--- Log opened Fri Mar 01 00:00:03 2019
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09:12 < kanzure> "Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice" http://science.sciencemag.org/content/early/2019/02/27/science.aaw7166
09:27 < nsh> mmm, rise
09:38 < ebowden__> I wonder if people are developing Cytosine base editors as we speak.
09:38 < ebowden__> *I wonder if people are developing higher fidelity Cytosine base editors as we speak.
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10:55 < nsh> .wik Cytosine
10:55 < yoleaux> "Cytosine (/ˈsaɪtəˌsiːn, -ˌziːn, -ˌsɪn/; C) is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an amine group at position 4 and a keto group at position 2)." — https://en.wikipedia.org/wiki/Cytosine
10:56 < nsh> how useful is it to be only able to edit one of the bases?
10:56 < nsh> or just easier for some reason?
11:32 < yashgaroth> you can "edit" two, cytosine and adenine; it's because they're just bringing a deaminase enzyme near the site, and the cell repairs the damaged base - only C and A have amines that can be removed
11:34 < yashgaroth> ofc the problem is you're adding an active deaminase enzyme into the nucleus, so it can float around and do off-target mutations; the bigger problem is that the site you're trying to edit probably has more than one C at/near the target and they're just as likely to get edited
11:34 < yashgaroth> aaand since the vast majority of mutations they're targeting are in protein coding regions, even one off-target edit nearby can be just as dangerous as the original mutation they're trying to fix
11:39  * nsh nods
11:40 < nsh> really i think one of the main breakthroughs will be accurate chromosome targeting of editing apparatus
11:40 < nsh> but i'm not sure where that'll come from
11:40 < nsh> i mean accurate exact sequential/locus targeting
11:40 < kanzure> let me tell you about restriction sites
11:42 < nsh> kk
11:42 < kanzure> .wik restriction site
11:42 < yoleaux> "Restriction sites, or restriction recognition sites, are locations on a DNA molecule containing specific (4-8 base pairs in length) sequences of nucleotides, which are recognized by restriction enzymes." — https://en.wikipedia.org/wiki/Restriction_site
11:43 < nsh> so can base editors be paired with tailored restriction enzymes?
11:43 < nsh> and can they be rendered inactive when they have performed their prescribed tasks
11:45 < yashgaroth> restriction enzymes are still far less accurate than Cas9, even with an 8 bp recognition sequence that's still 50,000 sites in a human genome
11:48 < nsh> yeah i think some kind of nonmolecular targeting might be best
11:48 < nsh> but people still assume motion in the cell is more or less random
11:48 < nsh> and if people think something is random it really puts them off trying to understand and master it
11:49 < nsh> very common human error
11:49 < nsh> in theory an enzyme should have a resonance that means it can be radiatively steered
11:49 < kanzure> some angries about researchgate http://www.responsiblesharing.org/
11:49 < nsh> through phononic modes or the like
11:50 < nsh> or by having some peripheral that responses to light and creates something that results in a motility gradient
11:50 < nsh> *responds
12:25 < nsh> .t https://osc.universityofcalifornia.edu/open-access-at-uc/publisher-negotiations/uc-and-elsevier/
12:25 < yoleaux> nsh: Sorry, I don't know what timezone that is. If in doubt, see https://en.wikipedia.org/wiki/List_of_tz_database_time_zones for a list of options.
12:25 < nsh> .title
12:25 < yoleaux> List of tz database time zones - Wikipedia
12:25 < nsh> "UC terminates subscriptions with Elsevier in push for open access to publicly funded research"
12:25 < nsh> yisss
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12:49 < fltrz> has anyone attempted to write up the pseudocode equivalent of a formal grammar of DNA? i.e. "gene = DNA_binding_site proteincode" etc?
12:50 < fltrz> even if the mapping is imperfect or sequence functions are missing? like a rough start?
12:51 < fltrz> for a TAD domain loop, is the loop a single strand of DNA or the double strand? if a single strand, what happens to the other strand? similarily looped or loose?
13:03 < fltrz> "It recognizes the format of input sequences and whether the sequences are nucleic acid (DNA/RNA) or amino acid (proteins)." how does one detect if a sequence encodes amino acids? is it by illegal triples of bases that don't code for an amino acid?
