Friday, March 16, 2007

Genomic diversity and cancer

First we sequenced the human genome, then we started working on SNPs to generate the Hapmap, and finally we started mapping methylation sites to generate the epigenome. Together these polymorphisms generate the bulk of the human phenotypic diversity. Recently it has come to my attention that there exists an additional source of diversity between humans: copy number variation (CNV). This, I am ashamed to admit, was complete news to me. Apparently you and I differ not only in the alleles we carry but also in the number of copies of the allele we carry. Traditionally we think of allelic variation has having 0, 1 or 2 alleles of a particular gene. However it is also possible to have the locus of the gene deleted, or have that locus duplicated or in multiple copies whitout having any sort of disease. Imagine if you had 4 copies of the gene for brown eyes versus someone who was just a regular homozygous brown+/+. Because of gene dosage your eyes would be darker. A recent study estimates that CNVs account for up to 17% of genetic variation in gene expression. And this isn't even a rare event, most people will have copy variants within their genome, and there are already almost 1500 variable regions covering 12% of the genome. They do tend to be outside of coding areas, probably because of negative selection, but are prevalent in regions containing genes important for immunity, environmental stress, etc... in other words regions where faster evolution is more likely to be beneficial. They may also account for complex "spectrum" diseases like autism. Cancer is another obvious disease which has been known to use this evolutionary mechanism for a long time. It is an evolutionary disease that uses all of the variation producing tricks evolution has to offer to mutate it's way to full blown malignancy. It uses normal genetic events like gene conversion, duplication, deletion, methylation, single base mutation but at an accelerated rate. If it manages to stay alive while generating enough diversity to evade the immune system and come-up with solutions to all of the built-in roadblocks we have it will have reached an "escape velocity". At this point it has reached a perfect balance of mutation rate / functionality in the genome, and has deviated so much from a normal cell it is barely recognizable. The corrolary is that the mutation rate is a fine balance, too low and you can't escape the body's counter measures, too high and you risk reaching catastrophy where the cell is no longer able to duplicate sucessfully. This is why radiation therapy is like having too much of a good thing for cancer. Remarkably the same thing is observed in viruses, as I recently learned at a seminar. The mutation rate is a very fine balance between evading the immune system but not compromising virulence. The lesson of the story is, if we can figure out how to increase mutation rates in cancer cells selectively, we might have a way to fight fire with fire...