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.