Human Genome More Like a Functional Network

bshell writes "An article in science blog says we may have to rethink how genes work. So called "junk DNA" actually appears to be functional. What's more it works in a mysterious way involving multiple overlaps that seems to be connected in some sort of network." From the article: "The ENCODE consortium's major findings include the discovery that the majority of DNA in the human genome is transcribed into functional molecules, called RNA, and that these transcripts extensively overlap one another. This broad pattern of transcription challenges the long-standing view that the human genome consists of a relatively small set of discrete genes, along with a vast amount of so-called junk DNA that is not biologically active. The new data indicates the genome contains very little unused sequences and, in fact, is a complex, interwoven network. In this network, genes are just one of many types of DNA sequences that have a functional impact. "Our perspective of transcription and genes may have to evolve," the researchers state in their Nature paper, noting the network model of the genome "poses some interesting mechanistic questions" that have yet to be answered."

Of course its not junk

Its what we in the programming field would call the Data Segment.

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I doubt it. Analogies always fall down.

Re:Of course its not junk

If an analogy were something standing up, it could fall down. But if it's a car then the analogy would drive away.

Re:Of course its not junk

Its like lego. At a glance it looks like you've made a castle. But if you study it too closely you realize you've just put a whole bunch of blocks on top of each other.

Re:Of course its not junk

It's like masonry. At a glance it looks like you've put a bunch of rocks on top of each other. But if you study it closely you realize you've just made a castle.

Re:Of course its not junk

It's like the Internet. At a glance it looks like you've made an insightful comment. But if you study it too closely you realize you've just made another redundant posting.

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It's like a potato, because I like potatoes, and lobsters crawl the depths of the sea.

Re:Of course its not junk

A metacar?

Or would that be a car that would only allow other cars to ride in it?

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Well, I never metacar I didn't like.

Re:Of course its not junk

The genome is fractal - governing fractal growth of organelles, organs and organisms. Even from a single fractal template (e.g. the algorithm of z=z^2+C) an enormously "complex" pattern, full of self-similar repetitions will develop. The "gene"-parts of the genome determine "fractal templates" of proteins, while the "PostGene"-sequences supply the auxiliary information necessary for iterative hierarchical development (architecture of complex protein structures). This concept/utility (FractoGene) triggered 300+ entries in slashdot in 2002 when an algorithmic approach first challenged the "gene/junk" dogma. The saga (including slashdot reference) is recorded at http://www.junkdna.com/ [junkdna.com] (as well as on http://www.fractogene.com/ [fractogene.com] ) Of course it is not junk... "junkDNA" is not a scientific term any more - but an important nickname for "the biggest mistake in the history of molecular biology". pellionisz_at_junkdna.com

Re:Of course its not junk

In laymans terms, the "Junk DNA" provides the bootstrap routine and program code of an life form building nano-machine. The "Gene DNA" provides the instructions to the life-form-building-machine on how to make this life form a "human" or "fly" or "bacteria".

Papers such as A minimal gene set for cellular life derived by comparison of complete bacterial genomes [pnas.org] provide some first steps into understanding how all this DNA works together.

And to the grandparent post - I would argue that the "junk DNA" is not the data segment. For decades we've been thinking of the "Gene DNA" as the program when it is in fact the input data, while the "Junk DNA" is the boot loader, operating system and interpreter. But the machine doesn't build stuff and then move on (like a human-built factory) - it replicates itself, subtly altering the replicants to become more specialised along a growth path that will make one new machine produce stuff that will eventually become a femur, while the other new machine starts building stuff that will eventually become a gluteus maximus.

I've heard of a project where a company set out to create a synthetic bacteria based on the minimal possible DNA, which they could then patent, and use as a base for testing genome manipulation or gene therapy or some such nonsense. Not sure if that's fact or fiction though.

Re:Of course its not junk

Not quite. Your analogy appears somewhat broken.

Here's the question - is non-gene DNA /machinery/ or /DATA/?

If it's the latter, junk DNA would be conceptually closer to filesystem metadata (and maybe even "free diskspace" in as far as introns etc. go) than the OS.
I fail to see how it bootstraps anything. A DNA molecule does not to my best knowledge start proliferating on its own when put on agar. Cellular facilities are required. True, you build said cell facilities from data stored in genes, but still I can't find any underlying principle shared by the bootloader, OS or whatever interpreter on my computer and my non-gene-coding DNA.

