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Sunday, July 08, 2007

Stop the Press!!! ... Genes Have Regulatory Sequences!

Ira Flatow interviews John Greally (see photo) on Science Friday. Greally talks about the ENCODE project and junk DNA. You might be surprised to learn that the expression of genes is controlled by ... wait for it ... REGULATORY SEQUENCES! According to Greally the discovery of these regulatory sequences reveals that junk DNA isn't junk at all. Greally says,
It would be a very brave person who would call it junk at this stage.
Count me as a very brave person. I claim that most of the human genome is junk and I'm not alone.

This is just one more example of the hype surrounding the ENCODE project. Read Ryan Gregory's summary at More about ENCODE from Scientific American for a good summary of what the study really says about junk DNA. The study does not say that all junk DNA has a function in spite of what you might gather from the podcast (below). The study does not say that the discovery of regulatory sequences in noncoding DNA is a breakthrough in our understanding of how genes work. In fact, as almost all of you know, the existence of regulatory sequences that control gene expression has been known for four decades. John Greally misses a good opportunity to educate the public about science and instead uses inappropriate framing to hype his own interest in gene expression. Shame.

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John Greely is the author of the News & Views article that described the original ENCODE work published in the June 14th issue of Nature. In that review he mentioned the role of regulatory sequences but focused much of his attention on the fact that large parts of the genome were transcribed. He expressed some appropriate skepticism of the results in the Nature piece but not when being interviewed on the radio. Is this appropriate? Is it what Nisbet and Mooney are talking about when they say that scientists should do a better job of framing?

[Hat Tip: Eye on DNA]


T Ryan Gregory said...

I think he may believe that it is all functional. He certainly declined to state otherwise in the interview, especially when one caller brought this up explicitly. He's a medical researcher, though, so his emphasis on function isn't that surprising, nor is his apparent lack of familiarity with the long string of literature on non-coding DNA that takes a broader perspective.

A. Vargas said...

this is the new scourge of these times: molecular adaptationism...imagine, a just-so story for every nucleotide susbtitution! haha

T Ryan Gregory said...

Technically, it's the "pre-discovery of transposable elements, pseudogenes, introns, replication slippage, and unequal crossing over" scourge of genome adaptationism. We're basically back to about 1975, before non-function became the null hypothesis (but not an inflexible or universal assumption) for good reason based on known mechanisms of non-coding DNA accumulation. And as should be pointed out as often as possible, current evidence one way or another suggests that 5% of the human genome is functional, let alone that of an onion or a salamander.

A. Vargas said...

Good Point, TR
I just can't believe the ease which with the discovery of new regulatory functions in non-coding sequences (neato as it is) becomes for some a reason to assume that all non-coding DNA is functional.
There's just no logic there, asides from the fact it requires to swipe away the rock-solid evidence of neutral molecular evolution.
Just think about the enormous extent of functional redundancy in eucariotes. If I remember well, most protein-encoding genes when knocked down in yeats cells do not have a phenotype. And it's worse in metacellulars. Hello??? We are talking protein level here!!. And then we have all the non-adaptive change at the phenotypic level as well. And so, it's going to turn out that just non-coding DNA is going to be all functional, huh? YEAH, right hahaha

A. Vargas said...

and then we have drastic genome size reduction with no organismal or evolvability consequences, as occurred in the dinosaur bird transition where the genome got cut down half size.

Anonymous said...

how do you know the size of dinosaur DNA?

A. Vargas said...

Nature. 2007 Mar 8;446(7132):180-4.
Origin of avian genome size and structure in non-avian dinosaurs.

Organ CL, Shedlock AM, Meade A, Pagel M, Edwards SV.
Avian genomes are small and streamlined compared with those of other amniotes by virtue of having fewer repetitive elements and less non-coding DNA. This condition has been suggested to represent a key adaptation for flight in birds, by reducing the metabolic costs associated with having large genome and cell sizes. However, the evolution of genome architecture in birds, or any other lineage, is difficult to study because genomic information is often absent for long-extinct relatives. Here we use a novel bayesian comparative method to show that bone-cell size correlates well with genome size in extant vertebrates, and hence use this relationship to estimate the genome sizes of 31 species of extinct dinosaur, including several species of extinct birds. Our results indicate that the small genomes typically associated with avian flight evolved in the saurischian dinosaur lineage between 230 and 250 million years ago, long before this lineage gave rise to the first birds. By comparison, ornithischian dinosaurs are inferred to have had much larger genomes, which were probably typical for ancestral Dinosauria. Using comparative genomic data, we estimate that genome-wide interspersed mobile elements, a class of repetitive DNA, comprised 5-12% of the total genome size in the saurischian dinosaur lineage, but was 7-19% of total genome size in ornithischian dinosaurs, suggesting that repetitive elements became less active in the saurischian lineage. These genomic characteristics should be added to the list of attributes previously considered avian but now thought to have arisen in non-avian dinosaurs, such as feathers, pulmonary innovations, and parental care and nesting.

