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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 11, 2007

A Real Genetic Headscratcher

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Posted by Derek

As you root through genomic sequences - and there are more and more of them to root through these days - you come across some stretches of DNA that hardly seem to vary at all. The hard-core "ultraconserved" parts, first identified in 2004, are absolutely identical between mice, rats, and humans. Our last common ancestor was rather a long time ago (I know, I know - everyone works with some people who seem to be exceptions, but bear with me), so these things are rather well-preserved.

Even important enzyme sequences vary a bit among the three species, so what could these pristine stretches (some of which are hundreds of base pairs long) be used for? The assumption, naturally, has been that whatever it is, it must be mighty important, but if we're going to be scientists, we can't just go around assuming that what we think must be right. A team at Lawrence Berkeley and the DOE put things to the test recently by identifying four of the ultraconserved elements that all seem to be located next to critical genes - and deleting them.

The knockout mice turned out to do something very surprising indeed. They were born normally, but then they grew up normally. When they reached adulthood, though, they were completely normal. Exhaustive biochemical and behavioral tests finally uncovered the truth: they're basically indistinguishable from the wild type. Hey, I told you it was surprising. This must have been the last thing that the researchers expected.

Reaction to these results has been a series of raised eyebrows and furrowed foreheads. Deleting any of the known genes near the ultraconserved sequences confirms that they, anyway, are as important as they're billed to be. And these genes show the usual level of difference that you see among the three species. So what's this unchanged, untouchable, but apparently disposable stuff in there with them?

No one knows. And it's a real puzzle, the answer to which is going to be tangled up with a lot of our basic ideas about genes and evolution. To a good first approximation, it's hard to see how (or why) something like this should be going on. So what, exactly, are we missing? Something important? And if so, what else have we missed, too?

Comments (88) + TrackBacks (0) | Category: Biological News


1. Lisa on November 12, 2007 2:19 AM writes...

Honestly, I'm just waiting for someone to try cryptographic techniques on the ultraconserved segments.

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2. Canuck Chemist on November 12, 2007 2:25 AM writes...

Hmmmm...maybe these ultraconserved sequences affect expression in some important pathway which does not lead to a phenotype observable under normal circumstances? For example, maybe these mice don't feel a need to run away from cats?

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3. Kevin on November 12, 2007 2:54 AM writes...

I think Canuck hit it on the head (though not squarely). My big beef, heavily shaded by the opinions of my last PI, is that these studies don't replicate real organismal biology. For the longest time people went on about no-phenotype knockout mice until a small group of biologists started asking the right questions, and showed that there was no phenotype because the mice weren't asked to be mice - sitting around in a cage feeding ad libitum is /not/ a mouse's natural ecology, and doesn't even begin to call upon everything an organism requires.

My bets? 1) We could be missing minor effects. This is the most boring of answers, but always possible. There are some fitness effects that are so fractional that they exist beyond the scope of most normal studies. People who research with semi-natural enclosures are all too keenly aware of this.

2) There is an effect, but we don't see it until the homozygote knockout mice try to mate. I don't remember off hand if the PLOS paper mice were bred, but I recall a PNAS paper were they weren't; they had a bigger deletion they were claiming no effects for (Gosh, was it up to one Megabase? My memory fails me at this hour.)

3) It could be an effect we only see in the presence of competing sperm.

My inkling is it's something involved in chromosomal structuring. I have long, boring reasons why I've been sold on this, but I'll spare you all them until some of the people who took up working with these knockout strains get around to publishing some new stuff in the near future.

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4. Morten on November 12, 2007 5:07 AM writes...

If the fitness effects are fractional then the area wouldn't be ultraconserved...
Maybe something with recombination? Which means that my money is on chromosomal structure as well. They might begin to see effects when they breed them into very heterozygous mice.

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5. C. Ventner on November 12, 2007 9:13 AM writes...

Derek, do you realize what the ultraconserved sequence is? It's a transmitter. It's a radio for speaking to God. And it's within my reach.

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6. Mike Cane on November 12, 2007 9:58 AM writes...

>>>Honestly, I'm just waiting for someone to try cryptographic techniques on the ultraconserved segments.

I've always thought that too. I keep thinking of how file transfers use checksums to verify data integrity. I think this might be along those lines.

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7. ZZ on November 12, 2007 10:06 AM writes...

Like previously noted, if it doesn't affect the organism physically then it should affect it somehow mentally. Maybe certain built in survival mechanisms like fear? I can see how some ultraconserved dna sequences could be the hard coded effect of being fearful of creatures of a certain characteristics or types (ie cats).

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8. elliottcable on November 12, 2007 10:11 AM writes...

I thought the answer was obvious as soon as I read this... therefore I'm probably wrong, because I'm no genetic scientist.

But if I were to guess about one thing (in a mutable structure that is BUILD to change) that wouldn't change - it would be that which does not need to change, right?

The things important to the system, that need to change and evolve to allow the system to survive and advance, will do so - the unimportant extra parts will not.

I guess the only surprising thing to me is that they are still in the system if they're useless. Maybe they serve some basic but almost 100% unimportant function - something important enough to not remove (like the appendix in humans) but not important enough that it needs any more advancement or change.

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9. tom bartlett on November 12, 2007 10:16 AM writes...

