4 ms·

Most genetic variants associated with common diseases fall in non-coding DNA areas, previously thought to be junk DNA. Many of these non-coding areas are actua

by nextos 5y ago

Most genetic variants associated with common diseases fall in non-coding DNA areas, previously thought to be junk DNA. Many of these non-coding areas are actually enhancer elements. These elements produce enhancer RNA, previously thought to be noise, and regulate distant genes thanks to chromosome conformation. Chromosome conformation means DNA folds in complex 3D patterns. The interplay between chromosome conformation, enhancer RNA, gene expression and disease variants is very complex and interesting [1,2]. I know some startups trying to regulate genes by targeting enhancer elements. The field is very promising, but a big roadblock seems to be to deliver compounds to the right cell type. Junk DNA was always contentious because there was evidence of conservation in these areas. In other words, evolution was selecting against mutations in some junk DNA regions. My impression is that junk DNA fell quickly out of favor once the ENCODE Project started to publish large scale epigenetics data in the early 2010s. [1] https://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1285-0 https://genomebiology.biomedcentral.com/articles/10.1186/s13... [2] https://www.nature.com/articles/nature13138 https://www.nature.com/articles/nature13138

f6v 5y ago
The fact that enhancers can be transcribed is quite interesting. I’m not sure what’s the function of these transcripts though. It seems like the transcription is terminated prematurely once RNA pol realizes it’s not a functional gene.
- nextos 5y ago
  There's a lot of literature on this, but you are quite right as there are tons of open questions. Some enhancer RNAs are non-functional. Others seem to help stabilizing chromosome contacts. Some do seem to encode secondary structures, so they are probably functional ncRNAs. Irrespective of this, enhancer RNA transcription is very useful to track active regulatory regions and to perform QTL studies.
otherme123 5y ago
For starters, junk DNA is a fuzzy term. I would never include regulatory regions or introns in junk DNA, just non-coding. To me, junk are tranposons and friends, or pseudogenes: they rarely have any purpose, and sometime they cause troubles.
derbOac 5y ago
I remember talking to my colleagues about 15 years ago about trying to do research on some noncoding polymorphisms and was ridiculed. The basic response was something along the lines of "those are noncoding, why would you look at those?" as if I was an idiot who didn't understand current genetics. It's been long ago enough that I don't remember all the details, but my perspective was that it was naive and arrogant to assume we had a good handle on everything about DNA, especially then as it was all new, and there was evidence then that a lot of the noncoding DNA had function. Dogmatic attitudes are surprisingly prevalent in academics. There's definitely a weird hubris accompanying published findings that goes something like peer reviewed -> established fact as if the point of academics isn't to understand things but to score points like on a test. Some skepticism about certain things seems warranted but other times there's really nothing but overly simplistic models that were really never evaluated to begin with. I wish there was more awareness of the topography of uncertainty in research findings.
- quickthrowman 5y ago
  > Dogmatic attitudes are surprisingly prevalent in academics. https://en.m.wikipedia.org/wiki/Planck%27s_principle https://en.m.wikipedia.org/wiki/Planck%27s_principle “Science progresses one funeral at a time.”
ijidak 5y ago
The idea of junk DNA never made sense to me. Having a list of proteins (coding DNA) does nothing to tell an organism how to combine those proteins to form working systems. It's like claiming that the parts list in an assembly manual is the only information of importance. And the step-by-step instructions are junk, because they don't describe a useful part in the box. Did we think that the whole organism just self-assembles once it makes the tens of thousands of individual parts described in coding DNA? "Junk DNA" was a terrible terrible phrase to begin with. Disclaimer: I believe in a creator. (https://www.jw.org/en/bible-teachings/science/ https://www.jw.org/en/bible-teachings/science/)
- shpongled 5y ago
  While an interesting thought experiment, no one is proposing that you will get self-assembly of an organism by expressing 10,000 genes. We really don't know what the beginning steps of this process were - since it only happened once (or however many times life arose). Once an organism was made, now it can just express whatever proteins it currently needs, based on lifecycle/nutrients/metabolic requirements/etc.
- andrewflnr 5y ago
  Besides its DNA, every living thing has at least one whole functioning cell to use as a template, since they all start as dividing cells.
- jostmey 5y ago
  Natural selection doesn't care about what looks pretty, only that it works. A modern operating system is millions of lines of code. Do you think it is possible that some of the code are no longer used but nobody dares remove it?
  - HPsquared 5y ago
    That would presuppose an intelligent designer who doesn't dare to try and remove the code. (Unless that's what you are saying)
jacquesm 5y ago
I should update this: https://jacquesmattheij.com/junk-dna-no-way/ https://jacquesmattheij.com/junk-dna-no-way/ with the newly found insights. Still: No Way. Just not-yet-understood-DNA.