FWIW, I'm a coder, a unix sysadmin and a (somewhat late-aged) biochem undergrad student, so feel free to dive as deep as you like into a technical comparison. I've been playing with comparison models of my own for a while (all of which have the annoying habit of breaking at one point or another) and am intrigued to hear more ideas on this.

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Here's the question - is non-gene DNA /machinery/ or /DATA/?

How about this:
The non-gene DNA is software - i.e. the CODE segment.
The gene DNA is data - the DATA segment - and defines how to build specific molecules.
The cell and its internals are the har

Re:Of course its not junk

Nonono... any LISP programmer could have told you this... the code IS the data. And viceversa, ofcourse.

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Actually, that is pretty relevant to brain operation where neural networks both store data and compute.

But on to my original reason for posting. If some kind of networks are involved in DNA operation, three ideas come to mind: 1) genetic spam 2) denial

Re:Of course its not junk

Its what we in the programming field would call the Data Segment.

Overlapping, independent sequences? It's quite obviously spaghetti code.

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So, does that mean I can submit my genome to Worse Than Failure?

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fucking hell, you mean God wrote our DNA in Perl?!

We've known this for a while [xkcd.com].

Messy Speghetti Help

They need to hire some Perl and 60's-style-COBOL programmers who know how to read tangled code ;-)

Re:Messy Speghetti Help

They need to hire some Perl and 60's-style-COBOL programmers who know how to read tangled code ;-)

My experience with Perl developers is that writing tangled code isn't a problem for them. It's reading, even their own, tangled code that they find difficult. I sat down with a Perl guru where I worked some years ago trying to debug a particularly nasty piece of Perl code. The whole time he kept going on about "Who writes code like this!?!" until we looked it up in the CVS repository and it turned out it was he himself who wrote that particular block a few years earlier. Syntactic flexibility is nice but it has a downside.

Obligatory..

Imagine a Beowulf cluster of...wait a minute.

My hairbrained idea...

It's somewhat funny - I remember having this exact discussion with my genetics professor. I was a chem major who is now a developer.

It seems to me that DNA/RNA is "machine code" and data which runs on the laws of nature. It's a layer removed from silicon design, more akin to a self-modifying FPGA.

In other words we're so far only looked at the boot code and associated data. The "program" is what we were calling junk.

And it makes sense - if you think of the program as a massive recursion network which builds common parts (stem cells) and then organizes and specializes.

I know that's a simple bastardization ... but perhaps I've just looked at too much dissassembler. I will feel a little vinticated if this is proven.

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Human constructs are often used as metaphors for biological systems. There is nothing wrong with this. Comparing natural systems to our own creations is simply one of our primary methods of understanding those natural systems. I, however feel, that the

I never read the instructions

After assembling something, if there are any parts left over I simply declare them to be extra junk. With scientists declaring the same thing about DNA they can't identify, I guess the old saw is true, great minds do think alike.

interesting

From the article:

The collaborative study focused on 44 targets, which together cover about 1 percent of the human genome sequence. or about 30 million DNA base pairs. The targets were strategically selected to provide a representative cross section of the entire human genome.

The ENCODE consortium's major findings include the discovery that the majority of DNA in the human genome is transcribed into functional molecules, called RNA, and that these transcripts extensively overlap one another.

actually if I remember correctly, there are 30,000 known genes which produce about 100,000 proteins [a little more than 3 per gene] which span a much larger amount of DNA that actually codes for proteins. genes have been known to code for multiple proteins since the Human genome project was completed. It has also been known that certain non-coding regions of DNA are not useless but in fact code for things like ribozymes etc. The article also talks about non-coding regions acting as a source for new structures. that is to say that the non-coding regions mutate and are selected for or against over time to form new proteins/enzymes etc.

The Selfish Genomicist

My patent for "a functional network of multiply overlapping genetic transcripts distributed in 'junk' DNA" is on its way to the PTO.

Hmm...

So called "junk DNA" actually appears to be functional.

Well that just proves it once and for all - it's not junk, hence it was designed properly.
Therefore, God exists! /runs /trips over cat

FUCK! /kicks cat, keeps running

Re:Hmm...

