Tuesday, March 24, 2009 - 10:25
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.