"I keep thinking of how file transfers use checksums to verify data integrity. I think this might be along those lines."

Not impossible, but I think nature is "dumber" than that.

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10. cyber_rigger on November 12, 2007 10:26 AM writes...

These scientists just deleted the "comments" section of the genetic code.

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11. petru on November 12, 2007 10:30 AM writes...

Yes, but did anyone check if the genome of the 'knockout' mice contained the deleted sequences anyway?

As an engineer I would think maybe there is some redundancy mechanism that protects/restores critical sequences, which would also explain the 'conservatism' of those areas of the genome.

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12. Jose on November 12, 2007 10:35 AM writes...

By the by, did you know CAS has checksums built in?

From wiki-

A CAS registry number is separated by hyphens into three parts, the first consisting of up to 6 digits, the second consisting of two digits, and the third consisting of a single digit serving as a check digit. The numbers are assigned in increasing order and do not have any inherent meaning. The checksum is calculated by taking the last digit times 1, the next digit times 2, the next digit times 3 etc., adding all these up and computing the sum modulo 10. For example, the CAS number of water is 7732-18-5: the checksum is calculated as [SNIP] = 105; 105 mod 10 = 5.

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13. Joel on November 12, 2007 11:07 AM writes...

Might these genes just be the code for preserving themselves, biochemically?

After all, such a phenotype (preserving that particular gene from modification) would be quite useful for the gene's survival, if not the survival of the organism.

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14. Ben on November 12, 2007 11:25 AM writes...

My entirely uneducated guess would be that if the code isn't expressed via changes in the animal, it probably exists for a more basic function such as error-checking, or possibly having a physical component in the replication/reproduction process (apparently non-essential, but maybe it shows after a few generations or under more stressful conditions).

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15. Ben on November 12, 2007 11:30 AM writes...

My entirely uneducated guess would be that if the code isn't expressed via changes in the animal, it probably exists for a more basic function such as error-checking, or possibly having a physical component in the replication/reproduction process (apparently non-essential, but maybe it shows after a few generations or under more stressful conditions).

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16. Wavefunction on November 12, 2007 11:31 AM writes...

Wow. That again demonstrates how much we still have to discover. Knockouts keep on delivering surprises. I remember a Nature report a couple of months ago in which they knocked out every cylin-dependent kinase but CDK1 and still got viable mice.

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17. John S on November 12, 2007 11:40 AM writes...

I don't understand the confusion this article has created.

These sequences are nothing more then sequences of DNA that are not expressed - genetic code that doesn't code for any particular protein (or anything at all basically).

Most DNA is garbage DNA - if you were to splice out intronic sequences we'd be left with short strands indeed.

Is the discovery of common DNA sequences (between humans and rodents)that code for nothing that intriguing?

Quick someone call Watson and Crick...and while they're at it someone dig up Gregor Mendel too.
This is just a bunch of garbage DNA in the rodent genome, with the added caveat that these particular garbage strands are also common with some of our garbage strands.

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18. Kit Peters on November 12, 2007 11:40 AM writes...

As I can offer no useful comment, i'll offer a silly one. :)

Maybe it was the EULA.

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19. greg on November 12, 2007 11:44 AM writes...

Perhaps it's just extra storage space. We are not done evolving afterall. Perhaps this sequence is just the default / uninitialized pattern.

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20. josh on November 12, 2007 11:49 AM writes...

"The things important to the system, that need to change and evolve to allow the system to survive and advance, will do so - the unimportant extra parts will not."

That would only make sense if evolution were intelligent and knew which parts were important. Instead what you would expect is that unimportant parts would exist today in more varied forms, because mutations don't happen selectively, they are only selected because of their effect. No effect means no selection means many variations.

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21. John S on November 12, 2007 11:49 AM writes...

I am also assuming that the fine scientists at Berkely were not speaking out of turn in their conclusion when they state that these knock-out mice were "indistinguishable from the wild type"

Actually they conlcuded that they were "'basically' indistinguishable from the wild type, which isn't the same thing as being "indistinguishable from the wild type".

The current neuroscience faculty at my Alma Mater is 'basically' identical to what it was when I graduated....but there are still 3 new members.

Indistinguishable? or 'Basically' Indistinguishable?

Maybe we can make this a little more fuzzy...

Perhaps 'virtually basically indistinguishable'

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22. Christian Martin on November 12, 2007 11:58 AM writes...

To assure stability of DNA sequence, some mecanisms must assure protection, stability and viability. Among other mutagen, UV light is a mutagen.

If you consider that DNA is actually wrapped withtin specific proteins, it offers a mean to protect the DNA from UV light exposure. If you add an extra 'layer' of non-functional DNA to this, you gain in protective measure against mutagens (could be other form than UV). Of course, being so close to important genes make them less likely to change its sequence. It would be interesting to expose these mice to UV light (or other mutagen) and see it any increase in mutation occurs compared to non modified one (control mice).

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23. Pierre on November 12, 2007 11:59 AM writes...

Man, this has got to be some of the smartest comments I've seen in a blog in a long time. Congratulations! You better hope the hoi polloi don't find this. (I came here from Reddit).

"Talking to God". That's poetic.

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24. chris Corwin on November 12, 2007 12:00 PM writes...

i would expect that even data that goes un-used for thousands of generations would still experience mutations in the interim.


