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. 2014 Jun:163:24-36.
doi: 10.1016/j.cbpc.2014.01.005. Epub 2014 Jan 30.

Connectivity of vertebrate genomes: Paired-related homeobox (Prrx) genes in spotted gar, basal teleosts, and tetrapods

Ingo Braasch  1 , Yann Guiguen  2 , Ryan Loker  3 , John H Letaw  4 , Allyse Ferrara  5 , Julien Bobe  6 , John H Postlethwait  7
Affiliations

Connectivity of vertebrate genomes: Paired-related homeobox (Prrx) genes in spotted gar, basal teleosts, and tetrapods

Ingo Braasch et al. Comp Biochem Physiol C Toxicol Pharmacol. 2014 Jun.

Abstract

Teleost fish are important models for human biology, health, and disease. Because genome duplication in a teleost ancestor (TGD) impacts the evolution of teleost genome structure and gene repertoires, we must discriminate gene functions that are shared and ancestral from those that are lineage-specific in teleosts or tetrapods to accurately apply inferences from teleost disease models to human health. Generalizations must account both for the TGD and for divergent evolution between teleosts and tetrapods after the likely two rounds of genome duplication shared by all vertebrates. Progress in sequencing techniques provides new opportunities to generate genomic and transcriptomic information from a broad range of phylogenetically informative taxa that facilitate detailed understanding of gene family and gene function evolution. We illustrate here the use of new sequence resources from spotted gar (Lepisosteus oculatus), a rayfin fish that diverged from teleosts before the TGD, as well as RNA-Seq data from gar and multiple teleost lineages to reconstruct the evolution of the Paired-related homeobox (Prrx) transcription factor gene family, which is involved in the development of mesoderm and neural crest-derived mesenchyme. We show that for Prrx genes, the spotted gar genome and gene expression patterns mimic mammals better than teleosts do. Analyses force the seemingly paradoxical conclusion that regulatory mechanisms for the limb expression domains of Prrx genes existed before the evolution of paired appendages. Detailed evolutionary analyses like those reported here are required to identify fish species most similar to the human genome to optimally connect fish models to human gene functions in health and disease.

Keywords: Craniofacial; Fin/limb bud; Genome duplication; Ohnolog; Paired appendages; Prrx1; Prrx2; RNA-Seq.

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Figures

Fig. 1
Fig. 1. Cladogram showing phylogenetic relationships among vertebrates analyzed in the present study
Tree topology was adopted from Near et al. (2012). VGD1/2: vertebrate genome duplication 1/2; TGD: teleost genome duplication. The results of our Prrx gene surveys are shown to the right. Presence/absence of genes is indicated by colored/white boxes. Within teleosts, a and b refer to the presence/absence of the a- and b-paralogs of prrx1, with the special case of x/y referring to the two prrx1 paralogs of from butterflyfish, for which the orthology to other teleost prrx1 genes remains unclear. The relationship of the single lamprey prrx gene to other vertebrate prrx genes also remains unresolved (see text for further information).
Fig. 2
Fig. 2. Conserved synteny between human and spotted gar Prrx genes
A) A dotplot comparing the human PRRX1 gene region on chromosome 1 (Hsa1) to the spotted gar (Loc) genome shows extensive conserved synteny to spotted gar LG10. B) Conserved synteny of human and spotted gar Prrx2 genes. C, D) Orthologous pairwise clusters between human and spotted gar.
Fig. 3
Fig. 3. Rayfin conserved synteny and phylogeny of Prrx genes
A, B) A dotplot analysis comparing the chromosomal neighborhood surrounding spotted gar prrx1 on LG10 shows double conserved synteny with chromosome segments containing prrx1 co-orthologs in zebrafish on Dre2 and Dre20 (A) and in medaka to prrx1b on Ola4 and to Ola17, which lacks a prrx1 gene. C) Nucleotide maximum likelihood phylogeny of vertebrate Prrx genes (GTR+I+G model, 50% bootstrap consensus) rooted on amphioxus prrx. Node values indicate % bootstrap support. Note that gene names were assigned taking conserved synteny and/or splicing information into account. Aal: allis1 shad; Aja: Japanese eel; Ame: Mexican tetra; Bfl: amphioxus; Cmi: elephant shark; Elu: Northern pike; Gac: stickleback; Gga: chicken; Gmo: cod; Hsa: human; Lca: Arctic lamprey; Lch: coelacanth; Loc: spotted gar; Mmu: mouse; Ola: medaka; Oni: tilapia; Pbu: butterflyfish; Phy: striped catfish; Xtr: frog.
Fig. 4
Fig. 4. Genomic environments of vertebrate Prrx genes
Orthologous genes contributing to conserved synteny are similarly color-coded.
Fig. 5
Fig. 5. Splice variants of Prrx genes
Three domains characterize Prrx proteins: the prx domain, the homeodomain and the OAR domain. The OAR domain is missing from the amniote Prrx1 splisoform B as well as from the rayfin Prrx1 splisoform B' (spotted gar) and the teleost prrx1b gene due to the use of alternative fourth exons. Evidence of splisoform B' for Prrx1b was found here for clupeocephalan teleosts (i.e. zebrafish, acanthomorphs, etc.) and elopomorph teleosts, i.e., eels), but not for osteoglossormph teleosts (i.e., butterflyfish) (see also Fig. 1).
Fig. 6
Fig. 6. Conserved synteny of Prrx paralogons after VGD1 and VGD2
Prrx genes in spotted gar (A) and human (B) are part of larger paralogons. Intragenomic paralogy dotplots in spotted gar (C) and human (D) show that additional paralogons are present in vertebrate genomes (i.e., Loc2, 6 and 19, and Hsa6 and 19) despite the absence of additional Prrx genes, as would be expected after two rounds of whole genome duplication followed by gene loss.
Fig. 7
Fig. 7. Expression of prrx genes in rayfins
A) Expression of prrx genes during spotted gar development. RNA whole mount in situ hybridizations are shown for prrx1 to the left, prrx2 to the right. The upper row shows embryos at Long/Ballard stage (st.) 28-29 at left with a dorsal view of the gar embryo (heads to the left) and at the right a lateral view of the head and anterior trunk region. Both genes are expressed in the pectoral fin buds (fb), branchial arches (white asterisks) and head structures. The lower row shows embryos at stage 32-33. At the left, lateral views of the embryos are shown with a box insert highlighting the region around the pelvic fin bud (fb) that is shown in the magnification on the right. Both prrx genes are expressed in the pelvic find buds at this stage, while expression is no longer detectable in the pectorals. B) RNA-Seq based expression analysis of prrx genes in tissues of spotted gar, European eel, zebrafish, and medaka. Expression level is measured as reads per kb per million reads (rpkm).
Fig. 8
Fig. 8. Model for the evolution of vertebrate Prrx genes
The Prrx gene family evolved through three rounds of whole genome duplication [vertebrate genome duplications 1 and 2 (VGD1/VGD2), and the teleost genome duplication (TGD)] followed by several instances of gene loss in multiple lineages (OGM: ohnolog gone missing).
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