Answers.Body: <p>If you want the closest approximation to true randomness in native DNA (i.e. the most random location), look up information about somatic hypermutation in B-cell and T-cell receptors. This is mutation in coding regions of DNA:</p>
  <p><a href="https://en.wikipedia.org/wiki/Somatic_hypermutation" rel="nofollow noreferrer">https://en.wikipedia.org/wiki/Somatic_hypermutation</a></p>
  <p><a href="https://en.wikipedia.org/wiki/Affinity_maturation" rel="nofollow noreferrer">https://en.wikipedia.org/wiki/Affinity_maturation</a></p>
  <blockquote>
  <p>Mutations in the variable, antigen-binding coding sequences (known as complementarity-determining regions (CDR)) of the immunoglobulin genes. The mutation rate is up to 1,000,000 times higher than in cell lines outside the lymphoid system. Although the exact mechanism of the SHM is still not known, a major role for the activation-induced (cytidine) deaminase has been discussed. The increased mutation rate results in 1-2 mutations per CDR and, hence, per cell generation. The mutations alter the binding specificity and binding affinities of the resultant antibodies.</p>
  </blockquote>
  <p>In the specific variable regions where somatic hypermutation occurs, these sorts of single-base substitutions can be regarded as random, in the sense that they happen independently for each location. Due to the nature of the chemical reactions involved, there may be some base bias, but I expect it'll be difficult to determine that for sure given the issues in sequencing the immune receptor region.</p>
  <p>There's also other sequence reassortment that goes in the VDJ regions which appears random, but is spliced from existing genomic locations.</p>
  <p>These are likely to be the regions in the genome that have the most randomness. Everywhere else - as far as I know - the DNA is replicated and spliced from existing DNA using an error-correcting method.</p>
  