No one thinks that flight just popped into existence. There are all sorts of useful traits prior to actual full flight that the earliest flyers would have developed: heck, things like feathers pretty clearly evolved long before flight was even remotely possible, and likely for very different reasons than flight. As for the thing itself, there are lots of different adaptions and traits on the way to flight that are all useful: things like decreased weight for sprinting across the ground, and of course brief gliding from tree to tree without actually being able to fly.

Its just code that's there for debugging purposes

These scientists have probably been looking at cells running in the debugger...

sneaky

Our perspective of transcription and genes may have to evolve

well played ... well ... played.

Junk DNA

I walk down the street and see 100s of people who appear to be predominantly junk DNA.

This is hardly 'news'..

Why it was called junk before you'd ask? Because our definition of what is useful wasnt all that accurate.. just looking at so called open reading frames and declaring everything else to be junk does not work. There is also the problem with insertions in a gene sequence that are either not or alternatively used. There are plenty of sequences that are never translated (no proteins are made of it) BUT without them we would be missing a big chunk of regulators etc. 'Recent' findings like ribozymes, IRES elemtens, attenuation elements etc. are all not translated into a protein yet serve a very specific function. Some of this 'junk' also serves as a insulator / separator between various sequences. We may never be able to map every nucleotide to some function but declaring it junk from the get go was just looking to be proven wrong. Just look up NCBI and look for some good reviews on this topic ;)

The whole "junk" DNA thing always bothered me

I'm sure it wasn't a responsible scientist who popularized the term, it was probably a science writer. But it's just a variation on the pointy-haired boss credo "Anything I don't understand is therefore easy" morphed into "Anything I don't understand is therefore unimportant or unnecessary." It's like that other popular fact, "we only use 10% of our brains!" No, we only know what 10% of it is doing.

I guess this bugs me so much because I see the problems caused by an ignorance of the facts every day. "Hey, quit standing around! Let's git'r'done!" Yeah, charge into a situation like a bull in a china shop. Hey, asshole! There's a reason why we didn't want you to go through that wall, the cat-5 was back there! Wow, a new hire that I just found out about this morning? Why yes, we have no computer for him, we told you there's a reason why we have to be informed of hires once a position is announced.

this is familiar to anyone who's studied GA

Machine simulation of genetic/evolutionary algorithms often produces so-called "junk" which when analysed further, this frequently proves to be tied to the function of the overall organism in mysterious ways. I'm sure that leading GA researcher John Koza made this observation in early papers, but it's something that anyone playing with genetic algorithms will encounter sooner or later.

I couldn't find the quote I was looking for, but only this broad statement from Genetic Programming: Biologically Inspired Computation that Creatively Solves Non-Trivial Problems, Koza (1998):

The design of complex entities by the evolutionary process in nature is another important type of problemsolving that is not governed by logic. In nature, solutions to design problems are discovered by the probabilistic process of evolution and natural selection. There is nothing logical about this process. Indeed, inconsistent and contradictory alternatives abound. In fact, such genetic diversity is necessary for the evolutionary process to succeed. Significantly, the solutions evolved by evolution and natural selection almost always differ from those created by conventional methods of artificial intelligence and machine learning in one very important respect. Evolved solutions are not brittle; they are usually able to grapple with the perpetual novelty of real environments.

Re:error correction

I don't think evolution would be very kind to unneeded material.

There's really almost no selection pressure against extra DNA sequences, particularly ones with no associated promoter. One of the proofs of this is the fact that the human genome is comprised more of endogenous retroviruses than actual functional sequences.

Re:error correction

Genome space is damn cheap, just like disk space. The added tax on each cell to carry bloat is minimal. No matter how much is transcripted, we can analyze the sequences that we do see in the "junk". They are often very repetitive, with some sequences clearly deriving from viruses that integrate into the genome. The added selectional advantage of having the same (possibly now suppressed, but originally pathological) sequence, over and over, should be quite small, and the pattern and frequency of changes seems to indicate that most of these regions do not undergo any directed selection, i.e. mutations that do appear are kept at random, indicating "no value".

We have this huge disk, and most of it is malware or free space. The results in RTFA are interesting, but the general idea that we can measure the frequency of changes and statistically determine whether evolution is working on a specific sequence, should still be sound, so if they are indeed used, it is probably in a far less sequence-sensitive context (sometimes overall folds, sometimes just stochastic effects from the whole pool of junk transcripts affecting the balance in the nucleus).

Re:error correction

crashfrog, you may have to correct me, but here's a start...