by nextos 5y ago

f6v 5y ago

The fact that enhancers can be transcribed is quite interesting. I’m not sure what’s the function of these transcripts though. It seems like the transcription is terminated prematurely once RNA pol realizes it’s not a functional gene.

nextos 5y ago
There's a lot of literature on this, but you are quite right as there are tons of open questions. Some enhancer RNAs are non-functional. Others seem to help stabilizing chromosome contacts. Some do seem to encode secondary structures, so they are probably functional ncRNAs. Irrespective of this, enhancer RNA transcription is very useful to track active regulatory regions and to perform QTL studies.

otherme123 5y ago

For starters, junk DNA is a fuzzy term. I would never include regulatory regions or introns in junk DNA, just non-coding. To me, junk are tranposons and friends, or pseudogenes: they rarely have any purpose, and sometime they cause troubles.

derbOac 5y ago

I remember talking to my colleagues about 15 years ago about trying to do research on some noncoding polymorphisms and was ridiculed. The basic response was something along the lines of "those are noncoding, why would you look at those?" as if I was an idiot who didn't understand current genetics. It's been long ago enough that I don't remember all the details, but my perspective was that it was naive and arrogant to assume we had a good handle on everything about DNA, especially then as it was all new, and there was evidence then that a lot of the noncoding DNA had function. Dogmatic attitudes are surprisingly prevalent in academics. There's definitely a weird hubris accompanying published findings that goes something like peer reviewed -> established fact as if the point of academics isn't to understand things but to score points like on a test. Some skepticism about certain things seems warranted but other times there's really nothing but overly simplistic models that were really never evaluated to begin with. I wish there was more awareness of the topography of uncertainty in research findings.

quickthrowman 5y ago
> Dogmatic attitudes are surprisingly prevalent in academics. https://en.m.wikipedia.org/wiki/Planck%27s_principle https://en.m.wikipedia.org/wiki/Planck%27s_principle “Science progresses one funeral at a time.”

ijidak 5y ago

The idea of junk DNA never made sense to me. Having a list of proteins (coding DNA) does nothing to tell an organism how to combine those proteins to form working systems. It's like claiming that the parts list in an assembly manual is the only information of importance. And the step-by-step instructions are junk, because they don't describe a useful part in the box. Did we think that the whole organism just self-assembles once it makes the tens of thousands of individual parts described in coding DNA? "Junk DNA" was a terrible terrible phrase to begin with. Disclaimer: I believe in a creator. (https://www.jw.org/en/bible-teachings/science/ https://www.jw.org/en/bible-teachings/science/)

shpongled 5y ago
While an interesting thought experiment, no one is proposing that you will get self-assembly of an organism by expressing 10,000 genes. We really don't know what the beginning steps of this process were - since it only happened once (or however many times life arose). Once an organism was made, now it can just express whatever proteins it currently needs, based on lifecycle/nutrients/metabolic requirements/etc.
andrewflnr 5y ago
Besides its DNA, every living thing has at least one whole functioning cell to use as a template, since they all start as dividing cells.
jostmey 5y ago
Natural selection doesn't care about what looks pretty, only that it works. A modern operating system is millions of lines of code. Do you think it is possible that some of the code are no longer used but nobody dares remove it?
- HPsquared 5y ago
  That would presuppose an intelligent designer who doesn't dare to try and remove the code. (Unless that's what you are saying)

jacquesm 5y ago

I should update this: https://jacquesmattheij.com/junk-dna-no-way/ https://jacquesmattheij.com/junk-dna-no-way/ with the newly found insights. Still: No Way. Just not-yet-understood-DNA.