NEW DISCOVERY OF MicroDNA CIRCLES: Your genes and mine differ at thousands of individual points (SNPs, or single nucleotide polymorphisms) and in the number of copies of individual genes (CNV, or copy number variations). But did you know that there are differences in DNA between the individual cells of your body?
• Searching for evidence of genetic mosaics within the brain, researchers found tens of thousands of tiny circles of DNA representing a completely different form from the usual chromosomes. These microDNA circles are typically 200-400 base pairs long, and represent only 0.2% of the total chromosomal DNA, but given that we have 3,156,105,057 base pairs of DNA that’s still a lot. They are thought to arise from genes due to errors in replication or repair. Both single and double stranded circles were found. The electron microscope image shows a microDNA circle with a larger molecular model in color on the outside.
• Researchers reasoned that microDNA would leave behind microdeletions, or small gaps in the chromosome. Indeed, when they set about looking for these gaps, they found them at a rate of 1 in 2000, giving rise to considerable genetic variation between cells. Not only could these deletions potentially affect gene function, but they may serve as a genetic cache of information that may play a role in non-Mendelian inheritance.
• Fun fact: Do you know the origin of the word genome? It is thought to come from the Greek (γίνομαι) for “I become, I am born, to come into being”.
• Source: Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues. Shibata Y, Kumar P, Layer R, Willcox S, Gagan JR, Griffith JD, Dutta A. Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA. Science. 2012 Apr 6;336(6077):82-6. http://www.ncbi.nlm.nih.gov/pubmed/22403181
madame scientist's not-so-mad musings 
Did not know this : ” But did you know that there are differences in DNA between the individual cells of your body? ” very interesting Rajini Rao …as always a amazing and knowledge provoking post 🙂
I didn’t know of these little circles and microdifferences either, Kershaw Rustomji (this is hot off the press) so I’m learning too!
Rajini Rao smiling
So G+ circles are all through our DNA. Nice! 🙂
Please, Google, add DNA Circles to the ribbon…
I wonder if this has a bearing on certain autoimmune disorders, where the cells feel “threatened” by an “alien” invasion…
LOL, I was thinking of G+ circles too! 🙂
Kyle Debs
I’m betting this super interesting biology lesson is no where to be found on Facebook – and they call Google+ a ghost town!
Quantum fx at play at the level of the earthly genome? Anybody ’round here familiar with Penrose’s theories on microtubules. I’d like to know if there is a connection…
Damn, that’s cool. Not entirely unexpected, but no less miraculous.
I’m not seeing a connection with microtubules (or immunity), but feel free to inform me of your ideas and I can give you my two cents.
Oh, Rajini, I’m not sure that there is any connection between Penrose’s now decades old surmise and this DNA work. But it does seem to beg looking into the quantum interactions at the molecular scale as it smears into the atomic scale in our ability to observe. That would yank quantum theory into the equations.
Obviously, I am not a scientist. I’m just curious.
I’ll have to do some googling on that and get back to you if I find something to report 🙂
Good morning, Feisal Kamil . Certainly, we know which genes are for what, with may be a few exceptions. We know a little bit about nearly all their functions, and a lot of detail on some of them. Still can’t fix the “broken” ones that are mutated in various disease, though. 🙂
I missed the early release, Drew Sowersby . It is pretty cool. They also see periodic sizes of 150 bp that is about the length that wraps around the nucleosome. What they did not address in the paper is their stability. I would have thought that these little snippets of DNA would get degraded..I guess circularization protects them (no free ends for the nucleases to nibble), but still….
No, they come from Okazaki fragments or actual glitches during replication. The authors also speculate that there are double stranded breaks in the DNA and the ends circularize, leaving a small deletion. Basically, they represent enzyme errors.
Do politicians have the most enzyme errors?
Politicians must have macrodeletions in their promises genes and circular DNA encoding pointless arguments and rhetoric 😉
Thank you for that quick research ;-).
That explains why they run round in ever-decreasing circles of self-interest.
Very interesting. Does that mean doing a DNA test to check twin to see if they are identical could never come up 100%? And to clone yourself might produce variations depending where the cells are taken? I shall tell my twin daughters about this today
Mike McLoughlin I think it’s such a small percentage that I don’t think it will affect the DNA testing you’re thinking of, but I’ll let the experts answer.