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Answers.Text: Interesting thanks. Can we regard these sorts of single-base substitutions as random, in the sense that they happen independently for each location, and are equally likely to produce an A, T, G or C?
Answers.UserDisplayName: ludog
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Answers.Text: In the specific variable regions where somatic hypermutation occurs, probably, but there may be a base bias. There's other sequence reassortment that goes on which appears random, but is spliced from existing genomic locations.
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Answers.Text: I think that these are good examples of _random processes affecting DNA sequences_, but they don't have the result of _a random sequence_. In fact, cytidine deamination quite deterministically yields uridine and thus thymidine. So while the occurrence of a C->T mutation is a random variable, the result is not random sequence but more or less always a T. So if cytidine deamination is the main mechanism, it's not random! Granted, other kinds of mutations may show more random outcomes. Similarly for VDJ, the distribution of sequences that result is quite sparse and "complex"!
Answers.UserDisplayName: Maximilian Press
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Answers.Text: @MaximilianPress yes, I understand this. I've changed my wording to "most random location"; I don't think there is anywhere else in the genome that would be more random than immune receptor binding regions.
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Answers.Body: <p>You seem to have learned that what genomics terms mean by &quot;low complexity&quot; seems to be quite different from what you mean- it is in fact specifically <em>not</em> random.</p>
  <p>There are of course many regions of noncoding DNA that show higher complexity (in the sense of &quot;different from what you'd expect as a random sampling of nucleotides&quot;, such as promoters, enhancers, telomeric/centromeric arrays, etc. This can be either for functional reasons or due to repetitiveness. If you include <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137791/" rel="nofollow noreferrer">elements like LINE, SINEs, etc., this accounts for most of the genome</a>, since most of these elements are just repeats of each other.</p>
  <p>It's worth recalling that DNA sequences are not generated randomly. Rather, they tend to be generated by a historical process of copying and expansion. That makes it somewhat difficult to find sequences that are random in the sense that you want (though I'm sure you can find them). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817411/" rel="nofollow noreferrer">Sequences in genomes tend to be deleted</a> if they're not important or advocating for themselves in some way.</p>
  <p>People have sometimes used so-called <a href="https://watermark.silverchair.com/6li.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA1cwggNTBgkqhkiG9w0BBwagggNEMIIDQAIBADCCAzkGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQM53pJQDQb8fcSoGAuAgEQgIIDCsCRpedJme-8UUG5fzooOvodBDZq3lK54cJUWmYDKKkjn-p_LZBxiuhIRq7TJkQcv_gTmp8cyx6IL1IwIp-4PLUmzgakNbmTPQsHkQAUQIphED9EnghwrRWJQmKkY2QvzPnA0H1DhrKNvjVrbz3PunuEgUlDZzPsp7mu5kezx_hVL5qQMiLMg6NnMidwyRSikpG9CteFj2Gc3yTWAziv7l_HhUjSi23AJiwkZaGbrGoigBlYU8d2Ayz7nTqbTjzai0zSi8k8LIgvsGyxai5YmYpDwidqUn2yvIW-8A9rPx267z0ag01YnS6rUtYI9iES3y8e4VB3cBnkM45sdLOUd3oFkOKAdmPwsmVYpxdLq2On1Bo4kYu1U6siobWpvcdUpx5ym93hmnI4zylHkgVm4Pc4-D2YUSNJGnzI54Doqi4KP9COif4On8pFVgURBecGG9lsNBeMGCdsrdikU9RktCTldmDrZsXb25VALr0sxV3vzXHFqDoBF8Nfl_SW7mkQ2vqjKqA_ypbER2E4Ii_IAn4P6oK5BTVgu3-Z2JfflkU2BhcoMKKr824vFxa-sDTycfRClX3Uw3dIqNZ4TP1Q3M8QMvKnofqUr1_6CPGzeBr2hH5NsVPDKosXP4vcUzXP3LR_ps0dE3dVqhhIZQeuVMPaB6-hawiafq2QKO_i7dHxjAHtv4wwLWcLpuFSiQ0RSPTzJweLmraO6A_gLEbt7mW8r9y54I4hnagSvSqkRGnMLVFfm98XhtWFAJBF3vmjNtC0JCi7lh4w7KO-reazDzBRcA-ZNlR51A1joy_9cXiM7pBgZZqRmr878pEtVypxjj9NCVmNGmT4srp3nx_OHrUoV-lsjH_sDyy1WDgI-hAsOrsiFKMoBccCy7iso5DZ81ekNoun17NySTw6RMbInc-fQrt5bdMkEOhe9XN2WX_TGXSbgqr7-8EaoPmrCCQETroeisO4_m-w9156bILFAcLPxNoIaNxYJjn-yIklaIyYy8tWoxeS9ZqXV0mnGRwCT6w8EMxPWIVqKWM" rel="nofollow noreferrer">fourfold degenerate sites</a> where mutations are pretty well tolerated for e.g. estimating mutation rates. On the other hand, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242499/" rel="nofollow noreferrer">these sequences are themselves somewhat constrained</a>.</p>
  <p>When people want random sequences, they tend to just simulate them.</p>
  <p>I would be interested to know if someone else knows of such sequences!</p>
  
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Answers.Text: Yeah this question of whether randomness is complex is part of what I'm investigating. You say people simulate random sequences, in what contexts would people want random sequences?
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Answers.Text: Sometimes, people use random sequences to test if there is signal in biological sequences. Random sequences also sometimes used to evaluate tools that e.g. align DNA sequences. 
  As Maximilian points out, the term "low complexity" in genomics (I think) comes rather from repetitiveness, which makes it hard to e.g. assign the origin of a subsequence in the original.
  In biology, even if the process generating the sequence is random (we do not really know), selection acts on sequences and the sequences we observe in pretty much any cell underwent selection, and may no longer be random.
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Answers.UserDisplayName: Maximilian Press
Body: <p>I'm a computer scientist studying measures of complexity across various data domains. One of these is DNA sequences, about which I have only basic knowledge.</p>
  <p>I believe that masking out so-called 'low-complexity' sub-sequences is a common practice when comparing two genetic samples, and the algorithms I've seen for doing that, e.g. DUST and SEG, roughly equate low-complexity with repetitiveness, and say that the less a sequence repeats itself, the more complex it is.</p>
  <p>My question is about sequences that are completely random, in the sense that each position is drawn uniformly, independently from <span class="math-container">$\{A, T, G, C\}$</span>. Such sequences would be minimally repetitive and tend to get a very high score from DUST or SEG. My understanding is that the distribution in coding DNA is quite obviously not random in this sense, but are any sections, maybe non-coding sections, that are? If not, why not? From my naive perspective, they seem somehow like the default.</p>
  
Tags: <r><genetics>
Title: DNA sequences of random base pairs
ThreadText: # DNA sequences of random base pairs
  
  (Asked by: username_0 on 2024-08-06)
  
  I'm a computer scientist studying measures of complexity across various data domains. One of these is DNA sequences, about which I have only basic knowledge.
  
