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Are microRNAs the Backbone of Vertebrate Complexity?

NAME: Kevin Peterson
POSITION: Associate professor, biological sciences, Dartmouth University
Postdoc, California Institute of Technology — 1996-2000
PhD, geology, University of California, Los Angeles — 1996
BA, biology, Carroll College — 1989

This month, Kevin Peterson and colleagues from Dartmouth University and the University of Bristol published data in the Proceedings of the National Academy of Sciences suggesting that an expansion in non-coding RNAs including microRNAs was a key driver of vertebrate complexity.
Specifically, the investigators reported that 41 miRNA families evolved at the base of the subphylum Vertebrata, but rule out the possibility that these miRNAs resulted from the genome duplication events that occurred early in vertebrate history.
This week, RNAi News spoke with Peterson about the findings.
When we spoke last, it was about your paper regarding how microRNAs may have been involved in the origin of organ and body part evolution (see RNAi News, 7/20/2006). This newest paper is about the role of microRNAs in vertebrate development and complexity.
Correct. Working from the first paper, we had this idea that if complexification — and that’s what we’re talking about with the origin of new cell types, new organs, new tissues — is related to microRNAs, then when you have dramatic changes to morphological complexity … we [should] find a correlation with the number of microRNAs.
The most obvious place to look at that was the base of the vertebrates, [which is before the divergence between the living jawless and jawed fishes but after the divergence of vertebrates from invertebrate chordates]. What we knew at the time was that there are quite a few microRNA families established between Ciona [intestinalis] and the boney fish — in other words, the last common ancestor of zebrafish and mouse — but we didn’t know whether those microRNAs would also be found in shark and the jawless fishes [such as lamprey]. If we were right, they should all turn up in the jawless fishes. If [the miRNA families] showed up much later in vertebrate history, then you couldn’t necessarily tie that to the changes in morphology.
Since no one had looked in sharks or jawless fishes, we started there. We found that virtually all of [the miRNA families] are in shark and lamprey, so we couldn’t reject our hypothesis. Given that many of these microRNA families are expressed in vertebrate-specific tissues … it actually might be causative and not just a simple correlation [between miRNAs and morphological complexity].
We’re going to be pursuing that now by asking where these [miRNAs] are expressed in lampreys.
What were the experiments you conducted to get these findings?
Just a combination of Northern analyses and genomic screens. We basically took all of the basal vertebrate [miRNAs], some ones that evolved later, and all the ones that we thought may have evolved earlier, and searched the genomes, then ran Northerns on everything.
In a few cases, for example, we detected transcripts of microRNAs we couldn’t find in the genomes because none of these genomes are complete. The reverse is also true: In the genomes, we can find microRNAs that we couldn’t detect by Northern because not all of them are expressed at high enough levels.
We found a couple of olfactores [miRNAs], a couple chordate ones, a couple of boney fish ones, and then this huge number of vertebrate-specific ones.
Do you have any hypotheses about what triggered this rapid growth in the number of microRNAs?
Not a clue. The one hypothesis we could reject … was genome duplication events. We thought these would be an obvious way [the miRNA population could increase] because not only would you increase the amount of transcribed DNA that would presumably be under neutral selection, at least initially, but you would also dramatically increase the number of available targets because you would quadruple the number of 3’ UTR sequences.
What is a genome duplication event?
Just as it sounds: you go from two N to four N. Vertebrates did it twice, going from two N to eight N. They literally duplicated their genome and they did it twice. Some time between our split from Ciona and the split between shark and boney fish, there were unequivocally two [genome duplication events].
What our data show is that it looks like most of these microRNA families were there before the genome duplication events. So if it’s not genome duplication events [that led to the increase in miRNAs], what is it? We don’t have any idea.
We do know that you have a lot of microRNAs at the base of the tripoblasts, which is what we talked about in our [Journal of Experimental Zoology] paper, and there is no genome duplication event there. [Additionally], the fish have duplicated their genome again compared to, say, mammals, and there is not a concombinant increase in the number of microRNAs.
So what establishes microRNA innovation can easily be disassociated from genome duplication events, but that just leaves us [without] a clue.
I couldn’t begin to imagine how you’d try to track down an answer for this. Is there some avenue you’d be able to go down to fine one?
Maybe people far smarter than me will be able to answer it. [Laughs] I’m hoping that the [David] Bartels and the [Victor] Ambrosesof the world will decide to attack this and they’ll figure it out.
Vertebrates … transcribe a lot more of [their genome] than most invertebrates. [The vertebrate genome] is globally methylated, whereas most invertebrate [genomes] are mosaically methylated. We’ve been trying to figure out if there is a link between methylation and microRNA innovation.

We haven’t come up with anything yet. Given that we don’t even understand the population genetics behind the origin of a single new microRNA, how in the world are we going to understand how vertebrates evolved 40 new microRNA families in such a short geological window?

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