Interesting post again Rajini Rao. I’m actually just starting a project to try to use imaging to guide DNA damage. The basic idea is to take various functional images to “prescribe” where you need to irradiate the tumor more. Then you give poly ADP ribose polymerase (PARP) inhibitors to prevent the tumor cells from repairing the damage from irradiating them. We are at the beginning stages and the DNA damage side of the story is new to me. Thanks for the cutting edge news.
The more we study and learn about this body of ours the more we know we don’t know much about it. By the time scientists think they know a lot about genes, DNA, mutation and so forth, new findings can create more unknowns. I’m glad there are scientists devoting their life into those research that one day can develop ways to fight diseases. I think the mystery largely lies in gene, genome, DNA …the linkage, interactions, electro-biochemical signals are the hints ?
By the way Rajini Rao it’s nice to know the origin of the word genome !
Wait… What?
“Not only could these deletions potentially affect gene function, but they may serve as a genetic cache of information that may play a role in non-Mendelian inheritance.”
Wouldn’t that be HUGE? :p
I am having trouble understanding this and it raises a boatload of questions. If these microDNA circles are produced by errors… and these deletions alter gene function… Isn’t that bad? When you speak of a cache of information you mean the absence of the genes that got cut right? If the deletion is an error/random, this cache could just as well be garbage or even detrimental to your health? It could have cut out something necessary? Any chance that these circles and gaps could be formed by a directed impulse? As in; it cuts out parts that are “holding you back”.
Do they only occur in the brain? Any chance that they are related to brain diseases? And finally, this might be a silly question but how exactly does this tie into heredity? We are talking about the brain here right? Shouldn’t this be happening around your reproductive area if you are hoping to pass these gaps on to your children? :p
/bionoob ^^
Feisal Kamil I don’t disagree with the sentiment of you comment but there are at least a few clear examples where a base pair is known to be wrong. That’s not the case all of the time so I appreciate your statement. There are a lot of knock-out mouse models where a particular gene is knocked out to see the effect. Sometimes in breeding these mice you find other mistakes (relative to the parent line) yet the mice might appear “normal”.
I seem to have missed out a lot..darn, why did I go to sleep? 🙂 Koen De Paus , I think this is potentially huge (apparently, so did Science, hence the high impact pub!). First off, after they found these in brain, they extended their findings to a range of other mouse and human tissues, and cell lines (in culture). So it is reproducible and widespread.
As for the microdeletions, certainly these could be deleterious if they occur in coding regions or regulatory regions of genes where they could alter function. For example, damage to tumor suppressor genes could trigger cancer. They make a point in the paper of saying that these microDNA’s did not come from vast stretches of repetitive DNA or junk, but were from regions known to be functional. If they are germline mutations, they will be passed on to offspring. If not, they could damage local regions (remember, these happen to individual cells). To put it in perspective, this is another source of damage to our DNA, in addition to chemical/radiation/aging.
Cache in this context means extra-chromosomal snippets of information that are not inherited according to the laws of Mendel (simple genetics based on chromosomes segregating). If these snippets survive or are replicated, then they can persist to code for variants of genes or “silence” other genes by binding to their message and muzzling them. There is some evidence for long lived information that can survive for more than one generation in Arabidopsis and C. elegans.
Hey, Rajini Rao — ya snooze, ya lose. But science is timeless, right? Thanks for whatever you bring us, whatever your state of consciousness…
Regarding the comments on individual differences in DNA: yes, it’s a small percentage as Chad Haney points out, so it won’t effect DNA identification of twins Mike McLoughlin (in any case, these tests do not involve sequencing the entire genome..I bet they are just RFLP’s that monitor migration of DNA fragments after cutting. These are good enough to follow lineage. Or they sequence some ‘marker genes’ by PCR, does anyone know? e.g, Matt Kuenzel).
Feisal Kamil is correct about our perception of “error” in that there are thousands of differences in the DNA between people. These are called polymorphisms. If they lie in areas that do not impact gene function, or they are “silent” changes regarding function they serve as handy way of tagging genes. However, if they impact function they are then called mutations, it’s just a matter of our perspective. For example, in my lab, we are evaluating whether polymorphisms associated with autism in our favorite gene alter function. When the geneticists reported this, they had no way of knowing whether they were relevant to autism or not. We have found that they knock out function, so this implicates a role for the ion transporter we study in autism disorders.
