Tag: ENCODE

This is how ENCODE members speak to other scientists, and how they should have spoken to the public

I know I’m beating a dead horse, but here’s a paragraph every single reporter writing on ENCODE should have read, and every single scientist from the consortium speaking to the media should have referred to:

A User’s Guide to the Encyclopedia of DNA Elements (ENCODE) PLoS Biol. 2011 April; 9(4): e1001046.

The major goal of ENCODE is to provide the scientific community with high-quality, comprehensive annotations of candidate functional elements in the human genome. For the purposes of this article, the term “functional element” is used to denote a discrete region of the genome that encodes a defined product (e.g., protein) or a reproducible biochemical signature, such as transcription or a specific chromatin structure. It is now widely appreciated that such signatures, either alone or in combinations, mark genomic sequences with important functions, including exons, sites of RNA processing, and transcriptional regulatory elements such as promoters, enhancers, silencers, and insulators. However, it is also important to recognize that while certain biochemical signatures may be associated with specific functions, our present state of knowledge may not yet permit definitive declaration of the ultimate biological role(s), function(s), or mechanism(s) of action of any given genomic element.

This is the kind of language you hear at conferences – language that I’d say is not controversial at all. By this criterion, ENCODE has been a great success. And this paragraph makes it clear that ‘junk DNA is debunked’ cannot possibly, under any scenario, be the immediate conclusion of the experiments conducted by ENCODE.

The non-functional concept of genome function

This month there has been a bit of a dust-up over the question of how much of our genome is functional. ENCODE results say 80% – or do they? Is it 20%? Or more like 8%?

Did ENCODE scientists play fast and loose with the definition of function, or is genome function legitimately defined as those activities the consortium measured? Is functional DNA something that has an effect on phenotype? (Does that include damaging gain-of-function mutations?) Is functional DNA only that DNA present in your genome because of natural selection? (Then what about hitchhiker alleles?) Is a novel mutation existing in only a single individual functional if that mutation is ultimately destined to become fixed in the population by natural selection?

We have to face the fact that, like much else in biology, boundaries between categories are fluid. It makes no sense to try to cleanly divide the genome into functional and non-functional elements. Even what seems like an obvious boundary line, the boundary between protein-coding and non-coding DNA is blurry: many coding regions have cis-regulatory sites with a non-coding, functional role. To divide the genome into categories of coding- and non-coding function, or function and non-function, may satisfy our insatiable desire to classify for our own cognitive comfort, but from the perspective of the cell there is no such distinction. Continue reading “The non-functional concept of genome function”

Your genome is an ecosystem

I’m not sure how many of the people writing Science news features, press releases for ENCODE*, or completely uninformed and baseless rants on the idea of junk DNA are familiar with the work discussed in this review, none of which is refuted by the ENCODE results:

“The ecology of the genome — mobile DNA elements and their hosts”, John F. Y. Brookfield, Nature Reviews Genetics 6, 128-136 (February 2005):

One activity of evolutionary biologists involves looking at features of organisms and seeking to explain them in adaptive ways — demonstrating that the feature to be explained will confer on its bearer a higher inclusive FITNESS than an alternative would. However, as applied to phenotypic features, this approach is not always intellectually rigorous — only knowledge of the ways in which genes influence the phenotype can allow the identification of realistic alternatives to observed traits. This approach is more valid when applied to genomic components — an explanation of the presence of a DNA sequence consists of demonstrating that an organism with that sequence is fitter than one that lacks it or one in which the sequence is mutated. The methodology is straightforward — we make mutations and observe the reduction in fitness that is created. All parts of the genome could therefore potentially be seen in this same light — every sequence present is there because its removal or replacement would cause a reduction in the organism’s fitness. In discussing microorganisms, such a view might be tenable. However, the genomes of multicellular eukaryotes possess sequences, which could perhaps form the majority, that are not there for reasons related to their present use.

Why does a simplistic view of an entirely functional genome fail? In essence, it does so because some genomic components, notably interspersed repetitive DNA sequences, are indistinguishable from parasites…

This paper develops the ecosystem analogy of the genome. Later this week, I’ll develop the analogy of your genome as a post-apocalytpic wasteland.

*Sadly, a significant number of ENCODE scientists seem completely unaware of this literature as well.

Genome PR is OK

There was some criticism of this video out there, but I liked it. Given how little attention the average news reader/online browser is going to devote to genomics, I think this kind of thing is just right (except for the misleading throwaway line about junk DNA).

Sure, the video hypes ENCODE as biology’s latest, greatest, development, but nobody outside the scientific community is going to know the difference between ENCODE and all of the rest of us genome biologists anyway. So basically, the video us hyping all of us.

An ode to junk

It is an unfortunate circumstance that ENCODE publicity decided to declare “junk DNA” dead, again. It’s not a totally unique position. Creationists and John Mattick have argued that there is no useless DNA for ages.

The demise of “junk DNA” is a fait accompli of the way “functional” is defined. It is not a definition of “functional” most of us would recognize. Ewan Birney, who should know, explains that when ENCODE says “functional” they mean “not biochemically inert in at least one of our many assays*”. As Mike has noted from his own research experience, many totally random DNA sequences synthesized in a tube are “not biochemically inert” nor are they biologically “functional”.

The fact is, if you only think of “junk DNA” as a problem, you aren’t seeing the forest for the trees – and you certainly are lacking a touch of poetry in your bleak soul. Continue reading “An ode to junk”