Friday, September 07, 2007

Adaptive Evolution of Conserved Noncoding Elements in Mammals

 
"Adaptive Evolution of Conserved Noncoding Elements in Mammals" is the title of a paper that's just been published in PLoS Genetics [Kim and Pritchard (2007)].

With a title like that you'd think the paper would be really interesting because conserved noncoding elements are a hot topic. Recall that these are short sequences in the genomes of diverse mammals that are highly similar. They were thought to be examples of regulatory sequences but deleting them from the mouse genome seems to have no effect [The Role of Ultraconserved Non-Coding Elements in Mammalian Genomes]. It's a little puzzling to see "adaptive evolution" in the title since the very fact that these short sequences are conserved implies adaptation.

I took a look at the paper. Here's the abstract.
Conserved noncoding elements (CNCs) are an abundant feature of vertebrate genomes. Some CNCs have been shown to act as cis-regulatory modules, but the function of most CNCs remains unclear. To study the evolution of CNCs, we have developed a statistical method called the “shared rates test” to identify CNCs that show significant variation in substitution rates across branches of a phylogenetic tree. We report an application of this method to alignments of 98,910 CNCs from the human, chimpanzee, dog, mouse, and rat genomes. We find that ∼68% of CNCs evolve according to a null model where, for each CNC, a single parameter models the level of constraint acting throughout the phylogeny linking these five species. The remaining ∼32% of CNCs show departures from the basic model including speed-ups and slow-downs on particular branches and occasionally multiple rate changes on different branches. We find that a subset of the significant CNCs have evolved significantly faster than the local neutral rate on a particular branch, providing strong evidence for adaptive evolution in these CNCs. The distribution of these signals on the phylogeny suggests that adaptive evolution of CNCs occurs in occasional short bursts of evolution. Our analyses suggest a large set of promising targets for future functional studies of adaptation.
Okay. It's confusing but what they seem to be saying is that the sequences of these conserved noncoding elements change in various lineages. A lot of them seem to be evolving at a "neutral rate"—which raises the question of why they are "conserved" in the first place. Does it mean that the ancestor to all mammals had a functional sequence but that function has been lost? Some of these conserved elements evolve at a very rapid rate in some lineages and this is taken to be evidence of adaptive evolution in that lineage.

I read the entire paper. It's pretty much Greek to me. If anyone else can figure it out please feel free to post an explanation in the comments.

4 comments :

  1. If anyone else can figure it out please feel free to post an explanation in the comments.

    conserved regions are defined differently than "ultra-conserved" regions, with more leeway for change.

    the paper takes these elements and fits an overall evolutionary rate to each (this is not a "neutral" rate, that comes later). what they are then able to do is test whether that substitution rate increases along certain lineages (ie. if there is acceleration of molecular evolution along the branch leading to mouse, for example, compared to the other branches).

    that analysis, of course, doesn't distinguish between adaptive evolution and relaxation of selective constraint. what they then do is estimate a "neutral" rate in each region (by aligning non-conserved sequences on either side of the conserved sequences and calculating the substitution rate), and compare the accelerated rate from a specific branch (which they aren't sure is do to positive selection or relaxation of constraint) and compare it to that "neutral" rate, which should take into account regional variation in mutation.

    what they find is that many of the accelerations indeed outpace the neutral rate, thus the conclusion (adaptive evolution of conserved noncoding elements)

    it's a nice paper, similar to some things that have been done before, but with perhaps more statistical rigor, and considering all branches, not just the human.

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  2. Larry, In molecular popgen theory, selective constraint is not synonymous with adaptive evolution. Sequences that have less changes than expected are referred to as constrained or conserved (determining the neutral expectation for the number of substitutions is a whole other ball of yarn). Adaptive evolution implies the action of positive (or Darwinian) natural selection fixing an excess number of changes (once again, relative to the neutral rate). Simply, adaptive evolution is inferred when the sequence is evolving too fast.

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  3. rpm says,

    Larry, In molecular popgen theory, selective constraint is not synonymous with adaptive evolution.

    What I meant was that when you see similar sequences in diverse species you usually conclude that they are conserved from a common ancestor by negative selection. In that common ancestor it's reasonable to conclude that the sequence served some adaptive function.

    In other words, it got to be a "conserved" sequence in the first place because it was selected.

    If the sequences are changing rapidly in a given lineage then they must have lost whatever constraints existed before. They may just be degenerating by accumulating random substitutions or they might be changing under selection for a new function. They can't have changed very much in 100 million years or they wouldn't still be recognized as "conserved" sequences today.

    I understand that you can infer adaptation to a new function by noting "excessive" changes to the old conserved sequence in a particular lineage. It's just not clear to me how reliable those estimate are.

    Remember these are short sequences. If they're 100 bp in length then they have to about 50% identical in order to reliably conclude that they have been conserved. If they're 200 bp in length then you need about 35% identity.

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  4. I understand that you can infer adaptation to a new function by noting "excessive" changes to the old conserved sequence in a particular lineage. It's just not clear to me how reliable those estimate are.

    that's a fair point. I don't think anyone has a good idea of the reliability of rate parameters for inferring selection coefficients, etc.

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