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25. Roger on November 12, 2007 12:06 PM writes...

Did you study also the following generations? ie these enzymes are needed to keep chromosomal stability through generations?

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26. John S on November 12, 2007 12:10 PM writes...

25. Roger on November 12, 2007 12:06 PM writes...

Did you study also the following generations? ie these enzymes are needed to keep chromosomal stability through generations?

...remember Roger - 'Basically Indistinguishable'

So their answer to your question is 'uh...yes'

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27. vick on November 12, 2007 12:12 PM writes...

All this scares me. I did poorly in highschool biology. And I dont know anything about DNA. Heck, I haven't even read this article. But I do know one thing is for sure: mice are smarter than you think

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28. John S on November 12, 2007 12:16 PM writes...

27. vick on November 12, 2007 12:12 PM writes...

All this scares me. I did poorly in highschool biology. And I dont know anything about DNA. Heck, I haven't even read this article. But I do know one thing is for sure: mice are smarter than you think

I think we found one of the yokels that was involved in this highly scientific study.

Actually thats doubtful, your levity suggests the presence of higher brain function and enhanced neocortical activity.

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29. John on November 12, 2007 12:21 PM writes...

Maybe those genes are ultraconserved *because* they're right next to critical genes.

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30. Alex Tolley on November 12, 2007 12:23 PM writes...

I would concur that the most likely explanation is that the lab mice phenotypes are just too limited to determine the nature of this sequence. Almost by definition, a highly conserved sequence, whatever its role, is likely to be deleterious over several generations if removed or modified.

I haven't read the papers, but I would also like to rule out that the sequence is not some contamination or artifact introduced during sequencing. There is evidence that genebank has sequences that are ascribed to organisms but are contaminant from the bacterial cloning. It would be a bit embarrassing if the highly conserved sequence across these mammals was an e. coli sequence.

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31. ryan glinski on November 12, 2007 12:37 PM writes...

Our DNA contains the whole history of our evolution. The current body only ever needs a tiny percentage of it to build protiens. There are vast swaths of DNA that the ancestors of rats, mice and humans needed, but that species is no more, and the DNA it would have build protiens from is no longer useful. It's still there, all the DNA any of our ancestors ever transcribed from is still there, we just don't transcribe from it anymore. The fact that a certain DNA sequence is largely identical between disparate species is one, pretty good proof for long time fame evolution, and two, evidence that the DNA no longer matters to any of the species. Stick that stuff in an ecoli and see what happens. You'll learn something about the ancient world.

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32. Krassi on November 12, 2007 12:54 PM writes...

I would not so quickly call the deleted sequences "disposable". I assume the KO mice were grown in standard conditions. Many genes would "show" their importance when an individual is experiencing a challenge or a stressor. The conserved sequences might be regulatory elements for the expression of the nearby essential genes and their function might be critical in stressful situations.

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33. Chris Andersen on November 12, 2007 1:08 PM writes...

Wasn't the main premise of "Darwin's Radio" that 'garbage DNA' actually contained programming for dealing with stressful environments that were atypical but which occurred enough within the million years of genetic history that they still offered a survival bonus for the genome?

(btw, I also like the suggestion that conserved DNA is conserved *because* it is right next to DNA that are essential to survival. They kind of piggyback.)

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34. Wavefunction on November 12, 2007 1:14 PM writes...

If the DNA indeed is garbage DNA as some have suggested, is the only reason that it has not disappeared the fact the it has not been given enough evolutionary time to do so?

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35. Jordan Lund on November 12, 2007 1:31 PM writes...

The mice might APPEAR to be normal, but you can't say they are normal until they have gone through a full battery of life conditions.

Did the deletion affect breeding? Allergies? Disease resistance? Hard to say, the article doesn't indicate what tests the mice were put through.

It would be interesting to cross-breed two of the knocked-out mice and check the genome of the offspring.

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36. Matt McIntosh on November 12, 2007 1:38 PM writes...

FFS, to all you people who are going "it's just junk, nothing to see here" -- with apologies to Charles Babbage, I cannot rightly apprehend the confusion of concepts that could provoke such comments. If it was doing nothing you'd expect substitutions to occur on it at the baseline mutation rate of about 10^-4 to 10^-6 bp/generation. But it doesn't -- substitutions occur on those areas at a rate considerably lower than that. Departures from that rate mark something as having some sort of function beyond just sitting there taking up space.

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38. planetmcd on November 12, 2007 1:57 PM writes...

I read this and two things came to mind.
How many people take the time to uninstall software that they no longer use? Is this that different. If someone did remove it without telling them, would they notice if everything was working fine before and after the removal?

The other thing, when I was younger I tore my ACL. In the interim between the injury and the surgery to repair it, if I stepped on a curb or a crack in the sidewalk in the wrong way, my knee would buckle and I would collapse in pain. To avoid the injury and embarrassment, I developed the habit of walking while scanning the ground. It took me 2 weeks to pick up the habit. After the surgery and PT, I no longer need to worry about my knee giving out, but since there is no impetus like physical pain or embarrassment to prompt me to behave differently, I still walk while scanning the ground (12 years later). Imagine how hard it is to root out a genetic trait that doesn't have stressors that make that trait a negative characteristic for natural selection. If there is no reason to purge a characteristic, why would it go away, even if it is useless?