There's really almost no selection pressure [wikipedia.org] against extra DNA sequences,
This refers to the process in evolution where an organism fails to reproduce due to having a disadvantage that the other critters in the species don't have. So if a pig that has useless DNA sequences tacked on in its genome has a statistically lower chance of having piglets, there's pressure against those useless DNA sequences.

crashfrog is saying that for a reason he explains (below) extra DNA isn't going to have any effect on the organism's chances of reproducing.

particularly ones with no associated promoter [wikipedia.org].
A promoter is a marker in the DNA strand. The protein "machine" (a transcription factor [wikipedia.org]) that gets the "data" off the DNA and into the cell's outside chemistry has a "socket" that matches the "plug" formed by the specific pairs of the "promoter" marker. It's like the transcription factor searches for #! /bin/perl and that's how it knows to start copying off DNA code. (While on the subject, just because it has #! /bin/perl doesn't mean it will get executed, and even after it's been executed it might get a SIGKILL [wikipedia.org].) Promoters are not just found in DNA, but read on wikipedia for more on that.

One of the proofs of this is the fact that the human genome is comprised more of endogenous retroviruses [wikipedia.org] than actual functional sequences.
I'm not sure if I can do this last sentence piece by piece, so here goes...

An endogeneous retrovirus is a kind of virus that infects DNA. So when the cell splits, the virus gets copied along with it. For instance, some scientists think Multiple Sclerosis [wikipedia.org] is one of these retroviruses that has infected our DNA. So when we look at the entire human genome [genome.gov], all the pairs in the whole DNA sequence, and we look at where all the promoters are, it seems (according to current theory -- we may learn more about this!) at a first glance there are some pretty long stretches with no promoters. That is to say, they are either empty sectors on the disk, or some of them look like retrovirus DNA code.

How'd I do at explaining that? Like I said, crashfrog should probably amend my explanation...

Re:error correction

I've always suspected that "junk DNA" was the key to micro-evolution and speciation. I read an article once about how bacteria that could not metabolize lactose were cultured in a lactose-rich liquid. After about 60 generations, some bacteria that could metabolize lactose appeared. It turns out, they had non-functional genes for metabolizing lactose in their junk DNA, and somehow those genes were re-activated.

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I'm a Christian, and what annoys me about Christian creationists is according to "true Christianity" belief in creationism isn't necessary to be a Christian. All you need to do is follow Jesus.

Someone could say the creation part of the bible was figurative

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"No junk DNA would seem to indicate more of an overall design to the system, no?"

Not really. Exactly how and why DNA keeps or discards various sequences, coding or not, is not something on which design or no design rests: it's a matter of the particulars

Re:junk genes was a junk idea

Whenever I read something like this, I get a reminder how poor is biologists' comprehension of Computer Science, Information Theory, and languages.

Whenever I read a post like this, I get a reminder how poor is most techies' comprehension of biology, and more specifically, what biologists do.

Third, why this obsession with zeroing in on a magic gene that causes X? Do they think the language of DNA is context free? Defects could indeed be expected to have no context, but for the rest-- which genes determine a person's blood type? Eye color? Skin color? Going about that task by trying to find the magic gene for something like that is like a person who never learned to read trying to figure out the plot of a book by trying to recognize patterns of letters.

Okay, why do we care? Because finding the genes (note my use of the plural there) that influence certain traits is the first step toward understanding the overall processes that create them. Obviously this is most critical in the area of genetic disease, although it's interesting for everything else too. We've known for decades that most traits, including diseases, aren't controlled by a single "magic gene." What statistical geneticists try to do is find locations on the genome which have a strong relationship to the trait of interest. And we know perfectly well that there will be a whole bunch of these locations for most traits, and that some of them may represent genes and some may represent something else. The purpose is basically to give the wet-lab biologists something to zero in on.

Second, two of the examples you chose -- blood type and eye color -- are really terrible ones for your argument, because genetically speaking they're very simple traits (two or three loci each, IIRC) and, at least in the case of blood type, we know exactly where they are in the genome. Eye color I'm not sure about, and skin color is a little more complicated, but not a whole lot more so.

Please do not confuse the pop-sci "scientists seek gene for X" writeups with what really goes on in the world of genetic research. It has exactly as much to do with real science as TV portrayals of hackers have to do with real computing.

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Whenever I read something like this, I get a reminder how poor is biologists' comprehension of Computer Science, Information Theory, and languages.

