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I'm a bit curious as to how frame-shift mutation works. If you shift one amino acid towards another. How does this not affect the entire chromosome? Wouldn't this mean that the organism would be absolutely "scrambled" as it would essentially be "missing" a whole chromosome...Or having a chromosome that did all kinds of wrong things at least?

Thanks.

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  • $\begingroup$ have you read at least wiki article on frame-shift mutations? Basic structure of genome is blocks of (Promoter:gene) type sequences. So what happens inside gene sequence is isolated for that gene only $\endgroup$ – aaaaaa May 6 '15 at 21:41
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For transcription, the cell uses different signals from start- or stop- codons to determine the start and end of a transcript (see this wiki page). Codons (and hence frameshifts) are only relevant at translation of the mRNA to protein. Frameshift mutations occur in coding sequence, so the promoter and termination signals for transcription are unaffected.

Genes which are further downstream will be transcribed normally from their own promoter and their coding sequence is still in-frame with their own start-codon.

When a frameshift occurs in coding sequence, the genetic code downstream can indeed be considered 'scrambled', much alike random nucleotide sequence. In random sequence, three nucleotides have a 3/64 chance of being a stop codon. So one would not expect translation to go on beyond about 20 amino acids from the mutation. Additionally, non-sense mediated mRNA decay will detect these premature stop codons and destroy the mRNA.

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    $\begingroup$ The untranslated region (UTR) isn't translated by the ribosomes (hence its name), and therefore contains no reading frames, because it is never "read." Without a frame, the term "frameshift" mutation does not have a clear sense. Perhaps you mean a small indel in the 5'-UTR could affect the translation initiation site? By definition a frameshift can only occur in the region of the mRNA downstream of the initiation codon and upstream of the termination codon. Well, in the DNA that encodes that region of the mRNA. $\endgroup$ – mdperry May 7 '15 at 10:57
  • $\begingroup$ Also, any single frameshift (i,e., downstream of the ATG) HAS to throw the STOP codon out of frame. There is nothing special about proximity to the translational termination signal (e.g., "the terminal exon"). $\endgroup$ – mdperry May 7 '15 at 11:03
  • $\begingroup$ terdon, my first point is about transcription, not translation $\endgroup$ – Sleepses May 7 '15 at 11:33
  • $\begingroup$ Oh good grief. I was really on fire that day. I also had a stupid error in my own answer. Sorry about that, Sleepses, @mdperry, comment deleted. $\endgroup$ – terdon May 9 '15 at 23:41
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First of all, for a frame shift mutation to occur nucleotides (not amino acids) are either deleted or inserted into the sequence. Read about details on this wiki page. Here's an image about frame shifts.

On panel A a new stop codon is formed (TAG is trasncribed to UAG that is serves as stop codon during translation) thus the result is an abnormally short protein.

On panel B the codon 37 is swapped to a G thus the TA from the codon 38 is shifted left by two resulting in the new codon GTA.

On panel C exactly 3 nuleotides are deleted thus codon boundaries do not change, but a codon and the amino acid encoded by it is completely deleted.

On panel D 4 bases are deleted thus the T form codon 171 and the C from 172 are merged with the G from 170.

frameshift source: the linked wiki page.

It does not affect the choromosome in the way you describe because genes are separated and are independently transcribed (with some simplification). Every gene has its own translation start that determines the correct frame in that gene If you think of a chormosome as a chapter of a book and the genes are paragraphs, you can see that deleting letters or words may scrable one paragraph, but the others are not affected by this because they have their own boundaries.

EDIT: During translation the ribosome reads the mRNA in the form of triplets. When a single nucleotide is deleted then the whole sequence from that point shifts to the left by one thus the first letter of the subsequent triplet gets mixed into the frame where the mutation happened (the same goes for insertion but the sequence is shifted to the right). This causes the change in the meaning of the triplet, and can ruin stop codons that would affect the translation of the mRNA but not the transcription of the gene to mRNA.It is important to understand that transcription is a countinous process and the DNA is transcribed from base to base not in triplets, and that transcriptions stop is not encoded in the from of stop codon.

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  • $\begingroup$ So the stop and start codons are not frame shifted? $\endgroup$ – Paze May 6 '15 at 11:48
  • $\begingroup$ I've edited my answer I hope it helps. $\endgroup$ – Nandor Poka May 6 '15 at 12:03
  • $\begingroup$ Okay so when does the RNA polymerase stop then? I thought it would start coding for a gene at a start codon and stop at a stop codon? $\endgroup$ – Paze May 6 '15 at 12:50
  • $\begingroup$ As I indicated in my answer codons only play role and make sense in terms of translation. Genes have promoters and transcription start sites to initiate transcription and transcription termination signals and polyA signals to indicate the end of transcription. All these signals are longer than 3 basepairs. I suggest reading this wiki page.en.wikipedia.org/wiki/Gene this covers many basic things $\endgroup$ – Nandor Poka May 6 '15 at 13:30
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No, it wouldn't. In order to understand why, you must understand that

  1. Genes are translated independently of one another. The ribosome starts translating at a start codon (ATG) and stops at one of the three stop codons (TAG,TAA and TGA). Whether another gene has a frameshift mutation or not, does not affect the current gene in any way. The ribosome will always1 start at the ATG and stop at the STOP codon.

  2. Genes make up only a tiny portion of the total DNA, especially in eukaryotic organisms. In humans, for example, genes are ~5% of the total DNA. The vast majority of DNA falls in intergenic regions that do not code for protein. For example:

      gene1             INTERGENIC REGION               gene2
    ---------|----------------------------------------|---------
    ATGCCGTAGgcgtatagcgatatcgcatcgctatcgatacgctdcggcgcgATGCACTGA
    

    While a frameshift might throw the first gene out of sync, the second will not be affected. The intergenic regions are not translated, so frameshifts are irrelevant to them.

So, a frameshift will only affect the gene it occurs in.


1 There are some exceptions to this, some alternative start codons but they are not really relevant to the discussion here.

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  • $\begingroup$ A frameshift will affect all downstream coding sequence, regardless of what exon the mutation occurred in. $\endgroup$ – canadianer May 6 '15 at 19:10
  • $\begingroup$ @canadianer no, it will only affect the downstream sequence of its own exon. The splicing signals are not codons and won't be affected unless the frameshift occurs in the acceptor or donor sequences themselves. How would a frameshift affect a different exon otherwise? Remember that we're discussing frameshifts that happen at the DNA level. Naturally, post transcriptional modifications/mutations are a whole different ballgame. $\endgroup$ – terdon May 6 '15 at 21:56
  • $\begingroup$ The reading frame of the first exon defines the reading frame for all subsequent exons since they are literally ligated together into one long coding sequence. If you have two exons, say AUGGUA and AGUUGA, they are spliced together and translated to get the peptide Met-Val-Ser. If there's an insertion in the first exon such that it becomes AUGAGUA, the peptide, after splicing with the second exon, becomes Met-Ser-Lys-Leu-… Thus the frameshift in the first exon changes the reading frame of all downstream exons. $\endgroup$ – canadianer May 6 '15 at 22:22
  • $\begingroup$ @canadianer you're absolutely right, of course. I have no idea what I was thinking of. I leave genomics for 5 years and I forget the basics! Answer edited, thanks for pointing it out and my apologies for being dense. $\endgroup$ – terdon May 6 '15 at 22:39
  • $\begingroup$ Haha no worries. I'm sure you'll be able to return the favour for me someday ;) $\endgroup$ – canadianer May 6 '15 at 23:19

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