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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: derekb.lowe@gmail.com 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


COMMENTS

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.

no?

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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...

planetmcd,

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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