Anonymous said...

Thanks for the reference, interesting.
How is the exact relationship between size of genome and energy needed? (this might be a naive question from a non biologist)

Or is it just regarding the size of the animal? (I didn't think genome size
scaled with animal size)

Perhaps I should try to find the paper,
i guess they explain it in there.

Anonymous said...

John Greally is just revealing himself to be a fairly typical molecular biologist. Lurking beneath the reasonable surface is, as you put it, molecular adaptationism. If all that stuff is finely-tuned, then we can get lots more grants to study its function. Since the 1960s population geneticists and molecular evolutionists have been impressed by the counter-argument that there would be far too high a mutational load if all the DNA were constrained in its sequence by being functional. Maybe this is wrong -- the reports that much of it may be transcribed are certainly puzzling. But most molecular biologists have never given much thought to the mutational load issue so they happily fantasize about the extent of undiscovered function.

Anonymous said...

Oops, mistyped my web page address there. Corrected.

Larry Moran said...

Joe Felsenstein says,

Maybe this is wrong -- the reports that much of it may be transcribed are certainly puzzling.

I think it's mostly spurious transcription at a level that's far to infrequent to be functional but easily detectable by today's powerful techniques.

But most molecular biologists have never given much thought to the mutational load issue so they happily fantasize about the extent of undiscovered function.

I agree. It also seems as though most molecular biologists don't have a good understanding of evolution.

Joe Pickrell said...

I think it's mostly spurious transcription at a level that's far to infrequent to be functional but easily detectable by today's powerful techniques.

an empirical question :-)

your instinct is probably right, but it's still an open question (though if most transcription ended up being functional, I'd be very surprised). it's clear that sequence conservation isn't a perfect predictor of function, and it doesn't seem transcription is either. But by combining several of these data sources, we should be able to get at that question better.

Anonymous said...

It is hard for me to tell how much of the problematic language is just an attempt to use terminology that will be understandable by the public, but it does illustrate a problem with communicating modern biology to the public. I was struck by the caller who felt the idea of "junk" was absurd. The idea that every part of the genome has a function is precisely what makes ID/creationism so appealing to many people.

I think a major problem is the definition of the word gene. When folks like Greally restrict the term "gene" to protein-coding genes they are clearly setting up a straw man - probably semi-unconsciously. If one defines gene phenotypically - as heritable differences associated with specific phenotypic differences - then regulatory sequences would be genes.

"Junk" is a problematic category. There is obvious junk DNA - dead transposons and the vast majority of pseudogenes. But would we define a sequences that alters the expression of protein coding genes by some amount, but that change is not associated with a fitness difference. Would such a sequence be functional or junk? Modern methods for transcript profiling with could detect a heritable difference. But there would be no phenotypic difference - so would it mean anything? And if not, would that regulatory sequence be junk? I'm not sure how to communicate these ideas to the general public.

A. Vargas said...

Let me be the first to word it: "Junk RNA".

A. Vargas said...

I agree that regulatory sequences are genes, they have an effect on the phenotype and their own locus. Edward's question is interesting: are genes that produce phenotypic traits but no adaptive changes "junk"?
We certainly do not hesistate in characterizing certain kinds of phenotypic variation as neutral: that do not affect lifestyle or fitness. I think it's fair to consider morphological variation to be "junk", that is, non-functional and not obeying to selective pressures.

I like the term "junk" because junk is junk most of the time but some junk can someday become functional. It's just perfectly illustrative, hahaha

T Ryan Gregory said...

"Junk" is a problematic category. There is obvious junk DNA - dead transposons and the vast majority of pseudogenes.

This was, of course, its original definition.

Anonymous said...

tr gregory
This was, of course, its original definition.

Absolutely! The whole problem is the confounding of "junk" and non-coding in the minds of some people.

If the confusion between junk and non-coding only involved ID/creationists it would be one thing - their agenda blinds those folks to reality.