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39. RIAA on November 12, 2007 2:33 PM writes...

Those streches of DNA were our copyright notices. Do not touch!

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40. Hap on November 12, 2007 2:56 PM writes...


Sequences change because mutation happens - mutation is a natural occurrence like gravity. DNA is not replicated with perfect fidelity, and UV radiation and other sources change DNA sequences. A DNA sequence is like a bridge hanging in air - without something to hold it in place, it will fall (mutate). If a sequence changes more slowly than average (more slowly even than parts that are absolutely necessary), then work has to be done to keep it unchanged. People thus assume that there is some reason why organisms expend the work to keep the sequence unchanged - because in the absence of pressure to keep it unchanged, it will change at the background rate.

Unless there's something else we don't know.

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41. KBK on November 12, 2007 3:00 PM writes...

They grew up normally, but they have no souls.

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42. james on November 12, 2007 3:16 PM writes...

maybe mice, rats and humans have not mutated enough yet to "occupy" those strains?

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43. William Shatner on November 12, 2007 3:22 PM writes...

I got rid of those genes long ago and it didn't do me any harm. Although I do have an urge to eat cheese.

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44. JSinger on November 12, 2007 3:26 PM writes...

Derek, you should have figured out how to drive traffic like this while the voting was still going on! Anyway, to hit a few of the recurring theories:

1) These have an important function, but it's not being tested under lab conditions.

Possible, but Morten probably has it right -- any advantage that subtle is unlikely to have such a deeply, broadly conserved sequence underlying it.

2) It's junk DNA / it's "uninitialized sequence" / it's near something important:

The whole point is that we don't see such perfect conservation in the vast majority of the genome, so *some* explanation seems to be required. As others have explained, random mutation drifts in and needs to be selected out somehow.

3) The deleted sequence got replaced back into the genome:

Such correction does happen in some isolated situations, but not in transgenic mice. Besides, the process of breeding the mice requires following the deletions, so you'd know if the original sequence reappeared.

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45. David Fox on November 12, 2007 3:32 PM writes...

Do we know how statistically unlikely it is that such a stretch of unmutated DNA would exist if it is unimportant?

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46. abo on November 12, 2007 3:40 PM writes...

Next question:

What happens if you instead change those genes? Maybe they're harmless and useless, but any change in them turns them into something bad.

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47. As You Lean on November 12, 2007 3:57 PM writes...

Think of the genome very broadly to be a working engine. There are parts that are critical for its function, like cylinders, valves, and crank shafts, which have really not changed much over the course of engine history. There are other parts of the engine which are less important to the function which have undergone pretty significant change over the years, and there are intermediate elements.

Now think of mutations like a wrench. You can toss a wrench into an engine and, maybe not hit anything important at all, and it will keep ticking along like before. Or, you might hit something vital and it comes screeching to a smoky halt. Alternatively, you can take that same wrench and use it to tune up an existing engine and make it run better. As we all know, its a lot easier to break something than it is to make it better.

Like Matt McIntosh said, there is a predictable rate of mutation that occurs within the genome over time. Using the engine/wrench analogy, we would assume that sequences which are unimportant can withstand a rather high level of mutation with no discernible effects, whereas very important sequences would not tolerate mutation at all. Since these elements have been very well preserved not only within one species, but between distantly related species, we naturally assume they have some great deal of importance. If they were not so important they would have mutated away generations ago.

This report seems to be the same as saying that they pulled all the pistons out of an engine and it still starts up fine, accelerates well, and falls back to a smooth idle.

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48. Matt on November 12, 2007 3:59 PM writes...

I would lean towards the theory that the lab conditions didn't appropriately test all conditions. For example the number of generations of offspring included in the study.

If this sequence exists in all known variants of these species then any mutation --even slight-- from this sequence has not continued in nature for some reason.

Either there is a natural selector that is unknown but strong, or this sequence is preserved through some other method (perhaps the error correction role suggested by others). I really don't think there is another explanation based on our current understanding of DNA (or maybe just mine).

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49. hmm on November 12, 2007 4:20 PM writes...

could the conserved region be the side effect of something else? or a fixed point of some sort

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50. William Newman on November 12, 2007 4:36 PM writes...

I can imagine hypothetical lethal effects which'd take a while to show up. For example, what if the effect of the deletion is that the base mutation rate per generation is now many times higher than what it was before, high enough to outrace the rate at which errors can be corrected by evolution?

I'm reaching, though, even for such hypothetical subtly lethal effects alone. Once I add in the other part of the puzzle, that the long sequence is even more strictly conserved than the sequences coding for key enzymes, I become completely stumped.

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51. Mendel on November 12, 2007 4:39 PM writes...

I am myself a Human geneticist and I was wondering whether you could provide some references from the scientific literature. If true it will be of great importance. But I'm a bit pessimistic about this as you know SNPs happen every 250 to 1000 bp on average and very odd that this bit of DNA is conserved with no variation not only in humans at the intra and inter population level but also in animals from different phyla.

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52. micah on November 12, 2007 4:52 PM writes...

it seems to me that it could be very difficult to test every aspect of a mouse's normalcy. perhaps this has to do with the social behavior of mice? perhaps it has to do with a virus or bacteria that has recently disappeared? do they know that this strand is expressed in mice? in DNA, are there strands that are only expressed if other parts of the DNA are a certain way?

this certainly is baffling, now I'm going to be thinking about it all night...

