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. 2012;7(7):e41850.
doi: 10.1371/journal.pone.0041850. Epub 2012 Jul 25.

Evolution of the vertebrate paralemmin gene family: ancient origin of gene duplicates suggests distinct functions

Greta Hultqvist  1 , Daniel Ocampo Daza, Dan Larhammar, Manfred W Kilimann
Affiliations

Evolution of the vertebrate paralemmin gene family: ancient origin of gene duplicates suggests distinct functions

Greta Hultqvist et al. PLoS One. 2012.

Abstract

Paralemmin-1 is a protein implicated in plasma membrane dynamics, the development of filopodia, neurites and dendritic spines, as well as the invasiveness and metastatic potential of cancer cells. However, little is known about its mode of action, or about the biological functions of the other paralemmin isoforms: paralemmin-2, paralemmin-3 and palmdelphin. We describe here evolutionary analyses of the paralemmin gene family in a broad range of vertebrate species. Our results suggest that the four paralemmin isoform genes (PALM1, PALM2, PALM3 and PALMD) arose by quadruplication of an ancestral gene in the two early vertebrate genome duplications. Paralemmin-1 and palmdelphin were further duplicated in the teleost fish specific genome duplication. We identified a unique sequence motif common to all paralemmins, consisting of 11 highly conserved residues of which four are invariant. A single full-length paralemmin homolog with this motif was identified in the genome of the sea lamprey Petromyzon marinus and an isolated putative paralemmin motif could be detected in the genome of the lancelet Branchiostoma floridae. This allows us to conclude that the paralemmin gene family arose early and has been maintained throughout vertebrate evolution, suggesting functional diversification and specific biological roles of the paralemmin isoforms. The paralemmin genes have also maintained specific features of gene organisation and sequence. This includes the occurrence of closely linked downstream genes, initially identified as a readthrough fusion protein with mammalian paralemmin-2 (Palm2-AKAP2). We have found evidence for such an arrangement for paralemmin-1 and -2 in several vertebrate genomes, as well as for palmdelphin and paralemmin-3 in teleost fish genomes, and suggest the name paralemmin downstream genes (PDG) for this new gene family. Thus, our findings point to ancient roles for paralemmins and distinct biological functions of the gene duplicates.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Conserved organization of paralemmin isoform genes.
Exon sizes are roughly proportional relative to each other, whereas intron sizes are schematic. Kinked lines indicate differential splicing. Human (h-) and teleost fish (tf-) genes are shown as examples.
Figure 2
Figure 2. Paralemmin sequence alignments.
A) Alignment of the conserved sequence regions of paralemmin orthologs and paralogs. These sequence regions are colored in Figure 1 (exons F1–F3 and 5′ parts of exon G are excluded). The point where the less conserved region is excluded from the alignment is marked by a dashed vertical line at position 158. Asterisks mark invariant residues and dots mark conservative substitutions. The paralemmin motif (conserved in all paralemmins), the MIF motif (conserved in all but PALM3) and the C-terminal CaaX motif are indicated by boxes above the alignment. The alternative splice site of PALMD genes is indicated by a black vertical line at position 288. B) The alternatively spliced exon H in PALMD genes, with the KKVI motif marked. The alignment used in the phylogenetic analyses included the PALMD splice variants with exon H, including the KKVI motif, rather than the splice variants with the CaaX motif (see Results). Species name abbreviations: human (Hsa), mouse (Mmu), chicken (Gga), Western clawed frog (Xtr), zebrafish (Dre), medaka (Ola), fugu (Tru), three-spined stickleback (Gac), green spotted pufferfish (Tni), sea lamprey (Pma) and lancelet (Bfl). Chromosome, scaffold (s-) or ultracontig (u-) locations are given in the sequence names, followed by the assigned paralemmin isoform based on our phylogenetic analysis.
Figure 3
Figure 3. Phylogenetic analyses of the paralemmin protein family.
A) Bootstrapped neighbor-joining tree (1000 bootstrap replicates). B) Bootstrapped phylogenetic maximum likelihood tree (100 bootstrap replicates). Species name abbreviations are applied as in Figure 2. The chromosome, scaffold (s-) or ultracontig (u-) assignments are given in the sequence names after the species abbreviations. Both trees are presented as radial unrooted trees since no invertebrate orthologs could be identified to be used as outgroup.
Figure 4
Figure 4. Identified blocks of conserved synteny around paralemmin genes in human, chicken, zebrafish and stickleback.
Gene families that were selected had members located within ±5 Mb of at least three different paralemmin genes in the human genome. Genes in boxes with dashed frame were not included in the phylogenetic analyses (see Results). Gene family abbreviations: ATP-binding cassette sub-family A (ABCA), calponin (CNN), paralemmin downstream genes (PDG), plasticity related genes (PRG), polypyrimidine tract-binding protein (PTBP), sphingosine-1–phosphate receptors (S1PR). These gene families have additional members on separate chromosomes, not part of these identified blocks of conserved synteny (Table S1, Figure 5, Figures S1, S2, S3, S4, and S5); for the S1PR family these are S1PR1, S1PR3 and S1PR4 on zebrafish chromosome 22 and S1PR1 on stickleback group VIII; for the CNN family, CNN1A is located on chromosome 1 in zebrafish; for the ABCA family, ABCA1 in zebrafish is located on chromosome 1 and ABCA4A in stickleback is located on group XXI.
Figure 5
Figure 5. Phylogenetic maximum likelihood tree of the paralemmin downstream gene (PDG) family.
This family includes all identified homologs of the known AKAP2 genes. The PDG isoforms are named for the paralemmin genes to which they are adjacent, with the exception of PDG4, which are adjacent to PALMD genes. The phylogenetic analysis of this family, as well as the chromosomal data, are consistent with our proposed duplication scheme (Figure 6) and the phylogenetic analysis of the paralemmins (Figure 3), but also show a duplication of the region bearing PALM3 in teleost fishes, probably through 3R.
Figure 6
Figure 6. Proposed scenario for the evolution of the paralemmin gene family.
A single ancestral chromosome was quadrupled in the two basal vertebrate rounds of genome doubling (1R and 2R), giving rise to the four paralemmin isoform genes PALM1, PALM2, PALM3 and PALMD. The PALM3 gene appears to have been lost from the avian lineage (not shown here). Subsequently, the teleost-specific third round of genome doubling (3R), generated duplicates of PALM1 and PALMD. This duplication scheme is supported by the chromosome locations and phylogenetic analyses of the PALM gene family as well as the neighboring gene families ABCA, CNN, PDG, PTB, PRG and S1PR across a wide selection of vertebrate species. Here zebrafish (Danio rerio) and human are shown as examples. Note that two of the duplicated genome regions in zebrafish have ended up on chromosome 2, likely due to chromosome rearrangements in the zebrafish lineage. Similarly, two of the chromosome regions in the human genome harboring PALM1 and PALM3, respectively, are on different parts of chromosome 19. However, this seems to be due to a recent fusion in the linage leading to humans, as detailed in the Discussion. Note also that several genes have been lost after the chromosome duplications and that the gene order has been shuffled in both zebrafish and human compared to the predicted ancestral chromosome regions. Crossed-over boxes represent likely gene losses. Dotted lines between PALM2 and PDG genes indicate read-through transcription and splicing into the same mRNA. Gene family abbreviations and colors are applied as in Figure 4 with the PALM gene family in red.
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