5 ms·

Presumably, biology has a lot of safeguarding to prevent modified transfer-RNA from being functional. In terms of potential errors in gene expression, the gene

Presumably, biology has a lot of safeguarding to prevent modified transfer-RNA from being functional. In terms of potential errors in gene expression, the genetic code is rarely discussed as a potential source of error.

Reelin 7y ago
Not to be "that guy", but actually, it is. (https://elifesciences.org/articles/09945 https://elifesciences.org/articles/09945) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026258/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026258/) It's just difficult to study for various technical reasons related to how we sequence it. Sometime the mistranslation is even intentional! (https://www.ncbi.nlm.nih.gov/pubmed/25220850 https://www.ncbi.nlm.nih.gov/pubmed/25220850) As you mentioned though, there are also quite a few safeguards. * tRNA synthetase example: https://www.ncbi.nlm.nih.gov/pubmed/27226603 https://www.ncbi.nlm.nih.gov/pubmed/27226603 * trans-editing factor example: https://www.ncbi.nlm.nih.gov/pubmed/28737471 https://www.ncbi.nlm.nih.gov/pubmed/28737471 Damaged tRNA is even repaired (a bit, sometimes). (https://www.ncbi.nlm.nih.gov/pubmed/28901837 https://www.ncbi.nlm.nih.gov/pubmed/28901837) From an interesting (2018) review of tRNA in general (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103721/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103721/): > Surprisingly, a perfect proteome is not a pre-requisite for cellular viability even in the context of human cells. Lant et al. demonstrated that a single tRNA mutant can lead to significant mistranslation in human cells [17]. This was accomplished by expressing an Ala accepting tRNAPro G3:U70 variant in HEK 293 cells. The authors visualized a rate of ~ 3% mistranslation using a novel green fluorescent protein (D129P) reporter that fluoresces in response to mistranslation at proline codons. In contrast to previous studies in yeast [18], human cells in culture did not mount a detectable heat-shock response and tolerated the mistranslation without apparent impact on cell viability.
- klmr 7y ago
  The eLife paper you link to discusses errors in RNA synthesis (transcription), not in tRNA-dependent protein synthesis (translation). The abstract mentions “translation”, but only as an amplifier of transcription errors: each mRNA transcript is translated into proteins thousandfold, so every error in a single mRNA molecule will be present in thousands of protein molecules. Translation errors also exist, and some people hypothesise that there is selective pressure on protein-coding genes to reduce this source of errors by selecting codons in a way that reduces the error rate (potentially by slowing down the polymerase). This results in something known as “codon bias” but so far there is no good evidence that codon bias has an actual effect on error rate (it does have an effect on correct protein folding), or is selected for (http://dx.doi.org/10.7554/eLife.27344 http://dx.doi.org/10.7554/eLife.27344, http://dx.doi.org/10.1371/journal.pgen.1006024 http://dx.doi.org/10.1371/journal.pgen.1006024).
  - Reelin 7y ago
    My first two links are indeed about transcription! Rereading my comment in context now I'm realizing it was a bit unclear. I was responding to "the genetic code is rarely discussed as a potential source of error". However, I believe my third link is about environmental stress triggering intentional mistranslation (mRNA to protein). From that paper's figure 3: > Proteins arising from “statistical proteomes” have various folding and binding properties, resulting in phenotypic diversity in the host organism. I haven't bothered to pull up the related references (5 obvious ones) to assess their strength though. The papers you linked seem to be claiming that codon encoding preferences (which vary by gene category) are in fact due to (or merely correlated with?) GC content in mammalian genomes (as opposed to a number of other previously proposed mechanisms). This is surprising because individual tRNA abundance varies by cell state and type, so that would have been the obvious (but apparently wrong) explanation. It's doubly surprising because a number of single celled organisms utilize the mismatch between codon preference and tRNA availability in order to regulate protein translation, but these papers are claiming that's not a significant factor in mammals.
    - klmr 7y ago
      > This is surprising because individual tRNA abundance varies by cell state and type, so that would have been the obvious (but apparently wrong) explanation. tRNA gene expression varies by cell state, but isoacceptor abundance is in fact very stable (at least in mammals). Meaning, if you have a set of tRNA genes which all code for, say, Ala_AGC, the sum of the gene expression of all these genes is relatively stable, even if their individual expression varies (http://dx.doi.org/10.1101/gr.176784.114l; http://dx.doi.org/10.1101/gr.176784.114l; full disclosure: I’m an author on this and one of the previously linked papers). Why individual tRNA gene expression varies, and how the cell regulates the overall stability, is unclear (my personal pet theory is that secondary tRNA function as regulatory RNA, in the form of tRNA-derived fragments, causes the need to regulate tRNA genes, see e.g. http://dx.doi.org/10.1016/j.cell.2017.06.013 http://dx.doi.org/10.1016/j.cell.2017.06.013). > It's doubly surprising because a number of single celled organisms utilize the mismatch between codon preference and tRNA availability in order to regulate protein translation It’s not that surprising: gene regulation happens fundamentally differently in eukaryotes and prokaryotes, and even differently in different classes of eukaryotes. The effective population size (= evolvability) and genome complexity seems to play a role here. Simply put, higher animals have much more powerful and precise ways of controlling gene expression (enhancers and histone control). Regulation at the translation level is comparatively slow and wasteful (it’s several steps further down the line of the gene->protein production process).