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53. Mat B on November 12, 2007 5:09 PM writes...


This looks almost like the "problem" that GP (Genetic programming) exhibits called bloat.

These algorithms tend to create genome sequences that get larger and larger with unimportant junk towards the end of an evolutionary run.

In fact they are kind-of useful, they protect the individual from the possibly harmful repercussions of crossover and mutation. Who cares if the useless junk gets mutated, so its presence reduces the probability of important parts getting toyed with.

Could the 'biological' equivalent exist for a similar reason?

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54. Anonymous on November 12, 2007 5:12 PM writes...

the problem with the idea that it is just because they are near important genes is that the important genes differ between the these conserved sequences are even more conserved than the critical genes that they are next to. I will buy the chromosomal structure idea, that may have merit. If these are histone interaction sequences or something like that they may be afforded some protection from mutaton.

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55. kieth on November 12, 2007 6:36 PM writes...

Very amusing comments. Even for someone who doesn't know anything about the subject. I was not able to find the words "immune system" mentioned anywhere above (maybe very obliquely by C. Martin); why is that? couldn't the conserved sequences have provided some protection against a pathogen?
now long gone.

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56. NJBiologist on November 12, 2007 7:02 PM writes...

It's a little frustrating to say "we don't know," but at this point, that's the intellectually honest answer.

Personally, I wouldn't rule out compensatory mechanisms; this seems to have happened with knockouts of genes which have obvious and important functions (like the glucocorticoid receptor).

Or these sequences could be mattress tags....

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57. Miik on November 12, 2007 7:07 PM writes...

I think that perhaps waterboarding these gene sequences might lead to some answers- eh?

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58. Mon Jaxwell on November 12, 2007 7:13 PM writes...

These sections are reserved for future use.

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59. Ray on November 12, 2007 8:13 PM writes...

Deleting a gene isn't something that would randomly happen by mutation, at least not very often, I would think. So I'm not sure what that proves.

What if any mutation in that gene has a lethal effect?

I could easily imagine some sequence developing that has no purpose but to propagate itself exactly. It seems to me that the most effective way to do that isn't to have a more *useful* phenotypical expression, nor even to be harmless junk. Those are both susceptible to mutations that improve or leave constant the benefits of the gene.

The most effective way for a gene to ensure its own propagation *without change* is to terminate with extreme prejudice any mutation in the gene.

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60. Michael Terry on November 12, 2007 8:23 PM writes...

Let's say I had a very huge number and that digits in the number randomly changed at a predictable rate to create a new number. I would expect to be able to compare the latest version of the number (after many iterations) to the original and find matching sequences.

Is this a valid analogy? If so, I assume some sort of probability analysis was done to determine the likelihood of a matching pattern--as long as the one(s) studied--between mice and men? What was the probability?

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61. Terry Jones on November 12, 2007 9:09 PM writes...

I'm guessing those mice...... HAD HUMANS FOR PARENTS.

All laboratory staff should be closely questioned ASAP.

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62. Kevin on November 12, 2007 9:17 PM writes...

What if this gene sequence coded for a parasitic virus or other self replicating sequence? It's only purpose would be to conserve itself, so knocking it out wouldn't be detrimental to the host.

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63. Andy on November 12, 2007 9:17 PM writes...

I always thought God was an object oriented designer. :-) Think of one organism as being an overloaded class for the design of another. Any programmer will tell you when you overload things, you get a lot of old code left over which may never get called again.
Or it may be code required in very specific circumstances. Perhpaps it contributes to genetic variation in such a way as to promote differentiation into different species. Perhaps it is code for the immune system to fight various things the mice were not exposed to.
What appears to be useless code may have a profound effect on the evolutionary viability of that genome. It's hard to tell when we don't know what activates those sequences. Enter the cool new world of epi-genetics.

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64. Rich on November 12, 2007 9:30 PM writes...

Some wishful thinking in these comments.. Bible codes in DNA anyone?

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65. Gregory Bloom on November 12, 2007 9:46 PM writes...

Since these ultraconserved areas are located near critical genes, perhaps they're in an area where mutation inhibition overlap brings all mutation to a standstill. Such inhibition is too great to be evolutionarily useful.

If a selective pressure comes along that could be addressed by a small change to a critical gene, having that gene completely locked to mutation would be a disadvantage. Therefore the organism evolved to stop relying on that area for anything more than as evolutionarily useless filler.

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66. bob on November 12, 2007 10:03 PM writes...

They are the genes that explain paris hilton, the spice girls and george bush.

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67. Anonymous on November 12, 2007 10:11 PM writes...

Very interesting topic. A few scattered thoughts:

From a scan of some older papers, it looks like these ultraconserved areas go back to early vertebrates but no further-- they are not generally shared with fruit flies, for example. The suggestion presented by Bejerano et al is that the sequences in question suddenly began to experience either highly enhanced selection pressure or highly suppressed mutation rates starting 300 million years ago and continuing to the present day.

Michael Terry: I believe the probability is about 1 in 10^22. I got this from the 2004 Science paper by Bejerano et al.

The problem I see with the "compensatory mechanisms" argument is that if something else steps in to take over the important function of the gene when it's deleted, why is it ultraconserved in the first place? It seems like redundancy would greatly weaken the selection pressure on individual elements.

