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. 2015 Sep;25(9):1256-67.
doi: 10.1101/gr.190538.115. Epub 2015 Jul 20.

Evolution of selenophosphate synthetases: emergence and relocation of function through independent duplications and recurrent subfunctionalization

Marco Mariotti  1 , Didac Santesmasses  2 , Salvador Capella-Gutierrez  3 , Andrea Mateo  4 , Carme Arnan  2 , Rory Johnson  2 , Salvatore D'Aniello  5 , Sun Hee Yim  6 , Vadim N Gladyshev  6 , Florenci Serras  4 , Montserrat Corominas  4 , Toni Gabaldón  7 , Roderic Guigó  2
Affiliations

Evolution of selenophosphate synthetases: emergence and relocation of function through independent duplications and recurrent subfunctionalization

Marco Mariotti et al. Genome Res. 2015 Sep.

Abstract

Selenoproteins are proteins that incorporate selenocysteine (Sec), a nonstandard amino acid encoded by UGA, normally a stop codon. Sec synthesis requires the enzyme Selenophosphate synthetase (SPS or SelD), conserved in all prokaryotic and eukaryotic genomes encoding selenoproteins. Here, we study the evolutionary history of SPS genes, providing a map of selenoprotein function spanning the whole tree of life. SPS is itself a selenoprotein in many species, although functionally equivalent homologs that replace the Sec site with cysteine (Cys) are common. Many metazoans, however, possess SPS genes with substitutions other than Sec or Cys (collectively referred to as SPS1). Using complementation assays in fly mutants, we show that these genes share a common function, which appears to be distinct from the synthesis of selenophosphate carried out by the Sec- and Cys- SPS genes (termed SPS2), and unrelated to Sec synthesis. We show here that SPS1 genes originated through a number of independent gene duplications from an ancestral metazoan selenoprotein SPS2 gene that most likely already carried the SPS1 function. Thus, in SPS genes, parallel duplications and subsequent convergent subfunctionalization have resulted in the segregation to different loci of functions initially carried by a single gene. This evolutionary history constitutes a remarkable example of emergence and evolution of gene function, which we have been able to trace thanks to the singular features of SPS genes, wherein the amino acid at a single site determines unequivocally protein function and is intertwined to the evolutionary fate of the entire selenoproteome.

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Figures

Figure 1.
Figure 1.
(Enclosed poster) Phylogenetic profile of SPS and selenium utilization traits in prokaryotes. The sunburst tree shows the phylogenetic structure of the reference set of 223 prokaryotic genomes (taken from NCBI taxonomy) and the presence of SelD genes and other markers of selenium utilization.
Figure 2.
Figure 2.
(Enclosed poster) Phylogenetic profile of SPS genes and approximate selenoproteome size of eukaryotes. The plot recapitulates the results on 505 genomes analyzed, summarized to 213 displayed here.
Figure 3.
Figure 3.
Parallel gene duplications of SPS proteins in metazoa. The plot summarizes the phylogenetic history of metazoan SPS genes, consisting of parallel and convergent events of gene duplication followed by subfunctionalization. Each colored ball represents a SPS gene, indicating the residue found at the UGA or homologous codon: (U) selenocysteine; (C) cysteine; (T) threonine; (G) glycine; (L) leucine; (R) arginine; (x) unknown residue. The gene structures are schematically displayed in Figure 4. The names of the insect species lacking selenoproteins are in red. The main genomic events shaping SPS genes are indicated on the branches: (GD) whole gene duplication; (GDR) gene duplication by retrotransposition; (AE) origin of an alternative exon; (SL) Sec loss; (SC) conversion of Sec to Cys; (SO) conversion of Sec to something other than Cys; (GL) gene loss. In our subfunctionalization hypothesis (see text), we map the origin of a dual function at the root of metazoa. A star (*) marks the metazoan SPS2-Sec genes which did not duplicate. These genes are expected to possess dual function.
Figure 4.
Figure 4.
Structure and function of the identified SPS genes. SPS proteins are classified according to the residue found at the UGA or homologous position (Fig. 3). The presence of specific secondary structures is also indicated: (bSECIS) bacterial SECIS element; (SRE) Sec recoding element (Howard et al. 2005); (SECIS) eukaryotic SECIS element; (HRE) hymenopteran readthrough element. The rightmost column indicates the functions predicted for the SPS proteins. SPS2 function is the synthesis of selenophosphate. SPS1 function is defined as the uncharacterized molecular function of Drosophila SPS1-Arg (double underlined), which is likely to be similar to that of other SPS1 genes, as suggested by knockout-rescue experiments in Drosophila (underlined). (*) Eukaryotic SPS2; the parentheses indicate that some such genes are predicted to possess both SPS1 and SPS2 functions, those marked also with a star (*) in Figure 3 (essentially all metazoans with no SPS1 protein in the same genome).
Figure 5.
Figure 5.
Alternative SPS1/2 transcript isoforms sorted by retrotransposition within ascidians. This figure expands the section for tunicates in Figure 3. At the root of ascidians, the ancestral SPS2-Sec gene acquired a novel SPS-Gly transcript isoform through alternative exon usage at the 5′ end (AE). Then, at the root of the ascidian lineage, Styelidae and Pyuridae, the SPS-Sec transcript of this dual SPS1/SPS2 gene (SPS-ae) retrotransposed to the genome creating a novel SPS2-Sec gene (GDR). This presumably triggered the loss of Sec from the parental gene, which, because both the SECIS and the UGA containing exon degenerated (SL), specialized only in the production of SPS1-Gly.
Figure 6.
Figure 6.
Readthrough-enhancing hexanucleotide in SPS genes. The phylogenetic tree on the left shows the nucleotide sequence alignment at the UGA (or homologous) site in SPS sequences. Only SPS2 and SPS1-UGA genes are shown here. Codons are colored according to their translation, following the same color schema used in Figures 2 and 4 (gray for other amino acids). The presence of the hexanucleotide described in Harrell et al. (2002) is marked with a black dot. Green dots mark the genes for which a bona fide SECIS element was identified. The last column indicates the presence of SPS1 genes.
Figure 7.
Figure 7.
Rescue of the Drosophila melanogaster SPS1 mutant by heterologous SPS1 proteins. All images show wing imaginal discs dissected from larvae with the indicated constructs and genotypes. (A,B) The SPS1 mutant flies (SelDptuf/SelDptuf) result in defects in the whole organism, but can be easily monitored in the wing imaginal disc epithelia; the homozygous condition (A) strongly impairs size and morphology, whereas the heterozygous (B) is very similar to the wild-type condition. (C–E) The severe homozygous SelDptuf/SelDptuf phenotype is partially rescued by ubiquitous expression of heterologous SPS1 proteins. (C) SelDptuf/SelDptuf mutants with C. intestinalis SPS-Gly. (D) SelDptuf/SelDptuf mutants with A. cephalotes SPS1-UGA. (E) SelDptuf/SelDptuf mutants with human SPS1-Thr. (Scale bars) 50 µm.
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