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Back-translation for discovering distant protein homologies in the presence of frameshift mutations.

Girdea M, Noe L, Kucherov G - Algorithms Mol Biol (2010)

Bottom Line: Frameshift mutations in protein-coding DNA sequences produce a drastic change in the resulting protein sequence, which prevents classic protein alignment methods from revealing the proteins' common origin.Moreover, when a large number of substitutions are additionally involved in the divergence, the homology detection becomes difficult even at the DNA level.We developed a novel method to infer distant homology relations of two proteins, that accounts for frameshift and point mutations that may have affected the coding sequences.

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ABSTRACT

Background: Frameshift mutations in protein-coding DNA sequences produce a drastic change in the resulting protein sequence, which prevents classic protein alignment methods from revealing the proteins' common origin. Moreover, when a large number of substitutions are additionally involved in the divergence, the homology detection becomes difficult even at the DNA level.

Results: We developed a novel method to infer distant homology relations of two proteins, that accounts for frameshift and point mutations that may have affected the coding sequences. We design a dynamic programming alignment algorithm over memory-efficient graph representations of the complete set of putative DNA sequences of each protein, with the goal of determining the two putative DNA sequences which have the best scoring alignment under a powerful scoring system designed to reflect the most probable evolutionary process. Our implementation is freely available at [http://bioinfo.lifl.fr/path/].

Conclusions: Our approach allows to uncover evolutionary information that is not captured by traditional alignment methods, which is confirmed by biologically significant examples.

No MeSH data available.


Elapidae: neurotoxins (2). Two Bungarus candidus proteins, very similar at the DNA level ([Swiss-Prot:Q8AY47.1] and [Swiss-Prot:Q8AY48.1]). From the first 94 amino acid pairs, only 4 present mismatches (which are transitions at the coding DNA level). A frameshift mutation is visible at position 284 of the back-translated sequences. The fragments following it are almost perfectly aligned with a frameshift, with an E-value of 10-9.
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Figure 10: Elapidae: neurotoxins (2). Two Bungarus candidus proteins, very similar at the DNA level ([Swiss-Prot:Q8AY47.1] and [Swiss-Prot:Q8AY48.1]). From the first 94 amino acid pairs, only 4 present mismatches (which are transitions at the coding DNA level). A frameshift mutation is visible at position 284 of the back-translated sequences. The fragments following it are almost perfectly aligned with a frameshift, with an E-value of 10-9.

Mentions: Following the discovered frameshift of Figure 9, we took into consideration the sequences of Bungarus candidus species that were similar to the non-frameshifted presynaptic neurotoxin of Naja kaouthia. An interesting alignment is presented in Figure 10, showing a protein that aligns to it well but not perfectly (at least 4 non synonymous transitions before the frameshift and 1 transversion after): this lets open the potential "duplicated first then frameshifted" origin of the frameshifted protein. This assumption was strongly supported by the alignment of the two corresponding cDNA [GenBank:AY057881.1] and [GenBank:AY057880.1] of two homologous proteins.


Back-translation for discovering distant protein homologies in the presence of frameshift mutations.

Girdea M, Noe L, Kucherov G - Algorithms Mol Biol (2010)

Elapidae: neurotoxins (2). Two Bungarus candidus proteins, very similar at the DNA level ([Swiss-Prot:Q8AY47.1] and [Swiss-Prot:Q8AY48.1]). From the first 94 amino acid pairs, only 4 present mismatches (which are transitions at the coding DNA level). A frameshift mutation is visible at position 284 of the back-translated sequences. The fragments following it are almost perfectly aligned with a frameshift, with an E-value of 10-9.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2821327&req=5

Figure 10: Elapidae: neurotoxins (2). Two Bungarus candidus proteins, very similar at the DNA level ([Swiss-Prot:Q8AY47.1] and [Swiss-Prot:Q8AY48.1]). From the first 94 amino acid pairs, only 4 present mismatches (which are transitions at the coding DNA level). A frameshift mutation is visible at position 284 of the back-translated sequences. The fragments following it are almost perfectly aligned with a frameshift, with an E-value of 10-9.
Mentions: Following the discovered frameshift of Figure 9, we took into consideration the sequences of Bungarus candidus species that were similar to the non-frameshifted presynaptic neurotoxin of Naja kaouthia. An interesting alignment is presented in Figure 10, showing a protein that aligns to it well but not perfectly (at least 4 non synonymous transitions before the frameshift and 1 transversion after): this lets open the potential "duplicated first then frameshifted" origin of the frameshifted protein. This assumption was strongly supported by the alignment of the two corresponding cDNA [GenBank:AY057881.1] and [GenBank:AY057880.1] of two homologous proteins.

Bottom Line: Frameshift mutations in protein-coding DNA sequences produce a drastic change in the resulting protein sequence, which prevents classic protein alignment methods from revealing the proteins' common origin.Moreover, when a large number of substitutions are additionally involved in the divergence, the homology detection becomes difficult even at the DNA level.We developed a novel method to infer distant homology relations of two proteins, that accounts for frameshift and point mutations that may have affected the coding sequences.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Frameshift mutations in protein-coding DNA sequences produce a drastic change in the resulting protein sequence, which prevents classic protein alignment methods from revealing the proteins' common origin. Moreover, when a large number of substitutions are additionally involved in the divergence, the homology detection becomes difficult even at the DNA level.

Results: We developed a novel method to infer distant homology relations of two proteins, that accounts for frameshift and point mutations that may have affected the coding sequences. We design a dynamic programming alignment algorithm over memory-efficient graph representations of the complete set of putative DNA sequences of each protein, with the goal of determining the two putative DNA sequences which have the best scoring alignment under a powerful scoring system designed to reflect the most probable evolutionary process. Our implementation is freely available at [http://bioinfo.lifl.fr/path/].

Conclusions: Our approach allows to uncover evolutionary information that is not captured by traditional alignment methods, which is confirmed by biologically significant examples.

No MeSH data available.