Drew Sowersby , I’ve been hankering to run “journal club” on the G+ platform. I’m game, if others are. The trick is to find a paper that a lot of people are interested in, that is not too technical. Maybe something to do with human health/brain/social behavior would be an easy start 🙂
The authors of this paper did not address stability. Bacteria and yeasts already have stable, (extrachromosomal for yeast) circular DNA that self replicates. This is the first of such structures in mammals, but with major differences..they are much smaller, randomly generated and have no obvious way of replicating (ORI or Start sequences).
I’m also interested in G+ journal club type discussion. I agree with Rajini Rao that it will be tricky to find an interesting article that isn’t too technical, reaches a broad audience and doesn’t have troll bait, like evolution.
That’s a great idea, Rajini Rao ! May I humbly suggest a slight amendment, however — that somehow the “too technical” be translated and common-sense heuristics and every-day insights be incorporated by those who know the details. Otherwise, the circle will become a warren of complexities that will draw the interests of only the few sophisticated enough to indulge.
William McGarvey , some techniques are easily explained and not essential to the central thesis of a paper..that would be fine, right? Drew Sowersby , I’ll leave it to you to figure out any technical aspects re. Gdocs, etc. All one needs is to place the pdf version of the paper or any other relevant info (alternatively, we could choose an open access article). Haha, agree with Chad Haney that we probably don’t want to jump into controversy at first 😉
Rajini Rao I think the details of technique deserve scrutiny by those who know enough to provide a sensible, non-flaming critique, of course. But that’s a somewhat different target audience, to me. Like Feisal Kamil , the merely curious might like to know what everyday phenomena, disease or behavior underlies the work and how the results provide enlightenment.
My thinking, precisely put Drew Sowersby — thank you.
Rajini Rao I have done many online Journal clubs before. See e.g. http://www.leukippos.org/Leukippos_Institute/Journal_Club/Journal_Club.html It is a lot of work to organize. The success depends on the person who run it. Do not expect to much from the people who participate. It will be transient. Real projects might develop, but they will disappear from this format. I am really interested to discuss this kind of projects. However, I do not think anybody so far has really solved how to do this. Eg I see Mendely as quite dysfunctional. Let me know more about your ideas? How do you plan to engage people?
Great observations, Gerd Moe-Behrens — thank you.
Thanks for the link, Gerd Moe-Behrens , I’ll check it out. I’m not proposing a journal club at the level of scrutiny and expertise that I would find in my lab group for example. It’s more about outreach than output, although it would be great if real projects and collaborations developed (unlikely, at this stage in the game). I’m also not looking to make a lot of work for myself, lol. Engaging people is not a problem: they are already engaged 😉
William McGarvey Thanks. I really see great potential in collaborative science. It is worth to work on this questions. Rajini Rao I see the open source programming world as some role model and 30 years ahead science in respect to utilize online collaboration. This tells me that this riddle is solvable. A great inspiration can be found in this book: Michael Nielsen, Reinventing Discovery, The New Era of Networked Science, Princeton University Press 2012 “Michael Nielsen argues that we are living at the dawn of the most dramatic change in science in more than 300 years. This is being driven by powerful new cognitive tools, enabled by the internet, which are greatly accelerating scientific discovery….this is the first book about something much more fundamental how the internet is transforming the nature of our collective intelligence and how we understand the world” (cover text)
Rajini Rao Great. Looking forward to your comments. Please keep me informed about this project. I have big interest to see how it works…..
I am less sanguine with biomedical research (which is the kind that I do). Unlike open source programming, we need highly expensive lab set up and a lot of time to run experiments that involve anything other than bacteria or yeasts (two weeks just to get our cultured astrocytes ready to transfect, not to mention finding the mouse pups, etc.). I’m assuming expertise and tech support of course. But, I’m not being a naysayer. Just want to start off with what we already have here on G+. Who knows where it may go?
Astounding
Rajini Rao ditto with MRI, etc that I use. No chance for open source on any of the imaging systems that I use. As far as open source software for medical imaging, it’s been a mixed bag for me. Some are great and others are so difficult to figure out how to use. ImageJ from NIH is a positive example.
The engagement that Rajini Rao and other in the Science on Google+: A Public Database is really good. I think discussing topics, for example on #sciencesunday and #scienceeveryday is a great start. I am interested in pursuing the idea of an online journal club. There was also a comment in other threads about using online comments to correct/critique peer-reviewed articles.
Drew Sowersby so as to not hijack Rajini’s post, I have a discussion here http://goo.gl/bqLIo Where I talk about a non-peer reviewed commentary that was sensationalize in the general media. The irreproducibility of some cancer research was drawn into question in a commentary in Nature.
