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If it's junk, can we get rid of it?

This week's paper is "Deletion of ultraconserved elements yields viable mice" by Nadav Ahituv and collaborators, published online in PLoS Biology.

The instructions for "life as we know it" are coded in DNA, but it appears that only a fraction of our DNA is ever used. (This is probably not true of our brains, myths notwithstanding.) At least, only a fraction of it is ever translated into proteins such as enzymes. Some of the untranslated (noncoding) DNA has known functions, such as coding for the RNA part of the ribosomes that translate messenger RNA into protein, but much appears to be junk. Much of the junk is multiple copies of transposons, bits of unusually selfish DNA that reproduce like rabbits and burrow into the chromosomes, sometimes presumably disrupting functional DNA.

But if the noncoding DNA is mostly useless junk, why has some of it apparently been preserved by natural selection?

That was the question raised in an earlier post. About 5% of noncoding DNA is highly conserved. That is, the DNA sequence in related species is very similar, as if it hadn't changed in the millions of years since they diverged from a common ancestor. In that length of time, you would expect changes due to mutation.

Conserved DNA sequences are easy to understand when they code for protein. Mutant versions of the protein didn't work as well, so only those individuals with the original version survived and reproduced. But why would noncoding DNA sequences be conserved? Maybe they have some function, after all?

The authors of this week's paper conducted a direct test of this hypothesis, by deleting highly conserved (identical in mouse and man) but noncoding regions from the DNA of mice. They only deleted four sequences, but those were chosen to maximize the chance of seeing an effect. For example, although none of the deleted DNA coded for proteins, the sequences were near proteins previously shown to have a large effect. So if the deleted DNA regulated expression of nearby proteins, the mice should have been noticeably different. Dead, for example.

The DNA-deleted mice appeared normal, however, in growth and biochemistry. Matings among themselves or with normal mice gave the usual number of offspring per litter. 2% of the mice had only one kidney, versus an estimated 0.1% in normal mice, but that was the only abnormality found, and it wasn't necessarily caused by their deletions.

What can we conclude from these results? There seem to be several possibilities:

1) The deleted sequences (and by extrapolation, much noncoding but highly conserved DNA) really is junk. If so, why are they conserved? Maybe those parts of the chromosome are somehow more protected from mutation than other regions.

2) The deleted sequences are important, but only under conditions not tested in the laboratory. Although they don't appear to control nearby protein-coding genes, maybe they control ones farther away. Or maybe they code for RNA that (without translation into protein) interferes with a virus not found in the laboratory. The kidney defect needs more research.

3) The deleted sequences serve some important function, but there are backups with similar function (though perhaps with different sequence) elsewhere in the genome. The authors seem to like this hypothesis.

This paper reminded me of an earlier paper (Nature 395:905) in which genes for myoglobin (thought to be critical to oxygen supply in muscles) were knocked out in mice. Although their muscle tissue was pale rather than red, the mice were able to exercise normally. If we have backup systems that let us (us mice, that is) survive without myoglobin, perhaps it's not surprising that deletion of DNA sequences with no known function had little apparent effect.

T. Ryan Gregory has also posted an interesting discussion of this week's paper.

Comments

I am not a biologist but a lawyer. Question : isn't it possible that large chunks of this "junk" DNA were introduced a few tenthousand years ago by a bactery or a virus, and then simultaneaously in mouse and man?

Yes, viral DNA does sometimes insert itself into host DNA, leaving a record that supports the same family tree derived from other evidence, as discussed here:
http://vwxynot.blogspot.com/2007/06/endogenous-retroviruses-and-evidence.html
Insertion of bacterial DNA may be less common, but there's a recent paper showing lots of insects have DNA from the bacterium Wolbachia (see Aug. 31 post).

As you suggest, if that happened recently, you could get the same sequence in mice and humans, even if our common ancestor never had that sequence. But you wouldn't expect to see it in ALL humans unless it infected everyone with living descendants. Also, you wouldn't expect it to insert in the same place(s) in different individuals.

Shades of The Selfish Gene here. Perhaps those sequences are somehow especially good at getting themselves copied.

I'm not a biologist, so I don't know much about mechanisms, but I wonder if there's any way such sequences could guarantee they'd be passed on.

For example, are the neighbouring coding regions particularly highly-conserved themselves? Maybe the copy-protection systems in the nucleus just aren't very fine-grained and protect the "junk" along with the important stuff nearby. Or more directly, though probably less plausibly, the sequences produce RNA that insert themselves back into the genes of the organism's gametes.

I wonder about the hybrid mice: was their inheritance of the "normal" sequence skewed in any way, or did it follow a simple Mendelian pattern?

Joshua,
Interesting questions. I am glad some nonbiologists read this. Generally DNA that copies itself (transposons) tends to end up all over. I don't think that was the case with these sequences. They were close to important (presumably conserved) sequences because they were chosen that way, as more likely to have important regulatory functions. I assume there will be more related papers coming from this or other labs.

I read it precisely because I'm a non-biologist! It's interesting stuff that I didn't get into in school, but one article a week is pretty manageable to a layman.

Thanks for answering my question about the possibility of these sequences being transposons. The actually does make intuitive sense. A DNA sequence that tries to copy itself wouldn't necessarily care where it ended up as long as it got copied. You might also expect to see multiple copies of it in different places in one individual's DNA, yes?

I just noticed the link at the end of your post to Genomicron, so I think I'll look there for more info.

I read this article, its very helpful. But i have question, how the process translation of RNA into proteins happen? and what are the factors affecting on this process ( i mean inducing it or inhibiting it).

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