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RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons.

Kapitonov VV, Jurka J - PLoS Biol. (2005)

Bottom Line: Yet no transposase sequence similar to RAG1 or RAG2 has been found.Our results provide the first direct evidence linking RAG1 and RSSs to a specific superfamily of DNA transposons and indicate that the V(D)J machinery evolved from transposons.We also suggest that the RAG2 protein was not encoded by ancient Transib transposons but emerged in jawed vertebrates as a counterpart of RAG1 necessary for the V(D)J recombination reaction.

View Article: PubMed Central - PubMed

Affiliation: Genetic Information Research Institute, Mountain View, California, USA. vladimir@girinst.org

ABSTRACT
The V(D)J recombination reaction in jawed vertebrates is catalyzed by the RAG1 and RAG2 proteins, which are believed to have emerged approximately 500 million years ago from transposon-encoded proteins. Yet no transposase sequence similar to RAG1 or RAG2 has been found. Here we show that the approximately 600-amino acid "core" region of RAG1 required for its catalytic activity is significantly similar to the transposase encoded by DNA transposons that belong to the Transib superfamily. This superfamily was discovered recently based on computational analysis of the fruit fly and African malaria mosquito genomes. Transib transposons also are present in the genomes of sea urchin, yellow fever mosquito, silkworm, dog hookworm, hydra, and soybean rust. We demonstrate that recombination signal sequences (RSSs) were derived from terminal inverted repeats of an ancient Transib transposon. Furthermore, the critical DDE catalytic triad of RAG1 is shared with the Transib transposase as part of conserved motifs. We also studied several divergent proteins encoded by the sea urchin and lancelet genomes that are 25%-30% identical to the RAG1 N-terminal domain and the RAG1 core. Our results provide the first direct evidence linking RAG1 and RSSs to a specific superfamily of DNA transposons and indicate that the V(D)J machinery evolved from transposons. We propose that only the RAG1 core was derived from the Transib transposase, whereas the N-terminal domain was assembled from separate proteins of unknown function that may still be active in sea urchin, lancelet, hydra, and starlet sea anemone. We also suggest that the RAG2 protein was not encoded by ancient Transib transposons but emerged in jawed vertebrates as a counterpart of RAG1 necessary for the V(D)J recombination reaction.

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Diversity of the Transib TPases and RAG1 Core–Like Proteins in AnimalsThe phylogenetic tree was obtained by using the neighbor-joining algorithm implemented in MEGA [44]. Evolutionary distance for each pair of protein sequences was measured as the proportion of aa sites at which the two sequences were different. Its scale is shown by the horizontal bar. Bootstrap values higher than 60% are reported at the corresponding nodes. Species abbreviations are as follows: AA, yellow fever mosquito; AG, African malaria mosquito; BF, lancelet; CL, bull shark; DP, D. pseudoobscura fruit fly; FR, fugu fish; HM, hydra; HS, human; NV, starlet sea anemone; SP, sea urchin; XL, frog. (Transib1 through Transib5 are from D. melanogaster fruit fly).
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pbio-0030181-g002: Diversity of the Transib TPases and RAG1 Core–Like Proteins in AnimalsThe phylogenetic tree was obtained by using the neighbor-joining algorithm implemented in MEGA [44]. Evolutionary distance for each pair of protein sequences was measured as the proportion of aa sites at which the two sequences were different. Its scale is shown by the horizontal bar. Bootstrap values higher than 60% are reported at the corresponding nodes. Species abbreviations are as follows: AA, yellow fever mosquito; AG, African malaria mosquito; BF, lancelet; CL, bull shark; DP, D. pseudoobscura fruit fly; FR, fugu fish; HM, hydra; HS, human; NV, starlet sea anemone; SP, sea urchin; XL, frog. (Transib1 through Transib5 are from D. melanogaster fruit fly).

Mentions: The PSI-BLAST PSSM of Transib TPases approximates conservation/variability of the Transib TPase consensus sequence. The more diverse the TPases used in determining the PSSM, the more accurate is the approximation; some of the insect Transib TPases are less than 30% identical to each other, as shown in Figure 2. The RAG1 Ei values decreased as the number of Transib TPases used for the PSSM construction increased due to the fact that RAG1 evolved from a Transib TPase. In all cases, the E values obtained after several rounds of iterations were less than 10−20 at the point of convergence. Nearly the entire sequences of several Transib TPases, excluding their 100–140-aa N-terminal domains, converged with an approximately 600-aa portion of RAG1 defined by positions approximately 360–1010 (Figure S3). This portion of RAG1 corresponds to the “RAG1 core,” hereafter numbered relative to human RAG1 (residues 387–1011), which along with RAG2 is known to be sufficient to perform V(D)J cleavage even after deletions of the 383-aa N-terminal and 32-aa C-terminal portions of RAG1 [19,20].


RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons.