Kieth's idea, that the genes may code for protection against certain pathogens, is very interesting. But it can't be a "long gone" pathogen, or the sequences would have mutated since the pathogen disappeared. And it would have to be something not present in Berkeley.

Ray suggests that deletion of the gene has no effect, but slight mutation is lethal. This would certainly explain the results, but how would it be achieved in practice?

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68. Kevin on November 12, 2007 11:30 PM writes...

Wow. 67 comments. Here I thought I'd check back in and there'd be maybe a dozen at most.

Regarding the fractional returns reply in #4: If it was a coding sequence, and had room to wobble in its sequence, yes, you'd expect sequence diversity to increase. But there's no reason to expect these non-coding sequences play by the same amino acid encoding rules (Though, some people argue that this argument is a tautology). If there's no equivalent wobble on whatever these 'code for,' then its easier to see fractional returns managing to conserve them at this level over evolutionary history.

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69. NJBiologist on November 13, 2007 12:26 AM writes...

@67, on compensatory mechansims: Good point, I hadn't thought of that.

Which, of course, narrows it down to "I dunno" and mattress tags....

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70. Steven on November 13, 2007 1:19 AM writes...

What's the difference between this paper, and " Megabase deletions of gene deserts result in viable mice"?

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71. ryan glinski on November 13, 2007 1:25 AM writes...

I've always had a general conscern about a few evolutionary issues.

First, we know almost nothing about how complicated carbohydrate elements of enzymes are created in the first place, or how the cell manages to attach the right carbohydrate to the right enzyme at the right time.

Second, the amount of information in these carbohydrate structures is huge. On an atom per atom basis they contain far more information than DNA.

This is all part of a general question about cell decision making. What I've read lately says cells make decisions more based on what the conscentration of what molecule is at any given time, and also with electrical signals that flow through the membrane.

I think, and maybe this isn't a comment about these mice in particular, we all give too much credit to DNA. The membrane makes the decisions, heck, the membrane is the cell. The DNA is just a hard drive, the processor and the intelligence behind the software (whether it be god or evolution) are somewhere else.

I think the people talking about sequences only transcribed under stress have a great point. It's a bridge between the "trash" and "hidden value" points of view.

Also, could some of the DNA be structural? DNA is all wrapped up in a ball, and it's got to be easier to transcribe from genes on the surface of the ball. Maybe it's a bit of filler to maximize access to the really useful genes. I suppose that wouldn't explain why it's genetically selected for though.

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72. anonymous on November 13, 2007 7:48 AM writes...

Don't some viruses occasionally incorporate bits of themselves into the host genome?

What if these 'highly conserved' but useless sequences are actually evidence of a virus that infects basically every Mammal on Earth? But the infection, itself, is some benign as to go unnoticed, aside from this odd artifact left behind in our collective genomes?

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73. Dwight Deay on November 13, 2007 7:59 AM writes...

Hey, normally I'm just a lurker on this blog but late this night I'm thinking about how a sequence of unimportant DNA could resist the inevitable "static" effect of mutation which in principle should be accumulating at the same rate as any other unconserved(i.e. useless) part of the genome, hell correct me if I'm wrong, but don't we use the mutation rate of unselected junk DNA to calibrate gene clocks?

Maybe they are transposons that recruit a ultra fidel polymerase, or just modify the standard PolA to slow it down and tune it up? just ideas.... how else might evolution allow this? Even key metabolic proteins like respiratory chain electron carriers accumulate mutation slowly, despite good reason to stick to the plan. This is crazy.

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74. Dwight Deay on November 13, 2007 8:28 AM writes...

Ya know, upon further contemplation I think if I was a betting man I would bet on the predictions of many here, that the rat model is simply not sufficient(or not being looked at well enough). Knockout viability is certainly not the end all of gene functionality, but its either got be this, that the sequences in question really do serve a adaptive role that is highly sensitive to variation, or its got to be some kind of self serving genomic virus with a really good replication scheme. Lots of DNA is like this; transposons, temperate viruses and such..but they accumulate probably not. I'ma stick with the least complex hypothesis at this point. Totally useful DNA. The rat model is insufficient, or, not extensive enough observation is being done. If something else comes out of this then the definitional correlation between "conserved" and "beneficial" will need to be re-thought. GREAT THREAD~! THIS BLOG RULES! SCIENTISTS RULE THE WORLD!!!!

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75. Morten on November 13, 2007 8:35 AM writes...

I think one or two of these comments broke my brain... just to be a snobby biology person ;)

There are benign (as far as we know) retroviruses such as human foamy virus but they would have to be present in all of the mammals which seems... not unlikely but more along the lines of impossible. Retroviruses insert semi-randomly too AFAIR.

I liked the ideas of reduction of the mutation rate in the nearby DNA. We assume that critical genes mutate slowly because of heavy natural selection against mutations there - but no-one has shown that there aren't mechanisms to preserve this critical DNA. There would be heavy selection for such a mechanism and if it is based on DNA all bases would be under selective pressure (non-bio people: there is redundancy built into the genetic code so you can change some bases without actually changing the protein product).
I also still like the "useful-in-recombination" idea...

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76. Ray on November 13, 2007 12:42 PM writes...

