What if everything you thought you knew about the genome was wrong?

For the past few months, the shake-up that began with Next Generation DNA Sequencing has been forcing me to adjust to a whole new view of things going on inside of a cell. We've been learning things these past two years that are completely changing our understanding of the genome and how it works and it's clear we're never going back to the simple view we had before.

What's changed? The two most striking changes, to me at least, are the new views of the way the genome is put together and what the cell does with the information.

They just don't assemble chromosomes like they used to.
I used to think things like structural variations in our chromosomes were relatively uncommon. And, I wasn't the only one. I can even find those kinds of statements in some pretty recent genetics texts.

But, I was wrong and so was everyone else.

Copy number variations (CNVs) are regions of DNA where sequences, of variable lengths, have been duplicated or deleted. There are more CNVs, and more inversions, where a piece of DNA has been flipped around, and translocations, where bits of DNA have moved from one chromosome to another, than we would have ever expected.

It's not that we didn't know these structural variants existed, it's just that we (or at least I) always thought about these variations in the context of disease. When I learned about inversions, translocations, or copy number variations in genetics; it was because there were genetic diseases associated with these changes. Some cases of Down Syndrome for example, can occur when a piece of chromosome 21 is copied and pasted onto chromosome 14 Other well-known translocations are associated with certain types of cancer. Chronic myelogeneous leukemia can occur when bits of DNA are exchanged between chromosomes 9 and 22. In another more recent case, a copy number variation has been associated with autism susceptibility.

Now, we know that translocations can occur without producing some kind of genetic disease. Like inversions, deletions, and duplications, our new ability to scrutinize the genome is making it clear that individual genomes vary more than we ever knew.

They don't use the information the same way any more either

Our genetics texts used to present this nice simple picture of the way gene expression worked. We had a region of DNA called a "gene," the information from that gene was copied, producing a molecule of RNA. If that RNA contained the information for making a protein, it would be sent out of the nucleus into the cytoplasm, where the ribosomes would read the information and build a protein. Two steps, nice and sweet.

But the real picture is turning out to be much more complicated.

We used to be satisfied with three types: tRNA, ribosomal RNAs, and the messenger RNA that codes for proteins. But now, every experiment seems to be finding more and more kinds of RNA. Now, we've got ribozymes, telomerases, RNAs involved in splicing, micro RNAs, small RNAs, long non-coding RNAs, and everywhere you look there's some new kind of RNA with some unknown kind of function.

What's brought about this change?

We're being forced to change our view of the world because of the new technologies. In earlier years, we were look able to look at the genome by using Sanger sequencing to determine the order of bases in the DNA, and the transcriptome, by using either Sanger sequencing to look at the RNA molecules produced in a cell or microarrays or SAGE to look at small parts of RNA molecules. None of these methods were comprehensive enough to really gave us the whole picture.

It's a brave new world.

More like this

A lot of these new ways of looking at the genome were apparent about three or four years ago with the advent of high density genomic microarray technology such as ROMA. That is certainly when I realized the genome was more complicated than expected.
It has taken years, however, for the new picture to filter down to biologists in general.

I really dislike sensationalist "articles" like this. Not much content and giving the wrong impression to boot. No, not everything we know is wrong. It is like after just using whole number calculations you finally discover fractions - it is a whole new field which makes it more complicated and expands your understanding. But it doesn't invalidate what you know about whole numbers.

To anyone familiar with evolution and the RNA world hypothesis it doesn't come as a big surprise how involved RNA is either. That had already become very apparent when the structure of the ribosome was solved and it was shown that rRNA does not have a structural role supporting the proteins in their function, but that the proteins have a structural role and rRNA is the catalyst.

By Markus Winter (not verified) on 24 Mar 2009 #permalink

Don't worry Markus, later posts will have more detail.

I forgot to mention all the changes in our views of alternate splicing, alternate transcriptional start sites, multiple promoters, much more extensive RNA editing, and alternate polyadenylation. It's a taken some time for all the new bits of information to form a more comprehensive picture.

Even when you suspect that things might be more complicated than before, it's different when you start seeing the data.

It is the article I have issues with, not the biology.

Statements like "EVERYTHING WE KNEW IS WRONG" are not just sensationalist but plain simply wrong and undermine the credibility of science. A credibility which has been built on facts over hundreds of years. This article was pointed out to me by a layman (I didn't know this site before). How is a layman supposed to know that this article is , well, crap? How often do you thing creationists cite articles like this as evidence that Science got it wrong?

You write a blog. You think you have something to say. Then shouldn't that something be worth saying?

I don't think I will be coming back to read more.

By Markus Winter (not verified) on 25 Mar 2009 #permalink

The comments you've received on this post are fascinating. Expressing a bit of enthusiasm for new information that forces an adjustment to your previous understandings is not the same as sensationalized distortions meant to propagandize a particular worldview. Please do not take the feedback you've so far received as evidence of failure to communicate effectively. I think that you have. The new information is fascinating and highly representative of the way scientific understanding progresses. Such understandings aren't set. They aren't unchanging for all time. And they aren't complete as is. Not to everyone's taste, but certainly exciting and challenging for a great many, you and me included.

Hoping to read your next installment.