Reelin 7y ago

Not to be "that guy", but actually, it is. (https://elifesciences.org/articles/09945 https://elifesciences.org/articles/09945) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026258/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026258/) It's just difficult to study for various technical reasons related to how we sequence it. Sometime the mistranslation is even intentional! (https://www.ncbi.nlm.nih.gov/pubmed/25220850 https://www.ncbi.nlm.nih.gov/pubmed/25220850) As you mentioned though, there are also quite a few safeguards. * tRNA synthetase example: https://www.ncbi.nlm.nih.gov/pubmed/27226603 https://www.ncbi.nlm.nih.gov/pubmed/27226603 * trans-editing factor example: https://www.ncbi.nlm.nih.gov/pubmed/28737471 https://www.ncbi.nlm.nih.gov/pubmed/28737471 Damaged tRNA is even repaired (a bit, sometimes). (https://www.ncbi.nlm.nih.gov/pubmed/28901837 https://www.ncbi.nlm.nih.gov/pubmed/28901837) From an interesting (2018) review of tRNA in general (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103721/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103721/): > Surprisingly, a perfect proteome is not a pre-requisite for cellular viability even in the context of human cells. Lant et al. demonstrated that a single tRNA mutant can lead to significant mistranslation in human cells [17]. This was accomplished by expressing an Ala accepting tRNAPro G3:U70 variant in HEK 293 cells. The authors visualized a rate of ~ 3% mistranslation using a novel green fluorescent protein (D129P) reporter that fluoresces in response to mistranslation at proline codons. In contrast to previous studies in yeast [18], human cells in culture did not mount a detectable heat-shock response and tolerated the mistranslation without apparent impact on cell viability.

klmr 7y ago
The eLife paper you link to discusses errors in RNA synthesis (transcription), not in tRNA-dependent protein synthesis (translation). The abstract mentions “translation”, but only as an amplifier of transcription errors: each mRNA transcript is translated into proteins thousandfold, so every error in a single mRNA molecule will be present in thousands of protein molecules. Translation errors also exist, and some people hypothesise that there is selective pressure on protein-coding genes to reduce this source of errors by selecting codons in a way that reduces the error rate (potentially by slowing down the polymerase). This results in something known as “codon bias” but so far there is no good evidence that codon bias has an actual effect on error rate (it does have an effect on correct protein folding), or is selected for (http://dx.doi.org/10.7554/eLife.27344 http://dx.doi.org/10.7554/eLife.27344, http://dx.doi.org/10.1371/journal.pgen.1006024 http://dx.doi.org/10.1371/journal.pgen.1006024).
- Reelin 7y ago
  My first two links are indeed about transcription! Rereading my comment in context now I'm realizing it was a bit unclear. I was responding to "the genetic code is rarely discussed as a potential source of error". However, I believe my third link is about environmental stress triggering intentional mistranslation (mRNA to protein). From that paper's figure 3: > Proteins arising from “statistical proteomes” have various folding and binding properties, resulting in phenotypic diversity in the host organism. I haven't bothered to pull up the related references (5 obvious ones) to assess their strength though. The papers you linked seem to be claiming that codon encoding preferences (which vary by gene category) are in fact due to (or merely correlated with?) GC content in mammalian genomes (as opposed to a number of other previously proposed mechanisms). This is surprising because individual tRNA abundance varies by cell state and type, so that would have been the obvious (but apparently wrong) explanation. It's doubly surprising because a number of single celled organisms utilize the mismatch between codon preference and tRNA availability in order to regulate protein translation, but these papers are claiming that's not a significant factor in mammals.
  - klmr 7y ago
    > This is surprising because individual tRNA abundance varies by cell state and type, so that would have been the obvious (but apparently wrong) explanation. tRNA gene expression varies by cell state, but isoacceptor abundance is in fact very stable (at least in mammals). Meaning, if you have a set of tRNA genes which all code for, say, Ala_AGC, the sum of the gene expression of all these genes is relatively stable, even if their individual expression varies (http://dx.doi.org/10.1101/gr.176784.114l; http://dx.doi.org/10.1101/gr.176784.114l; full disclosure: I’m an author on this and one of the previously linked papers). Why individual tRNA gene expression varies, and how the cell regulates the overall stability, is unclear (my personal pet theory is that secondary tRNA function as regulatory RNA, in the form of tRNA-derived fragments, causes the need to regulate tRNA genes, see e.g. http://dx.doi.org/10.1016/j.cell.2017.06.013 http://dx.doi.org/10.1016/j.cell.2017.06.013). > It's doubly surprising because a number of single celled organisms utilize the mismatch between codon preference and tRNA availability in order to regulate protein translation It’s not that surprising: gene regulation happens fundamentally differently in eukaryotes and prokaryotes, and even differently in different classes of eukaryotes. The effective population size (= evolvability) and genome complexity seems to play a role here. Simply put, higher animals have much more powerful and precise ways of controlling gene expression (enhancers and histone control). Regulation at the translation level is comparatively slow and wasteful (it’s several steps further down the line of the gene->protein production process).