On BioScience and Life and Such

Posts Tagged ‘transcription’

Hey junk people, I accept your challenge (part II)

In Uncategorized on September 25, 2008 at 2:19 pm

A follow up from this post and an ongoing discussion with Professor Larry Moran over at Sandwalk.

Let me start by saying that even though this has been a lengthy discussion, I do not think we’re disagreeing that much, – on the basic facts that is. And the comments following my first post, his second post, my third, his fourth and this (the fifth) post on the topic hopefully will illuminate this fact.

Secondly I will introduce this post as I did the last, with my c-gamma gene (PRKACG). This gene serves as an example of how introns, retroposons and even alu-elements can contain indicators of function.

The c-gamma gene is transcribed in a species specific manner, (primates only), it’s expression is also tissue specific (testis only). The gene is contained within an intron of another gene, it’s 3′ sequence constitutes an exon of this other gene and lastly, putative regulatory elements where found in and around alu-elements in it’s upstream 5′-region.

Now, you can argue that these are all coincidences, … and refuse to speculate on any function. You may even be right in doing so, which I elaborated upon in my previous post. But, this gene is one of the reasons I refuse to put the label “junk” on everything that has not been ascribed a function. In my opinion, the species and tissue specific transcription, the conserved reading frame and the peculiar positioning of this gene, are all indications that this sequence may hide a function. There are other examples too, especially when it comes to transcription of alleged “junk” which in my mind is enough to warrant further investigation and scientific speculation.

There is, as has become very evident from this discussion, evidence pointing towards much of the genome being “junk”, but there are certainly scientifically viable indications to the contrary too.  Listening to the counter-arguments and following links in this two-post series will tell you this.

Then… moving on to answers to Professor Moran’s last 4 points:

5. Why is the Fugu genome so much smaller than that of other fish?

and

6. When two similar species differ in genome size by a factor of two—probably due to an ancient polyploidization—is the majority of DNA in both species functional?

His argument is that since the genome size differs between species, much of it must be junk. But, you could easily use the same argument towards a function, by saying that the difference in genome size is a defining (functional) difference between species. We just do not know do we ! And, why does the difference in size not give you reason to speculate on function at least in parts of these regions ? Others have however, speculated far better than me on this topic, and a thorough introduction to such research can be found at junkdna.com and following this link to “The Principle of Recursive Genome Function“.

7. In the human lineage there are over one million Alu sequences. They all look like degenerate versions of 7SL RNA. Are all of these sequences functional? If so, what function could they be doing? And why do the human Alus look so different from the mouse ones?

I am not saying all Alu-elements are functional. On the “what is junk” scale, one extreme is that everything that hasn’t been ascribed a function is junk (Larry Moran’s position !?) and on the other end is “nothing is junk”. My position is somewhere in the middle: Some of the DNA in our genome is possibly junk. A number of individual Alu-elements will undoubtedly end up in the “junk”-category when more is known about our genome. That said, it has been shown that Alu-elements can constitute (parts of) regulatory and functional elements. It’s rather hard to tell which ones are functional by just looking at them. I therefore refuse to call them “junk” by default, – I strongly feel that the “junk”-label is a dismissal of any possible function(s) and should be used with caution if at all, – even for Alu-elements.

8. Most intron sequences do not seem to have a function. Why does the size of introns in the same gene vary so much in related species and why isn’t the sequence conserved in most cases?

This argument is similar to the genome size argument above, and the answers for bullet 5 and 6 are equally valid here. Thus, there may be many reasons for a variation in intron size and this variation is not a very good argument to support the “junk” hypothesis. Also, the intron can contain regulatory elements and the c-gamma example above goes to show that introns can even contain functional (as in transcribed) genetic elements.

…..

My final note is this: A lot of this alleged “junk”-DNA is being transcribed into RNA. If it was just “junk” then why has selection preserved the transcription from these regions when transcription is an energy consuming process ? I think the position of “junk”-DNA may have some persuasive arguments, but it’s exceedingly harder to argue that the transcripts from these regions are also “junk”.

No matter what constitutes junk, and how much of it there is, this discussion has been extremely rewarding for me personally. I need to admit that the “junk”-position is more understandable to me now. I even find myself agreeing with many of the arguments, like the importance of drift over selection.

Conversely, even though I think he will never admit to it, Professor Moran indicates in one of his questions during the discussion, that he too is not completely locked into the “everything is junk” position:

How many of those transcripts are functional, according to your speculation, and what the heck are they doing?

Which I think is a perfect ending quote because it goes to show that we are all wondering about this……and that our disagreement is not as fundamental as some have suggested.

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How everything is a mess and still ok

In Uncategorized on May 26, 2008 at 9:09 am


post to news.thinkgene.com

I have recently finished reading a Nature news feature on noise in gene expression (The Cellular Hullabaloo). It left me with this increased understanding of cellular processes and in terms of controlling chaos, fitted nicely with something I have blogged about before, which is Hsp’s (especially Hsp90).

According to this news feature, several studies have found that there are significant differences in the expression of genes both in duration and strength, even between cells that were expected to be identical. This contradicts the current notion of gene expression as an orderly sequential and structured phenomenon. These studies seem to indicate that gene expression occurs randomly, throughout the whole genome.

How these cells are still able to differentiate in a predictable manner,…… and perform specialized functions in concert with thousands of other cells,…….. to build a functional multicellular organism, is a mystery to me. And it is enigmatic to the researchers behind these studies as well:

“People are fascinated by how we do what we do despite this noise.” — James Collins

and

“People ask how come an organism works so well. Perhaps it doesn’t work so well. Perhaps organisms without these fluctuations would outcompete us.” – Johan Paulsson

How the noise came about and why it persists is still somewhat unclear, but benefits from such chaotic conditions may arise from:

1. Controlling randomness (noise) requires a lot of energy, the more chaos the less energy spent. Consequently, only the most critical cellular processes are under tight control, and the rest are more or less random.

2. Expression noise may enable cells to fight off threats. Say a certain level of protein is required to survive a toxic compound attack. Then having cells with sufficient levels of defender protein is more probable in a (noisy) cell population with varying gene expression levels, than in cell populations with a constant level of expression.

3. Randomness may ensure variation in differentiation. An example given in the news feature is the differentiation of blue and green light sensing photoreceptors in drosophila.

So, the noise is there for a reason. Noise, or more precisely – random fluctuation, is an ubiquitous cellular phenomenon. But cells of a given type still end up with similar morphology and similar functionality. The beauty of nature is how the randomness is controlled just enough to achieve the minimum amount of order necessary for preserving functionality. Also, in keeping the random events, flexibility is preserved for future adaptation.

The chaos extends further than gene-expression. If you also consider variations in insertions/deletions, gene copy number and epigenetic differences, the potential for random variation at the gene level becomes evident. To control some of this genetic randomness you have proteins like Hsp90 that masks genetic variation at the transcription level (or folding level to be precise). This is an important control-mode for some of the chaos (DNA sequence variation and mutations) and at the same time it enables sudden exposure of chaos to achieve rapid morphological evolution if needed. I am pretty sure that similar (or very different) control mechanisms will be discovered for gene expression noise in the future.

The noisy expression story is another illustration of how we are not just our genes. The DNA-sequence may be a defining starting point, but there are levels and levels of variation on top of that. As multicellular and evolving organisms, we are constantly balancing between chaos and order. The chaos-level is maximized to minimize energy expenditure and to ensure a multitude of possible paths to follow in an organisms future biological evolution.

The balance is oh so beautiful, it’s called nature.