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Variations of the standard genetic code are pretty rare, but as the cost of high-throughput genome sequencing continues to drop, there is a greater possibility of discovering additional exceptions. That being said, there is a clear emphasis in genome projects on nucleotide (genome and transcriptome) sequencing, with much less (if any) effort put into proteomics work (correct me if I'm wrong there).

Let's assume we're sequencing the genome of a new organism and we're focusing completely on genome and transcriptome sequencing--no proteomics. Let's also assume this organism has slight variations to the standard genetic code. Would it be possible to annotate this genome (for protein-coding genes) completely incorrectly since the gene prediction software does not take into account these variations, or would it be pretty obvious? What would you expect to see in this case?

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Your question is very vague. Can you be more specific and/or more concrete? There are a dozen sequencing technologies and even more variations to the genetic code. –  Thomas Ingalls Dec 22 '11 at 5:46
    
Perhaps the vagueness comes from the fact that I don't know what to expect if I was trying to annotate the genome of an organism that uses an alternate genetic code. My basic question is: would I even be able to tell? Is that not clear from the original question? –  Daniel Standage Dec 22 '11 at 5:48
    
I think that's a clear question. –  Richard Smith Jun 12 '12 at 14:03
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If the organism uses an alternative code, the predicted protein sequences would always include the same type of amino acid substitution errors. This pattern should become apparent when you compare the proteins to other organisms. In reality, the most common alternative code uses UGA for tryptophan instead of the usual stop. If you make the mistake of using the standard code for these genomes, the predicted genes would become highly fragmented so it is almost impossible not to notice.

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You are correct to be a little concerned, especially with mitochondrial genomes (where non-standard genetic codes are more prevalent). In addition to the use of non-standard codes you should also consider RNA editing (changed codons or deleted/inserted nucleotides to shift reading frames) and special amino acids (e.g., selenocysteine). All together, the emphasis on DNA sequence to infer protein structure is safe in the bulk of cases, but don't be surprised by differences (for particular genes or for whole organisms).

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The short answer is yes, you could end up with many errors. See here for more detail:

NCBI: "The Genetic Codes"

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