13:18 < nsh> i'm not sure formal grammar is quite the appropriate notion
13:18 < nsh> a formal grammar constrains the language itself but you're talking about the dynamics of the molecule which contains the base-pairs we interpret as sequences of letters
13:18 < nsh> which is useful but it's not the whole thing
13:19 < fltrz> yeah I don't intend to capture the whole thing
13:19 < nsh> well i don't know that anything in the base sequence constrains TADs directly
13:19 < nsh> i'd be surprised in fact
13:19 < nsh> i think it's a pernicious meme that DNA is about the sequences only
13:20 < fltrz> just as a rough map, like gene = promotor proteinseq, ...
13:20 < nsh> if it can be reduced to the sequences then it's a highly nontrivial and nonlinear and very feedbacky system
13:20 < nsh> and formal grammars are too rigid and limited a thing for that
13:20 < nsh> you'd have to generalise a lot
13:21 < fltrz> the intention is not to simulate or predict cells, just a map / catalog of types of sequences one can expect,
13:21 < nsh> oh well there's certainly enough data to derive things statistically
13:21 < nsh> if you can fit some models to the data then great
13:22 < fltrz> and which are optional and which are not, i.e. is the operator optional in gene = promotor (operator) proteinseq, or will all genes have an operator for a repressor
13:22 < nsh> but already you're talking about the molecular cell biology and not the DNA
13:22 < nsh> well maybe not
13:23 < nsh> but the ascriptions of meaning derive from the downstream consequences of the sequences
13:23 < fltrz> nsh, the goal is not any prediction, just get a picture of all the known types of elements in the genome sequence
13:23 < nsh> so you are importing MCB-derived designations of function
13:23 < nsh> okay
13:24 < fltrz> it would be a useful reference for anyone trying familiarize oneself with genomics, to have a kind of catalog not of specific proteins, but still a catalog of types of sequences on the genome
13:25 < fltrz> I mean I can look at any introductory text, and view the picture *with* the operator region (for the repressor to optionally bind to), but that picture does not tell me if the operator region is optional or mandatory
13:26 < fltrz> nor does it tell me if it can have multiple operator regions for different types of repressors to block transcription of this gene
13:28 < nsh> probably a question to ask on a bioinformatics stack exchange or the like
13:28 < fltrz> its just a conceptual ideal example which does not really convey observed patterns, and formal grammars are typically used to convey the range of legal or observed patterns, but of course the formal grammar should never be treated as gospel
14:02 < fltrz> trannscription factor =?= activator =?= dna binding protein =?= regulatory protein ? are they all the synonymous?
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16:00 < fltrz> fenn: you proposed an alternative of sheer proximity + diffusion to explain the TAD isolation; lets call it option E (after the previous 4 options I listed)
16:00 < fltrz> all of the potential explanations listed A through D have serious problems (unknown membranes for the space multiplexing in vacuoles, unknown adhesion mechanism to DNA for the linear concentration mechanism, unknown timewise sequencing mechanism, ...) so I started reasoning some more about your option E, but I run into another conceptual issue:
16:00 < fltrz> after transcription, theres splicing the exons, translation, folding, forming complexes ... which takes time and motion and hence results in diffusion. I have a hard time imagining that the final protein the moment it is finally formed will be kept precisely in the TAD domain; furthermore this does not really explain the rigid TAD boundary sequence.
16:00 < fltrz> However this got me thinking: we know that a lot of mRNA can circularize by their UTR regions, what if they reliably circularize around the DNA strand? lets call it the "DNA-mRNA *threading* mechanism", this is insufficient as an explanation since the mRNA ring can still move freely along the DNA sequence... until it hit me: a physical TAD domain loop (locked by TAD boundary proteins) can hold the mRNA ring in place! so all the different TAD domain
16:00 < fltrz> loops are like keyrings with their own local collection of circularized mRNA rings?
16:00 < fltrz> So the "TAD keychain hypothesis" = "circularized mRNA" + "DNA-mRNA threading" + "TAD keyring locking"
16:01 < fltrz> I will call this option F after your optionn E (on which it is inspired)
16:02 < nsh> sounds testable
16:06 < fltrz> this only maintains location for up to and including translation, but folding and forming complexes can still result in diffusion and "out of domain" interference
16:07 < fltrz> but thats better than merely transcription isolation
16:11 < fltrz> nsh, im not knowledgeable enough to even imagine how to start testing this ;) sadly
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16:28 < fltrz> with TAD loop I was referring to https://en.wikipedia.org/wiki/Insulated_neighborhood
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--- Log closed Sat Mar 02 00:00:04 2019