Whenever I read a post like this, I get a reminder how poor is most techies' comprehension of biology, and mo

Re:junk genes was a junk idea

Whenever I read something like this, I get a reminder how poor is biologists' comprehension of Computer Science, Information Theory, and languages.

Be careful here--you might just show your own ignorance. "Biologists" is a very broad term that covers a vast array of topics. Sure, ecology might not require much knowledge of computers and information theory, but such things are required reading for fields like molecular biology or modern genetics.

First, evolution would weed that sort of thing out in a hurry. Two organisms with genes that achieve the exact same thing, but one has a more efficient encoding? No contest!

Not necessarily. Sure, that may be the case for single-celled organisms that rapidly reproduce, whose selective forces dictate sheer metabolic efficiency, but for multi-cellular organisms, like mammals, there's good reasons to believe that that simply isn't true.

Evolution isn't like a programmer. It isn't some transcendental force guiding a species to some aesthetically "perfect" design. The result of natural selection frequently isn't the "best" solution but rather whatever happens to work. In fact, many times adaptations based upon the selective pressures of the present are, in time, ultimately maladaptive for the species. A classic example of this is the trait for the disease sickle-cell anemia in humans which originally served to offer slight resistance to malaria but otherwise causes health problems and even death.

A more efficient genome doesn't necessarily mean greater fitness. Consider the following example. For a large multi-cellular organism, which do you think has more reproductive/survival significance: (1) a mutation that deletes a few bases of non-coding DNA OR (2) a mutation that brightens a metabolically-wasteful, colorful marking that attracts mates?

Second, ever tried compressing a DNA sequence? They don't compress very well! Meaning, they don't have much redundancy.

OR that they are mostly random. The current model of DNA/genetics states that most of the DNA in the human genome is non-coding, not (significantly) subject to evolution. As such, it gets shuffled around (i.e. randomized) during cross-over events and mutations. That being the case, one wouldn't expect it to be very redundant or compress very well.

Third, why this obsession with zeroing in on a magic gene that causes X? Do they think the language of DNA is context free? Defects could indeed be expected to have no context, but for the rest-- which genes determine a person's blood type? Eye color? Skin color? Going about that task by trying to find the magic gene for something like that is like a person who never learned to read trying to figure out the plot of a book by trying to recognize patterns of letters.

In short, because that's what's easiest. A holistic approach to genomics research like you're describing is not currently technologically, academically or economically feasible for a myriad of reasons. The science just is not there yet.

As an aside, I suspect we'll start to see a more integrated approach to genomics once the relatively low-hanging fruit of the one-gene --> one-protein research lines are throughly covered. However, I wouldn't expect such things to happen in our lifetimes given the difficulty of that aforementioned task and the sheer profitability of more conventional approaches. But what do I know? I'm "just a biologist." =P

-Grym

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The result of natural selection frequently isn't the "best" solution but rather whatever happens to work.

Exactly, and it's a popular misconception that evolution is always about the "best" and anything that is 1% "better" is going to dominate. Which simpl

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I think your understanding is a little naive... There *are* magic genes that do X. There are also pseudo-random sequences that we have found a use for, and there are, further, sequences we carry around that are malicious, or do exactly nothing. But we c

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Why flame? A different point of view can lead to a break through. You initial hypothesis doesn't have to be correct to discover something useful. And who knows, maybe some day God (pick your deity here) will reveal him/herself to us unbelieving humans and

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I believe likewise.

For me, its an Occam's Razor thing.

If I find a pencil on the sidewalk, the most obvious thing is someone dropped it.

I see life, and am at awe of its complexity. I have to conclude something designed it. Jehovah - Yahweh - the name

Teleological Argument

You found your belief in God on what is known as the Teleological Argument [wikipedia.org]. There are a number of formal reasons why this argument is a poor one. The wiki link I've given you is a good place to start learning why it's not good, and Richard Dawkins' The Bli

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I see life, and am at awe of its complexity. I have to conclude something designed it.

Weird. If you ask me, what's truly amazing about nature is the mind boggling complexity and variation that has grown out of beautifully simple principles such as natural

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Yes, and yes.

Anyway, it made sense to focus on the almost-understood parts first since the mapping techniques were very limited (but far more efficient each year) and the task so massively huge it would have been stupid not to limit the first steps to a be