Reminds me of what happened in physics over decades: I grew up learning that atoms were made up of protons, neutrons, and electrons. Many years later quarks were added to the description, and now today we have a mind-boggling 'particle zoo' that numbers in the multi-dozens even at the most fundamental level of matter. The original conception may not be entirely 'wrong' but it missed so much of the complexity that it might as well have been! And it should be expected that undiscovered complexity is even more inherent to the biological arena than to the physical. We remain at an incredibly primitive level in our understanding of genetics, subject to much change.

Very much agree with Arj and Greigos (and therefore disagree with Markus' harsh criticism): one has to be indeed careful how one puts into words such paradigm shifts that happen from time to time in various fields of science. It is clearly hard for a layman to understand how such drastic changes in our understanding do not completely invalidate the interpretations that were reached before, based on earlier (and less detailed) knowledge. Yet I agree with you very much that many of us had to (some might still have to!) quite radically reset our thinking about genome structure and genetics in general. Interesting times indeed!

I had a genomics grant turned down several years ago because I had a partial sequence of a genome that was closely related to another and had found several significant rearrangements. They essentially said I didn't know what I was doing. A few years later and nobody would've questioned my results.

This is an excellent summary of the startling sea changes that have occurred even since I took undergrad genetics, and that was just 3 years ago.

I am curious not so much about the content of this information but rather about how it is dynamically and spatially organized. Especially interesting to me are the many ways in which the establishment and dynamic changes of the gut microbiome could be programming our immune systems and thus overall health. There is already evidence that specific microbiota are strongly implicated in the development of inflammatory bowel disease.

I'm looking forward to the rest of the series.

A few weeks ago I had on my hands a New Scientist magazine stating "Darwing is wrong". I understood immediately the rethoric of the statement and actually have to say that the article was really well written and interesting. But there was immediate reaction from creationist in the UK celebrating that a prestigious scientific magazine was in their side nearly recognising their victory. That is why, although rather harsh, I understand Markus' point and concern. I have to say though that the article is interesting and I share the idea as to how new technologies and changing how we use to see the molecular world. The pioneers, like Einstein in physics, were not wrong, but they had wished having access to the technologies available nowadays.

By Lois Bello (not verified) on 26 Mar 2009 #permalink

While I also think you raised some very interesting points I'm a bit puzzled that you didn't even mention how much our understanding of epigenomics has grown and how this changed our view on how cells work, how inheritance works and therefore even how evolution works.

Krakonos: I would have, but I was pressed for time. You're right, our ability to identify all the methylated positions in a genome has certainly increased our understanding.

Fast sequencing and informatics are finally giving us a view of the hard drive of life. We are also getting closer to understanding the mechanism of evolution and development.
As each new shRNA or RNAi CNV or randomly conserved sequence is elucidated I see it as the uncovering of the ancient mechanism that got life going and evolving eons ago. Dawkins wrote about a Blind watchmaker but I believe the watchmaker devolped or evolved a kind of biochemical sight.

In this sense understanding the exact path we took from slime to cell is looking more and more like the key to nearly everything in biology and medicine.

I was talking to one researcher recently who showed me some data about prostate cancer risk being directly related to the path cells take from stem cell to tissue. In short to understand how the cancer develops they have to understand how specific tissues evolve.

My idea and it's probably not unique to me is to look at the analogy of cooks and recipes in a good restaurant.

You see an organism which wants to survive evolutionary forces is like the cook in nice restaurant. Most of the clients come to get the dish that they love but they also want to see something new. So most of the menu is a standard recipe but the cook has to put out experiments to see what the market likes. Now when the customers really like something the cook has to freeze the recipe and put it with the standards. The question in biology is how does variation get frozen when it's good?

Most people think it's all just natural selection acting on the whole organism each time a mutation happens but if that was the case it is unlikely we would have ever evolved beyond the complexity of a single cell like a bacterium. Also the process of evolution probably isn't driven by random mutation (changing single bases in the DNA) and then selection. Rather nature is like a good chef working with complex ingredients -- it moves and rearranges whole chunks of of already "evolved" DNA around. The reason is that random changes of single bases is too slow to have produced the changes we see in nature. In fact they are so rare that you can use them to date the divergence of races and species.

So for evolution to work there has to be some equivalent of a master chef at the heart of the evolutionary process that does "experiments" by moving bits of DNA around and there has to be the equivalent of a restaurant manager - the person who hovers around in the back and looks to see which new recipe is worth keeping and turning into a new standard. In evolution genes that are important are often "conserved" that is they are the same across a whole host of species. Well it turns out that large stretches of DNA that don't seem to code for anything are also conserved and the mechanism of what conserves them or lets them vary is going to be an important factor in understanding how evolution works.

What does this have to do with the new confusion in genomics in Sandra's post? I think we are just getting our first look at the chef and the restaurant manager at work even though most of us track them by watching the waiters and bussboys.

By William Press (not verified) on 26 Mar 2009 #permalink

The talk about a "master chef" is getting us into dangerous territories, I think. Maybe I shouldn't feed the trolls, but we should really stick to evidence based science here.
To make it short: No, there is no evidence of a "master chef". Nice try though.