Saturday, February 12, 2011

A New Way of Regulating Human Genes?


ScienceDaily is all over this revolutionary discovery [Primates' Unique Gene Regulation Mechanism: Little-Understood DNA Elements Serve Important Purpose].
Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. Though the human genome -- all the genes that an individual possesses -- was sequenced 10 years ago, greater understanding of how genes function and are regulated is needed to make advances in medicine, including changing the way we diagnose, treat and prevent a wide range of diseases.

"It's extremely valuable that we've sequenced a large bulk of the human genome, but sequence without function doesn't get us very far, which is why our finding is so important," said Lynne E. Maquat, Ph.D., lead author of the new study published February 9 in the journal Nature.
The actual paper is ...
Gong, C. and Maquat, L.E. (2011) lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470:284–288. [doi:10.1038/nature09701]
It's just one more example of how a transcribed Alu sequence can screw up gene expression. There's an outside chance that this is significant and has been selected as a regulatory mechanism but the most probable explanation is that it's just an accident. In any case, there's no reason to generalize from this single example.

This statement is unworthy of a scientist.
"Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we've shown that they actually have important roles in regulating protein production," said Maquat, the J. Lowell Orbison Chair, professor of Biochemistry and Biophysics and director of the Center for RNA Biology at the University of Rochester Medical Center.
The correct statement is that we've known for decades that the vast majority of Alu elements in the genome do absolutely nothing. However, there are a dozen examples already in the scientific literature of Alu sequences that affect transcription, RNA processing, mRNA, or translation. They've all proven to be unique, rare, cases. We strongly suspect that most long noncoding RNAs are junk but there are some excellent examples of ones that are functional.

Lynne Maquat has shown an effect of a transcribed Alu sequence but it's simply not true that every obscure phenomenon reveals an important role in regulating protein production. And it's simply not true that this example has any implications for the vast majority of Alu sequences in the genome. Save the hype for your grant application.


[Hat Tip: Ryan Gregory at Genomicron: Grumble grumble… media… evolution… junk DNA… grumble.]

20 comments :

  1. What's the betting that your fellow Torontonian Denyse O'Leary will seize on this as another nail in the coffin "Darwinism"?

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  2. The Captcha that I had to type in for the previous message was "ididotra": can this be the hand of god guiding your server as an answer to your frequent question, why do we call them Idiots? (If so, it would suggest that god isn't very good at spelling, or maybe he makes a lot of typos.)

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  3. You're such a killjoy, Larry!

    Put it this way: The oceans of the world are useful to mankind - but no every drop of it is essential. It is a reservoir waiting to be tapped even if it has no immediate benefit.

    Alu elements donate exonic sequences, promoters and other functional elements. of importance to transcription and translation.

    I just want to ask you this:

    Do you think that repetitive sequences in non-coding DNA have been accidentally formed by successive bouts of random slippage replication and serve no biological purpose?

    If so, why have they been preserved by natural selection?

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  4. Reza asks,

    Do you think that repetitive sequences in non-coding DNA have been accidentally formed by successive bouts of random slippage replication and serve no biological purpose?

    No, many repetitive elements have a function (centromeres and telomeres for example). The number of repeats doesn't seem to be all that important so there's a certain amount of sloppiness in the size of repetitive regions. This is due mostly to slippage, as you point out.

    These particular repetitive elements account for only a few percent of the genome (e.g., Centromere DNA).

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  5. "If so, why have they been preserved by natural selection?"

    Why would they need to have been so?

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  6. The point is that we have to expect that the following is the case:

    1) An awful lot of slippage replication has happened over time.

    2) The metabolic and others costs associated with reproducing any useless non-coding DNA has not been removed by natural selection.

    3) Genomes are on course to expand ad infinitum if Larry Moran is right.

    If we accept that repetitive non-coding elements do have *essential* functions (as with centromeres) then why do we choose to ignore the potentially important ,but also subtle way, in which other elements influence gene expression and regulation?

    Let us not also forget that there is much redundancy in the genome - a natural form of biological robustness.

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  7. Is it just me or has there been a shocking amount of paradigm shift - style claims in the popular and even sometimes scientific literature lately? New hypotheses are exciting when they're well supported, but all of these 'non-coding RNAs explain everything from evolution to disease' essay style review-synthesis papers seem a bit premature. Maybe I'm only perceiving this because I'm at an institute where cutting edge is all the rage :-p

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  8. @Carlo: Popular simply follows scientific literature. Hype is definitely increasing in the latter. It's a sign of times. With competition for funding getting tougher, scientists are trying to get competitive edge by any means necessary and hype is only a small part of the game.

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  9. Carlo asks,

    Is it just me or has there been a shocking amount of paradigm shift - style claims in the popular and even sometimes scientific literature lately?

    No, it's not just you. Something is definitely wrong with science these days.

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  10. Reza says,

    If we accept that repetitive non-coding elements do have *essential* functions (as with centromeres) then why do we choose to ignore the potentially important ,but also subtle way, in which other elements influence gene expression and regulation?

    I'm not ignoring it, I'm just putting it into perspective. The amount of DNA involved in those "subtle" influences is minuscule compared to the total amount of junk.

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  11. Isn't retrotransposition rather than polymerase slippage responsible for LINE expansion? To my best knowledge polymerase slippage only causes expansion of short repetitive sequences like tri-nucleotide repeats.

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  12. The problem for Larry is that he needs to explain why repetitive "junk" ncDNA has not degenerated but has been preserved by selection.

    Why do we not see big gaps (deletions)in these regions appearing both within members of the same species and between species?

