Hellsten U et al. (2007), Accelerated gene evolution and subfunctionaliza...

XB-ART-36320

BMC Biol 2007 Jul 25;5:31. doi: 10.1186/1741-7007-5-31.

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Accelerated gene evolution and subfunctionalization in the pseudotetraploid frog Xenopus laevis.

Hellsten U , Khokha MK , Grammer TC , Harland RM , Richardson P , Rokhsar DS .

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BACKGROUND: Ancient whole genome duplications have been implicated in the vertebrate and teleost radiations, and in the emergence of diverse angiosperm lineages, but the evolutionary response to such a perturbation is still poorly understood. The African clawed frog Xenopus laevis experienced a relatively recent tetraploidization ~40 million years ago. Analysis of the considerable amount of EST sequence available for this species together with the genome sequence of the related diploid Xenopus tropicalis provides a unique opportunity to study the genomic response to whole genome duplication. RESULTS: We identified 2218 gene triplets in which a single gene in X. tropicalis corresponds to precisely two co-orthologous genes in X. laevis--the largest such collection published from any duplication event in animals. Analysis of these triplets reveals accelerated evolution or relaxation of constraint in the peptides of the X. laevis pairs compared with the orthologous sequences in X. tropicalis and other vertebrates. In contrast, single-copy X. laevis genes do not show this acceleration. Duplicated genes can differ substantially in expression levels and patterns. We find no significant difference in gene content in the duplicated set, versus the single-copy set based on molecular and biological function ontologies. CONCLUSION: These results support a scenario in which duplicate genes are retained through a process of subfunctionalization and/or relaxation of constraint on both copies of an ancestral gene.

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Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: foxa1 idh2 skp1 sri

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	Figure 1. Four-fold synonymous transversion rates. (a) X. tropicalis-X. laevis mutual-best hits (LT MBH) show 4 DTv distances sharply peaked around 0.09 corresponding to the species divergence. The few hits in the high-end tail (4 DTv > 0.2) are due to the incompleteness of the gene sets and/or gene losses. The line marked LL doublets shows two-member clusters of recent (4 DTv < 0.15) X. laevis paralogs. Assuming uniform transversion rates across vertebrates, and dating the last common human-mouse ancestor at 75 Mya, the laevis-tropicalis and laevis-laevis divergence is ~50 and ~40 Mya, respectively. For comparison, paralogs from the much more ancient teleost duplication in zebrafish are also shown. After correcting for multiple transversions, the fish duplication is about eight times older than the X. laevis event, consistent with timings based on total synonymous substitution rates [13,14]. (b) 4 DTv distributions for orthologs in mouse-rat (red), mouse-human (blue), rat-human (green), and mouse-X. tropicalis (purple). Only orthologs supported by conserved synteny are considered. Using the same molecular clock as panel (a), the mammal-frog divergence is 350 Mya.
	Figure 2. Symmetric evolution of paralogs. Scatter plot of relative evolution between X. tropicalis peptides and their co-orthologous sequences in X. laevis. A total of 578 gene triples with 16 or more highly-conserved positions are shown (see text for details). L1 and L2 refer to co-orthologous genes 1 and 2 in X. laevis. The diagonal line represents a null model assuming symmetric evolution of L1 and L2. Black boxes are L1�L2 pairs inconsistent with this model at P < 0.01.
	Figure 3. Normalized peptide to nucleotide evolutionary rates show an accelerated divergence of duplicated X. laevis peptides. The chart shows the ratio of peptide evolution (P-distance) to synonymous transversion rates (4 DTv), normalized by the human-mouse P-distance/4 DTV value of 0.242 � 0.004, for three sets of multiple alignments corresponding to genes found in single copy in each of human, mouse, rat, and X. tropicalis, and two copies in X. laevis (sextuplets); pentuplets obtained by randomly selecting one X. laevis paralog from each sextuplet (5 A), and pentuplets in which only a single X. laevis sequence is known (5B).
	Figure 4. Expression of specific X. laevis paralogs and their X. tropicalis ortholog. Panels depict the expression of skp1a (a-c), isocitrate dehydrogenase (isoD) (d-f), foxA1 (g-i), sorcin (j-l). X. laevis paralogs were arbitrarily assigned as a (a,d,g,j) or b (b,e,h,k) and are compared to the X. tropicalis ortholog (c, f, i, l). All views are lateral with anterior to the left. Embryos (a-f, j-l) are at stages 31 while embryos (g-i) are at stage 37�38. The arrowhead in (b) indicates kidney expression of skp1a in X. laevis paralog b that is not seen in the a paralog. Insets in (d) and (e) magnify somite expression revealing the differential expression between X. laevis paralogs ((d) with narrow expression, (e) with broad expression). The arrow in (g) highlights posterior expression of foxA1 seen in paralog a but absent in paralog b. The arrow in (k) indicates weak lateral expression of sorcin in X. laevis paralog b that is not seen in paralog a. X. tropicalis embryos are shown at a higher magnification than X. laevis embryos, reflecting their smaller size.
	Figure 5. 4DS distances identify genome duplication event. Histograms of the 4DS distances for the 9905 mutual highest scoring L-T pairs (blue line) as well as for the 3358 unambigous L-L pairs (red bars). The L-L pairs with 0.05 < 4DS < 0.25, peaking around 0.16, are selected as originating from the genome duplication event.
	idh2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 30, lateral view, anterior left, dorsal up.
	skp1 (S-phase kinase-associated protein 1) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 30, lateral view, anterior left, dorsal up.
	sri (sorcin) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 30, lateral view, anterior left, dorsal up.

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Altschul, Basic local alignment search tool. 1990, Pubmed