  I believe that masking out so-called 'low-complexity' sub-sequences is a common practice when comparing two genetic samples, and the algorithms I've seen for doing that, e.g. DUST and SEG, roughly equate low-complexity with repetitiveness, and say that the less a sequence repeats itself, the more complex it is.
  
  My question is about sequences that are completely random, in the sense that each position is drawn uniformly, independently from $\{A, T, G, C\}$. Such sequences would be minimally repetitive and tend to get a very high score from DUST or SEG. My understanding is that the distribution in coding DNA is quite obviously not random in this sense, but are any sections, maybe non-coding sections, that are? If not, why not? From my naive perspective, they seem somehow like the default.
  
  **Tags:** r, genetics
  
  
  ---
  
  ## 2 answers
  
  ### Answer by username_1 on 2024-08-06. Score: 1 | Accepted answer
  
  If you want the closest approximation to true randomness in native DNA (i.e. the most random location), look up information about somatic hypermutation in B-cell and T-cell receptors. This is mutation in coding regions of DNA:
  
  <https://en.wikipedia.org/wiki/Somatic_hypermutation>
  
  <https://en.wikipedia.org/wiki/Affinity_maturation>
  
  > Mutations in the variable, antigen-binding coding sequences (known as complementarity-determining regions (CDR)) of the immunoglobulin genes. The mutation rate is up to 1,000,000 times higher than in cell lines outside the lymphoid system. Although the exact mechanism of the SHM is still not known, a major role for the activation-induced (cytidine) deaminase has been discussed. The increased mutation rate results in 1-2 mutations per CDR and, hence, per cell generation. The mutations alter the binding specificity and binding affinities of the resultant antibodies.
  
  In the specific variable regions where somatic hypermutation occurs, these sorts of single-base substitutions can be regarded as random, in the sense that they happen independently for each location. Due to the nature of the chemical reactions involved, there may be some base bias, but I expect it'll be difficult to determine that for sure given the issues in sequencing the immune receptor region.
  
  There's also other sequence reassortment that goes in the VDJ regions which appears random, but is spliced from existing genomic locations.
  
  These are likely to be the regions in the genome that have the most randomness. Everywhere else - as far as I know - the DNA is replicated and spliced from existing DNA using an error-correcting method.
  
  > **Comments:**
  > **username_0**: Interesting thanks. Can we regard these sorts of single-base substitutions as random, in the sense that they happen independently for each location, and are equally likely to produce an A, T, G or C?  
  > **username_1**: In the specific variable regions where somatic hypermutation occurs, probably, but there may be a base bias. There's other sequence reassortment that goes on which appears random, but is spliced from existing genomic locations.  
  > **username_2**: I think that these are good examples of _random processes affecting DNA sequences_, but they don't have the result of _a random sequence_. In fact, cytidine deamination quite deterministically yields uridine and thus thymidine. So while the occurrence of a C->T mutation is a random variable, the result is not random sequence but more or less always a T. So if cytidine deamination is the main mechanism, it's not random! Granted, other kinds of mutations may show more random outcomes. Similarly for VDJ, the distribution of sequences that result is quite sparse and "complex"!  
  > **username_1**: @username_2 yes, I understand this. I've changed my wording to "most random location"; I don't think there is anywhere else in the genome that would be more random than immune receptor binding regions.  
  
  ---
  
  ### Answer by username_2 on 2024-08-06. Score: 3
  
  You seem to have learned that what genomics terms mean by "low complexity" seems to be quite different from what you mean- it is in fact specifically *not* random.
  