    So far Larry seems to be arguing if you mess with junk there can be problems of association...you can't just surgically remove it without complications arising.

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  13. Do you think that repetitive sequences in non-coding DNA have been accidentally formed

    I was wondering how long it would take for the superstitious crew to use this as yet another means to try to shoehorn Jayzis and his little jewelers screwdrivers into the heart of the cell. One, two... three comments in. Thank you, Reza, for that magnificent Pavlovian display. Somebody get a mop.

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  14. The problem for Larry is that he needs to explain why repetitive "junk" ncDNA has not degenerated

    You first need to explain on what basis you suppose this to be the case in every circumstance.

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  15. "The metabolic and others costs associated with reproducing any useless non-coding DNA has not been removed by natural selection. "

    What are those costs, and how would selection 'know' to get rid of it?

    How did you calculate those costs?

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  16. Reza says,

    The problem for Larry is that he needs to explain why repetitive "junk" ncDNA has not degenerated but has been preserved by selection.

    There are several different ways I can interpret "repetitive DNA." I assumed you were talking about highly repetitive simple repeat sequences. Those have not been preserved by selection as you imagine. They don't change because it's almost impossible to mutate every single repeat—especially when the number of repeats expands and contracts almost every generation. Molecular drive tends to eliminate any rare mutations that do occur.

    If you're talking about the vast majority of junk DNA then that's a different story. LINES and SINES, for example, are highly degenerate. They acquire mutations at the expected rate for non-functional DNA. In fact, their non-conservation is one of the powerful arguments in favor of junk.

    Why do we not see big gaps (deletions)in these regions appearing both within members of the same species and between species?

    We do see deletions between individuals within a species and between species. DNA Fingerprinting is based on variation in the number of repeats between individuals.

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  17. Reza:

    The problem for Larry is that he needs to explain why repetitive "junk" ncDNA has not degenerated but has been preserved by selection.

    What do you propose as a process for doing this, Reza? The mechanisms that replicate DNA don't "read" them for content. They just copy what's there, regardless of what it does or doesn't do.

    If you want to propose an overall intelligence guiding this process -- which is what would be required for what you're asking and which is, of course, what you ultimately do purport to exist -- namely, your god -- then we're justified in asking YOU this question, actually. Why such sloppy coding by this supposedly perfect master keyboard-pounder you insist upon? And why so many almost, but not quite, identical sequences between animals that are supposed to be "separate creations" and not biologically related to one another at all? Barring being infinitely original, he couldn't even proof his own work from beast to beast to self-plagiarizing beast, up to and including his beloved humans?

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  18. "Something is definitely wrong with science these days."

    While this may be true, I was pleased to see a link to science.gc.ca on the bottom of Members of Parliament websites.

    While navigating the site, and in a belated celebration of Darwin Day, I typed Darwin into a search engine and discovered that NCR rare book room's
    "most famous volume is a first edition of On the Origin of Species by Means of Natural Selection, or, The Preservation of Favoured Races in the Struggle for Life, written by Charles Darwin in 1859."

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  19. [Below are some crucial excerpts from the paper by US President's Science Advisor Eric Lander's Nature for the Second Decade, http://www.nature.com/nature/journal/v470/n7333/pdf/nature09792.pdf ]
    ----

    Initial impact of the sequencing of the human genome
    Eric S. Lander

    The view from 2000

    Our knowledge of the contents of the human genome in 2000 was surprisingly limited. The estimated count of protein-coding genes fluctuated wildly. Protein-coding information was thought to far outweigh regulatory information, with the latter consisting largely of a few promoters and enhancers per gene. The role of non-coding RNAs was largely confined to a few classical cellular processes. And, the transposable elements were largely regarded as genomic parasites.

    A decade later, we know that all of these statements are false. The genome is far more complex than imagined, but ultimately more comprehensible because the new insights help us to imagine how the genome
    could evolve and function.

    The road ahead

    The ultimate goal is to understand all of the functional elements encoded in the human genome. Over the next decade, there are two key challenges.

    The first will be to create comprehensive catalogues across a wide range of cell types and conditions of (1) all protein-coding and non-coding transcripts; (2) all long-range genomic interactions; (3) all epigenomic modifications; and (4) all interactions among proteins, RNA and DNA. Some efforts, such as the ENCODE and Epigenomics Roadmap projects, are already underway.

    Among other things, these catalogues should help researchers to infer the biological functions of elements; for example, by correlating the chromatin states of enhancers with the transcriptional activity of nearby genes across cell types and conditions. These goals should be feasible with massively parallel sequencing and assay miniaturization, although they will require powerful ways to purify specific cell types in vivo, and the fourth goal will require a concerted effort to generate specific affinity reagents that recognize the thousands of proteins that interact with nucleic acids.

    The second and harder challenge is to learn the underlying grammar of regulatory interactions; that is, how genomic elements such as promoters and enhancers act as ‘processors’ that integrate diverse signals. Large-scale observational data will not be enough. We will need to engage in large-scale design, using synthetic biology to create, test and iteratively refine regulatory elements. Only when we can write regulatory elements de novo will we truly understand how they work.
    ---
    Addition by AJP: it will not be grammar, but as Dr. Lander, a mathematician who already co-published a paper Oct. 2009 on the fractal mathematics of genome structure, will agree with all others that only software enabling mathematical algorithms of e.g. The Principle of Recursive Genome Function", in terms of Fractal Recursive Iterations could help deploy High Performance Computers to untangle the intrinsic mathematics of genome/epigenome (hologenome) function.

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