My fellow F&P publican Josh Witten has drawn my attention to a rebuttal (PDF) of Graur et al’s rebuttal of claims made by ENCODE.
The authors, John Mattick and Marcel Dinger of the University of New South Wales, advance various claims to dispute the idea that most of the genome is non-functional, but here I’ll just focus on one:
We also show that polyploidy accounts for the higher than expected genome sizes in some eukaryotes, compounded by variable levels of repetitive sequences of unknown significance.
Uh, yeah. That’s the resolution to the C-value paradox, and it’s one reason why people argue that repetitive sequences, i.e. transposable elements, are, contra claims about ENCODE data, largely non-functional – because their numbers vary greatly between species with a similar biology. As Doolittle writes:
A balance between organism-level selection on nuclear structure and cell size, cell division times and developmental rate, selfish genome-level selection favoring replicative expansion, and (as discussed below) supraorganismal (clade-level) selective processes—as well as drift— must all be taken into account.
Reading into the paper, how is it possible that the following claims by Mattick and Dinger don’t contradict each other? Continue reading
Yesterday I wrote about why negative controls are important in a genome-scale search for functional DNA. Today, I’ll discuss the main focus of our recent work: understanding what makes a piece of DNA functional.
The particular DNA I’m interested in is known by not very functional term ‘cis-regulatory’ DNA – a term that requires six syllables, an italicized Latin prefix, and a hyphen. This is DNA that is crucial in gene decisions: cis-regulatory DNA helps to control when, where, and how much genes are expressed. This happens because cis-regulatory DNA serves as a landing pad for ‘transcription factors’, proteins that land on cis-regulatory DNA and control the expression of nearby (or sometimes not so nearby) genes.
The question that haunts me is this: why don’t transcription factors get lost? My worry follows from these three observations: Continue reading
Last September, there was a wee bit of a media frenzy over the Phase 2 ENCODE publications. The big story was supposed to be that ‘junk DNA is debunked’ – ENCODE had allegedly shown that instead of being filled with genetic garbage, our genomes are stuffed to the rafters with functional DNA. In the backlash against this storyline, many of us pointed out that the problem with this claim is that it conflates biochemical and organismal definitions of function: ENCODE measured biochemical activities across the human genome, but those biochemical activities are not by themselves strong proof that any particular piece of DNA actually does something useful for us.
The claim that ENCODE results disprove junk DNA is wrong because, as I argued back in the fall, something crucial is missing: a null hypothesis. Without a null hypothesis, how do you know whether to be surprised that ENCODE found biochemical activities over most of the genome? What do you really expect non-functional DNA to look like?
In our paper in this week’s PNAS, we take a stab at answering this question with one of the largest sets of randomly generated DNA sequences ever included in an experimental test of function. Continue reading
A new NIH RFA:
PsychENCODE: Identification and Characterization of Non-coding Functional Elements in the Brain, and their Role in the Development of Mental Disorders (R01)
The Encyclopedia of DNA Elements (ENCODE) project, by systematically cataloging transcribed regions, transcription factor binding sites, and chromatin structure, has recently found that a larger fraction of the human genome may be functional than was previously appreciated. However, our understanding of the role of these functional genomic elements in neurodevelopment and mental disorders is at an early stage. This funding opportunity will support studies that identify non-coding functional genomic elements and elucidate their role in the etiology of mental disorders.
Suddenly, the ENOCDE model is now the way to do science. It’s hard to disagree with Dan Graur on what the consequences are: Continue reading
The rebuttal to the ENCODE project’s claim to have vanquished junk DNA by Graur et al. got a lot of attention for its scathing rhetoric. If you already have enough troubles in your life, W Ford Doolittle penned a cogent, but polite rebuttal of the claim in PNAS.
…what would we expect for the number of functional elements (as ENCODE defines them) in genomes much larger than our own genome? If the number were to stay more or less constant, it would seem sensible to consider the rest of the DNA of larger genomes to be junk or, at least, assign it a different sort of role (structural rather than informational)…A larger theoretical framework, embracing informational and structural roles for DNA, neutral as well as adaptive causes of complexity, and selection as a multilevel phenomenon, is needed.
Unfortunately, you need a subscription to read the full length article, which I do not. Therefore, I’m not endorsing all of Doolittle’s arguments, but I do like that he seems to agree with my assertion from “Decoding ENCODE” that evolutionary theory expects junk DNA in species with the population and genomic characteristics of humans.
*Hat tip to Leonid Kruglyak.