  There are of course many regions of noncoding DNA that show higher complexity (in the sense of "different from what you'd expect as a random sampling of nucleotides", such as promoters, enhancers, telomeric/centromeric arrays, etc. This can be either for functional reasons or due to repetitiveness. If you include [elements like LINE, SINEs, etc., this accounts for most of the genome](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137791/), since most of these elements are just repeats of each other.
  
  It's worth recalling that DNA sequences are not generated randomly. Rather, they tend to be generated by a historical process of copying and expansion. That makes it somewhat difficult to find sequences that are random in the sense that you want (though I'm sure you can find them). [Sequences in genomes tend to be deleted](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817411/) if they're not important or advocating for themselves in some way.
  
  People have sometimes used so-called [fourfold degenerate sites](https://watermark.silverchair.com/6li.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA1cwggNTBgkqhkiG9w0BBwagggNEMIIDQAIBADCCAzkGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQM53pJQDQb8fcSoGAuAgEQgIIDCsCRpedJme-8UUG5fzooOvodBDZq3lK54cJUWmYDKKkjn-p_LZBxiuhIRq7TJkQcv_gTmp8cyx6IL1IwIp-4PLUmzgakNbmTPQsHkQAUQIphED9EnghwrRWJQmKkY2QvzPnA0H1DhrKNvjVrbz3PunuEgUlDZzPsp7mu5kezx_hVL5qQMiLMg6NnMidwyRSikpG9CteFj2Gc3yTWAziv7l_HhUjSi23AJiwkZaGbrGoigBlYU8d2Ayz7nTqbTjzai0zSi8k8LIgvsGyxai5YmYpDwidqUn2yvIW-8A9rPx267z0ag01YnS6rUtYI9iES3y8e4VB3cBnkM45sdLOUd3oFkOKAdmPwsmVYpxdLq2On1Bo4kYu1U6siobWpvcdUpx5ym93hmnI4zylHkgVm4Pc4-D2YUSNJGnzI54Doqi4KP9COif4On8pFVgURBecGG9lsNBeMGCdsrdikU9RktCTldmDrZsXb25VALr0sxV3vzXHFqDoBF8Nfl_SW7mkQ2vqjKqA_ypbER2E4Ii_IAn4P6oK5BTVgu3-Z2JfflkU2BhcoMKKr824vFxa-sDTycfRClX3Uw3dIqNZ4TP1Q3M8QMvKnofqUr1_6CPGzeBr2hH5NsVPDKosXP4vcUzXP3LR_ps0dE3dVqhhIZQeuVMPaB6-hawiafq2QKO_i7dHxjAHtv4wwLWcLpuFSiQ0RSPTzJweLmraO6A_gLEbt7mW8r9y54I4hnagSvSqkRGnMLVFfm98XhtWFAJBF3vmjNtC0JCi7lh4w7KO-reazDzBRcA-ZNlR51A1joy_9cXiM7pBgZZqRmr878pEtVypxjj9NCVmNGmT4srp3nx_OHrUoV-lsjH_sDyy1WDgI-hAsOrsiFKMoBccCy7iso5DZ81ekNoun17NySTw6RMbInc-fQrt5bdMkEOhe9XN2WX_TGXSbgqr7-8EaoPmrCCQETroeisO4_m-w9156bILFAcLPxNoIaNxYJjn-yIklaIyYy8tWoxeS9ZqXV0mnGRwCT6w8EMxPWIVqKWM) where mutations are pretty well tolerated for e.g. estimating mutation rates. On the other hand, [these sequences are themselves somewhat constrained](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242499/).
  
  When people want random sequences, they tend to just simulate them.
  
  I would be interested to know if someone else knows of such sequences!
  
  > **Comments:**
  > **username_0**: Yeah this question of whether randomness is complex is part of what I'm investigating. You say people simulate random sequences, in what contexts would people want random sequences?  
  > **username_3**: Sometimes, people use random sequences to test if there is signal in biological sequences. Random sequences also sometimes used to evaluate tools that e.g. align DNA sequences.  As username_2 points out, the term "low complexity" in genomics (I think) comes rather from repetitiveness, which makes it hard to e.g. assign the origin of a subsequence in the original. In biology, even if the process generating the sequence is random (we do not really know), selection acts on sequences and the sequences we observe in pretty much any cell underwent selection, and may no longer be random.  
  
  ---
  
  