>Ray suggests that deletion of the gene has no effect, but slight mutation is lethal.
>This would certainly explain the results, but how would it be achieved in practice?

Well, it's certain that such a gene couldn't arise incrementally, but if it ever occurred, it would, by definition, remain present and unchanged forever (or at least until a similar but opposite event occurred).

I'm not saying this is what's happening, BTW (I think the explanation of it having something to do with being near an ultraconserved gene is a better one. In fact, it's possible that this gene could serve as some kind of error detection code for that conserved gene... it's function could be as I suggested, but its purpose could be to make sure that the nearby gene survives with little little change).

Anyway, single mutations couldn't create such a gene, obviously. However, it's remotely possible that a recombination or retroviral insertion (or even massive multiple mutation) occurred in some common ancestor that happened to have this effect. I couldn't begin to calculate the probability of this happening.

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77. Dwight Deay on November 13, 2007 1:32 PM writes...

Morten, I hadnt seen any posts about recombination- thats a cool idea, they could act as a region of homology to facilitate consistent synapses, promoting recombination only at certain regions. chi sites might just be for fine control of recombination, with intron homology broadly targeting chromosomal recombination. But why be so intolerant to change? I was doing Pchem problems dealing with the Gibbs energy of annealing DNA strands the other day and its fairly high ~9kj/mole/base for an idealized strand, but I don't know how that compares to the free energy of synapsis, its probably much less, or more positive thon pressure not mediated is- this would make the impact of a single mismatch much greater on the success of annealing. The idea fits with the idea that Kevin and I think a few other mentioned, that this DNA is under selection unaffected by translational degeneracy.
Your right Morten about it being hugely beneficial to be able to "lock in" certain parts of the code, but ,like you mentioned, the current explanation of homology/retention of key sequences has been that when things try to change they die. I feel that you are probably right, there are probably some kind of preservation methods(maybe something involving the polymerase). I cant wait till we figure this out!

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78. tgibbs on November 13, 2007 6:28 PM writes...

I like the pathogen idea. Let's say the sequence is critical to provide resistance to some pathogen. Absent the pathogen, it does nothing much, but in the presence of the pathogen only the mice with the intact gene survive.

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79. biohombre on November 13, 2007 10:20 PM writes...

Anyone remember telomerase knockout? Compensation was involved, as was age, and generation time (was it 6 generations to sterility?)

As I recall those knockout results also caught us by surprise...

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80. Raymond on November 14, 2007 11:39 AM writes...

Perhaps these genes are responsible for different atavisms.
Perhaps they are important in the development of the embryo or serve the DNA like a foundation serves a house. Nobody remodels there foundation. All of the observed changes occur to the rest of the house, but without the foundation there would be no house.

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81. Raymond on November 14, 2007 11:49 AM writes...

Also, in response to error checking procedures, such as checksum and other cryptographic techniques. If the genetic data is redundantly storing information, 2 things would be expected:
1) Whenever the genetic code changes with respect to a mutation, the checking-bits would either a)correct for this mutation or b)would also need to change with respect to this new information. If the genetic code is redundant, then the changes should be redundant within the genetic code.
2) Also a mechanism would need to be established to employ the error checking process and to correct for any genentic errors or change accordingly.
As a result the ultraconserved parts would have to change to allow for a mutation to continue to appear.

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82. Sarah on November 14, 2007 1:34 PM writes...

the phenotype of these mice are seemingly normal, yes. but could this ultraconserved region of the genome function in a system of the body that isnt observed unless prompted...such as host defense. in this case, mice that havent been presented with a challenge (bacteria or virus) will seem normal, but once they are infected will possibly succumb more easily to disease.
i feel similarly to Kevin in comment 3, in that mice living in a cage do not represent a real-world scenario.

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83. Jonadab the Unsightly One on November 14, 2007 4:18 PM writes...

They could be left over from the template. I mean, if *you* were going to create a wide variety of different life forms, would you start over from scratch with each one, or would you copy-and-paste the whole thing a bunch of times and then make the changes needed to create the desired differences?

(Yes, I'm joking. Well, mostly.)

> Unless there's something else we don't know.

There's always something else we don't know, usually more than what we do know.

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84. Dana H. on November 14, 2007 6:06 PM writes...

Ray wrote:

> What if any mutation in that gene has a lethal effect?

I like this suggestion if only because it is a readily testable hypothesis (unlike many of the other conjectures here).

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85. RKN on November 14, 2007 8:23 PM writes...

the phenotype of these mice are seemingly normal, yes. but could this ultraconserved region of the genome function in a system of the body that isnt observed unless prompted...such as host defense. in this case, mice that havent been presented with a challenge (bacteria or virus) will seem normal, but once they are infected will possibly succumb more easily to disease.
i feel similarly to Kevin in comment 3, in that mice living in a cage do not represent a real-world scenario.

But these aren't protein coding sequences; technically speaking they're not genes. Are there any examples of non protein coding DNA conferring resistance to a pathogen?

I would have guessed given their adjacency to conserved protein coding genes that these sequences might be cis- or trans- acting elements. But even that wouldn't explain their ultra resistance to de-selection that the Science paper showed.

