Ortholog detection of slc39a12 was conducted with reciprocal BLAST hits with the amino acid sequence of human ZIP12 in comparison to the human paralog ZIP4 and conserved local synteny between genomes. ZIP12 is present in the genomes of almost all vertebrates examined, from humans and other mammals to most teleost fish. However, ZIP12 appears to be absent from the zebrafish genome. The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes. Splice variation, due to the inclusion or exclusion of a conserved exon, is present in humans, rats, and cows and likely has biological significance. ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell. These findings highlight multiple aspects of ZIP12 at the biochemical, cellular, and physiological levels with likely biological significance. ZIP12 appears to have conserved function as a zinc uptake transporter in vertebrate nervous system development. Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

Show MeSH
Related in: MedlinePlus