What is the potential function of ultra-conserved elements in the genome?

Question

If selection pressure results in conservation of DNA sequences, what is the most plausible explanation for the existence of ultra-conserved elements (refs here and here) given that there hasn't been any significant validation of the functional significance of these elements other than a lot of bioinformatic analyses across different genome datasets? If these are of such high significance, does this mean that there is still some significant gap in our understanding of fundamental biology or is there another explanation? The second reference in particular show that there are UCEs shared between plants and animals, but are not syntenic (which is not necessarily a surprise) so it might suggest that at least a class of UCEs are associated with structural rather than functional elements.

It appears that there are at least several different 'classes' of ultra-conserved elements, based on the number of matching/identical bps, their spatial distribution across the genome and the species in which they exist. Even though there is probably no single explanation that would account for all the possible functions they can have, it is surprising that they are difficult to test functionally. This is again probably due to a lack of understanding about their properties and therefore no real method to validate their function. I think this is where we need to think outside the box to come up with the answer.

What would be the most obvious (and possibly not so obvious) function for UCEs?

Answer 1

Probably development, in particular transcriptional regulation. To quote each link in turn,

They are found in clusters across the human genome, principally around genes that are implicated in the regulation of development, including many transcription factors. These highly conserved non-coding sequences are likely to form part of the genomic circuitry that uniquely defines vertebrate development.

and

[Highly conserved non-coding sequences] are significantly associated with transcription factors showing specific functions fundamental to animal development, such as multicellular organism development and sequence-specific DNA binding. The majority of these regions map onto ultraconserved elements and we demonstrate that they can act as functional enhancers within the organism of origin, as well as in cross-transgenesis experiments

Additionally,

Here we report that 45% of these sequences functioned reproducibly as tissue-specific enhancers of gene expression at embryonic day 11.5. While directing expression in a broad range of anatomical structures in the embryo, the majority of the 75 enhancers directed expression to various regions of the developing nervous system.

These regions tend to be highly clustered in around 200 areas, and most of them are non-coding. ncRNA is often regulatory, and those UCE clusters are associated closely with developmental genes. That being said, not all of them are clustered near known genic regions, which might be a good indicator that there are heretofore unknown genes in those areas; UCEs might be useful for discovery. And here's a paper trying to give a role to one in cancer.

Answer 2

It's with noting that just because something is evolutionary diverged sequentially through specialization does not mean that that function has not been to the same degree conserved. For instance non coding RNA are not characterized by sequential homology alone but through structural conservation. To a greater degree even this structure function relationship exists in other parts of the genome with retro elements and beyond the genome with proteins especially antibodies.

Answer 3

Conservation might indicate selective pressure as a general rule, but this isn't a given; you can delete some ultraconserved elements and still get viable mice...

http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0050234