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86. Ben Hemmens on November 19, 2007 2:15 AM writes...

well we normally assume that DNA mutates unless there is selective pressure to keep it the same. at least we are used to it looking like that in organisms whose DNA is practically all genes.

we think genes are great, well whaddya know, we just discovered what 0.01% or so of our DNA is doing. what the hell the rest of it is up to we still haven't a clue. some people say its garbage, but hey, thats what they basically thought about ALL DNA before watson & crick.

maybe there is something besides being genes that it does. maybe some of it just doesn't mutate.

maybe in another 100 years, genetics will be the minority branch of DNA studies...

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87. LWW on November 30, 2007 12:49 PM writes...

My comment comes from the history of our understanding of protein structure. First the importance of proteins was unknown; then the primary sequence was the focus of research; then the folding of proteins was recognized as important, and parts that didn't fold were a mystery; then the tertiary structures (the organization of the folded and unfolded parts) were recognized, and the roles they play defined in the formation of dimers, etc. Now we have progressed to the design of polypeptides that do some of the things we bid them to do (fold the way we predict and bind to things selectively). We also recognize the importance of misfolding in various diseases and conditions. Not long after the importance of proteins was recognized, when no one knew the mechanism of inheritance, DNA and RNA were considered unimportant or not central to inheritance (i.e., junk). Now I see the same thing happening with "junk DNA"; we don't understand non-coding regions so we label them junk; now it's a "surprise" that some parts of the junk are "highly conserved" (as an aside, we used to think only the maternal mitochondrial DNA made it into the offspring, or was "conserved", but a small and important contribution from the paternal DNA has been recognized recently, so we should be careful about interpreting "highly conserved"). I am a chemist and I see the genome not as an engine, but as the entire system used by us to go long distances (in time) with minimal effort. It includes engines with interlocking systems (the electrical system, the brakes, etc.), built into cars, carrying people and things on roads, needing parking lots, mechanics, garages, even junkyards and factories. THAT is the genome. If you focus too much on the engine and discover a door handle, you might be "surprised." What does a door handle have to do with an engine? What does a parking lot have to do with a road? Please don't be naive enough to believe that the coded information in the genome is all the cell, tissue, organism or its social system needs in order to propagate. DNA has to be handled by numerous species in solution and bound to membranes. It has to be read and not read, unfolded and refolded, dragged into daughter cells during division and released after, twisted and untwisted, etc. It is also a polymer and it has to be controlled or it will cross-link, tangle, interact with other species in the nucleus, get stuck on something and have to be unstuck, etc. When an invading virus is present, it goes for the machinery that manipulates DNA and transcription, folding etc., which has to be defended (actually, some cells might be sacrificed to defend the organism and its ability to pass on its genes, or protect the passage of its genes from its offspring to the next generation of offspring). The sea from which we evolved, the soil, the air are all loaded with countless viruses. It stands to reason the genome and its vehicle (vertebrates) need loads of protection, possibly more than we have the ability to detect today. They (viruses and many microbes) have no junk DNA (to the best of my knowledge); neither do bacteria. In fact genes in some prokaryotes (bacteria, archea) are encoded in overlapping frames, sometimes forward and backward, sometimes on both strands, evidencing the pinnacle of efficiency, the opposite of non-coding sequences, although in both, highly conserved. Perhaps the purpose of non-coding regions has to do with the advantage the cells of a vertebrate have over the micro-organisms from which we lease some space on the planet: vertebrates can support "waste" in the genome and a bacterium cannot. That seems like a big clue. Vertebrate cells get nourishment from blood (i.e. in vertabrates, nourishment is obtained and distributed by the cooperation of every type of cell, and every type of cell benefits, but no one cell has to swim around in pond water and engulf stuff to digest, sort out the keeper components from the unusable stuff, convert the useful components to energy etc., and safely eliminate the waste), and don't have to "fight hard" for every ATP. Lacking some of the functions of free-living microbes, the cells in our bodies have some "discretionary spending" energy. The energy economy of vertebrate cells and ultimately, vertebrate orgainisms, compared to the rest of the flora and fauna in nature, will be where we find the answer to the mystery of these "highly conserved" regions of non-coding DNA (i.e., the physical properties of these regions plays a role we don't understand, and it bequeaths to the cell a possible energetic advantage). Perhaps a first (baby-sized) step toward understanding them is not to call them junk, mainly because we don't know what they're good for. Could we at least stop doing that whenever we study something and don't understand a part of it?

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88. Karl on February 19, 2011 11:39 PM writes...

I'm not big on the animal testing so I didn't pay much attention in Physiological Psychology (though I have to admit that it was BY FAR the most amazing class I ever took.) But could all of the behavioral aspects of the mice really have been analyzed? Do the mice still want to reproduce, stop eating before they've eaten too much, etc.? It seems like there would be far too many things to test.

Or perhaps that DNA is responsible for a mechanism that protects against harmful mutations - it would make sense that the mice would act the same in the first generation, because such a mechanism (while super important) would only manifest in successive generations, or perhaps not until MANY generations later. I would think that mechanisms that protect against harmful mutations would be the first mechanisms to evolve. But I don't remember being taught anything about them in my classes. Then again, I was never especially good at this whole biology thing.

Anyways, interesting stuff. Makes me want to read a sci-fi where it starts with a biologist discovering that aliens have left their signature in every living creature as a sort of copyright and this is all just one big experiment... oh wait, the Hitchhiker's Guide to the Galaxy already did that... :)

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