This is fascinating! I read the paper that they reference, “Genome-wide non-mendelian inheritance of extragenomic information in Arabidopsis.” back in 2005 and thought it was too incredible to be true. (If it is in fact true it would be revolutionary.) I’ve been waiting ever since to see some follow-up that confirms the results or explains them in another way. I have to confess that I don’t understand how microDNA circles could explain the results in Arabidopsis. That would require a system of even more complexity than seems to be described here … somehow the stored information in the microDNAs would be preferentially generated by the cell … I need to think more about this!
I’ve only quickly scanned the responses, but here are some questions…
-> “Not only could these deletions potentially affect gene function, but they may serve as a genetic cache of information that may play a role in non-Mendelian inheritance. ” Why would one expect these to be involved in non-Mendelian inheretance, since they are found in quiescent neurons?
-> Has anyone really figured out how the transfer function of an individual neuron within a neural network is tuned, could it be perhaps through proton mediation from these circular DNA? In other words, we can mathematically describe a neural network, but as far as I know, we don’t really know how this description is effected in biology. Maybe I’m wrong, please enlighten me.
J Stasko They are thinking that the germ cells would contain microDNA. Here is my picture: Consider a plant P0 with parents P1 and P2. The non-Mendelian inheritance paper * showed that P0 could contain the genotype of P1’s or P2’s parent (the grandparents of P0) even though P1 and P2 do not contain that genotype. The authors postulated a “cache” of genetic information contained in the germ cells which would have to be generated in the grandparent or an earlier generation. The cache would be in the germ cells producing P1 and P2 and the germ cells producing P0. In P0 the cache would be used to revert back to the earlier genotype.
* S. J. Lolle, J. L. Victor, J. M. Young, R. E. Pruitt,
Genome-wide non-mendelian inheritance of extragenomic information in Arabidopsis. Nature. 434, 505-509
(2005).
Thanks, Matt Kuenzel, for explaining the Arabidopsis data. Another example is long lived gene silencing in C. elegans thought to be due to short RNA being transmitted. J Stasko the microDNA is not restricted to neurons.
J Stasko, we understand the biology of tuning neuron excitability and transfer at synapses FAR better than any mathematical model could approximate it,IMO. Am I understanding your question correctly? Also the microDNA has no way of controlling protons (pH). The key to neuron function is controlling membrane potential which is determined by Na, K, and Cl permeability (not H).
Um, there are immediate responses at the synapse as well as “memory,” that is, how a neuron will respond to the time-integrated history it has experienced… I’m really talking outside of my knowledge base here, only through school I can say nobody talked about this. Yes, they talked about response to a local excitation, sodium channels, neurotransmitter release at the junctions, etc…. It really reminds me of a sort of electrical model of signalling, very immediate and easily modelled which doesn’t seem to account for anything that happened in the distant past. Furthermore, it seems to me that the postulated perpetually passed excitations, resonances, throughout the network can’t really account distant memories… If a full-brain resonance accounts for a distant memory, then why would the dentate nucleus at all be required to store these memories?
This is why I think the whole epigenetics research program is so interesting. By epigenetics I mean any information that is carried by something other than the nuclear DNA sequence:
Evolution can explore the environmental “landscape” more quickly if offspring inherit a slightly more adapted genetic + epigenetic “genome” even for a single generation. As an example, imagine that in some environment the amount of water varies over long time periods: plentiful water then drought and so on. A particular species is optimized for the current conditions. When a change occurs, the response is some change of gene expression in the parent which can be inherited epigenetically by the offspring and which increases fitness in the offspring. Or genetic variation stored in microDNA can generate new variants of the offspring’s genes (maybe as the result of a stress response), some of which may come from an ancestor that was adapted to the new conditions.
Assume the epigenetic inheritance doubles the survival probability of the offspring. Now random mutation has twice as many opportunities to act in such a way as to adapt (or further adapt) the species to the new conditions. Assume this process continues to occur in succeeding generations. Then in two generations, random mutation would have four times the opportunities, and so on. It seems to me that compared with the pure mutation model, epigenetic effects + mutation would dramatically increase the probability that the species would successfully adapt.
“Wonder, en is gheen wonder”
Dutch for “Magic is no magic” by Simon Stevin. Thanks for the quote, Jose M. G. Guerreiro !