Kapitonov VV, Jurka J - PLoS Biol. (2005)

Diversity of the Transib TPases and RAG1 Core–Like Proteins in AnimalsThe phylogenetic tree was obtained by using the neighbor-joining algorithm implemented in MEGA [44]. Evolutionary distance for each pair of protein sequences was measured as the proportion of aa sites at which the two sequences were different. Its scale is shown by the horizontal bar. Bootstrap values higher than 60% are reported at the corresponding nodes. Species abbreviations are as follows: AA, yellow fever mosquito; AG, African malaria mosquito; BF, lancelet; CL, bull shark; DP, D. pseudoobscura fruit fly; FR, fugu fish; HM, hydra; HS, human; NV, starlet sea anemone; SP, sea urchin; XL, frog. (Transib1 through Transib5 are from D. melanogaster fruit fly).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1131882&req=5

pbio-0030181-g002: Diversity of the Transib TPases and RAG1 Core–Like Proteins in AnimalsThe phylogenetic tree was obtained by using the neighbor-joining algorithm implemented in MEGA [44]. Evolutionary distance for each pair of protein sequences was measured as the proportion of aa sites at which the two sequences were different. Its scale is shown by the horizontal bar. Bootstrap values higher than 60% are reported at the corresponding nodes. Species abbreviations are as follows: AA, yellow fever mosquito; AG, African malaria mosquito; BF, lancelet; CL, bull shark; DP, D. pseudoobscura fruit fly; FR, fugu fish; HM, hydra; HS, human; NV, starlet sea anemone; SP, sea urchin; XL, frog. (Transib1 through Transib5 are from D. melanogaster fruit fly).
Mentions: The PSI-BLAST PSSM of Transib TPases approximates conservation/variability of the Transib TPase consensus sequence. The more diverse the TPases used in determining the PSSM, the more accurate is the approximation; some of the insect Transib TPases are less than 30% identical to each other, as shown in Figure 2. The RAG1 Ei values decreased as the number of Transib TPases used for the PSSM construction increased due to the fact that RAG1 evolved from a Transib TPase. In all cases, the E values obtained after several rounds of iterations were less than 10−20 at the point of convergence. Nearly the entire sequences of several Transib TPases, excluding their 100–140-aa N-terminal domains, converged with an approximately 600-aa portion of RAG1 defined by positions approximately 360–1010 (Figure S3). This portion of RAG1 corresponds to the “RAG1 core,” hereafter numbered relative to human RAG1 (residues 387–1011), which along with RAG2 is known to be sufficient to perform V(D)J cleavage even after deletions of the 383-aa N-terminal and 32-aa C-terminal portions of RAG1 [19,20].

Bottom Line: Yet no transposase sequence similar to RAG1 or RAG2 has been found.Our results provide the first direct evidence linking RAG1 and RSSs to a specific superfamily of DNA transposons and indicate that the V(D)J machinery evolved from transposons.We also suggest that the RAG2 protein was not encoded by ancient Transib transposons but emerged in jawed vertebrates as a counterpart of RAG1 necessary for the V(D)J recombination reaction.

View Article: PubMed Central - PubMed

Affiliation: Genetic Information Research Institute, Mountain View, California, USA. vladimir@girinst.org

ABSTRACT
The V(D)J recombination reaction in jawed vertebrates is catalyzed by the RAG1 and RAG2 proteins, which are believed to have emerged approximately 500 million years ago from transposon-encoded proteins. Yet no transposase sequence similar to RAG1 or RAG2 has been found. Here we show that the approximately 600-amino acid "core" region of RAG1 required for its catalytic activity is significantly similar to the transposase encoded by DNA transposons that belong to the Transib superfamily. This superfamily was discovered recently based on computational analysis of the fruit fly and African malaria mosquito genomes. Transib transposons also are present in the genomes of sea urchin, yellow fever mosquito, silkworm, dog hookworm, hydra, and soybean rust. We demonstrate that recombination signal sequences (RSSs) were derived from terminal inverted repeats of an ancient Transib transposon. Furthermore, the critical DDE catalytic triad of RAG1 is shared with the Transib transposase as part of conserved motifs. We also studied several divergent proteins encoded by the sea urchin and lancelet genomes that are 25%-30% identical to the RAG1 N-terminal domain and the RAG1 core. Our results provide the first direct evidence linking RAG1 and RSSs to a specific superfamily of DNA transposons and indicate that the V(D)J machinery evolved from transposons. We propose that only the RAG1 core was derived from the Transib transposase, whereas the N-terminal domain was assembled from separate proteins of unknown function that may still be active in sea urchin, lancelet, hydra, and starlet sea anemone. We also suggest that the RAG2 protein was not encoded by ancient Transib transposons but emerged in jawed vertebrates as a counterpart of RAG1 necessary for the V(D)J recombination reaction.

Show MeSH
Related in: MedlinePlus