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Do your ears stick out? What color are your eyes? Who are you?
You are you because of a unique combination of your parents' genes, coded into the strands of DNA molecules, coiled tightly around an “X-shaped” structure. This is a chromosome, and you have 23 pairs of them, deep down in the nucleus of all 37 trillion cells in your body.
Dr. Beth Sullivan, Associate Professor of Molecular Genetics and Microbiology at Duke University, studies chromosome rearrangements in her lab and how they may cause disease.
You can think about chromosomes as a bus, and the genes are the passengers on the bus. And those genes have to travel to a destination every 24 hours.
Each chromosome has a region where the two pairs meet. It's filled with long and repetitive sequences that some consider to be “junk DNA.” This is called a centromere. (You can see an example in the image on the right.)
The centromere is the bus driver. So the centromere decides where the chromosome is going to go, how fast it's going to go.
Here's the thing…
More than half of our chromosomes have two potential bus drivers.
We wanted to understand why, and are there ever circumstances in which the bus drivers switch?
And that's where Dr. Sullivan and her lab's research, appearing online in the journal Genome Research, comes in.
We found that about 70% of the population “chooses” the bus driver that has the largest amount of DNA sequence, the repetitive sequence. So we call this the primary site for a centromere assembly.
Or, the “primary busdriver.”
And then we found that about 30% of the population actually form their centromere at the backup site. We wanted to understand, why would we want to use the backup driver instead of the primary driver?
They picked an important bus.
We focused on Human Chromosome 17 because it is involved in congenital defects - a lot of these are neurodegenerative diseases - and in acquired diseases like cancer. So we thought it was a good chromosome to study because if we could gain some insights into how the chromosome behaves, it would impact many areas of biomedical research.
If your primary array has a lot of sequence changes, or size changes, the smart thing for the chromosome to do is to build the centromere at the backup array. If you're in the primary array and you have no sequence or size changes, you're good. If you're on the backup array, you're also good because that means that the primary array was defective and you chose the backup array because it's a good place to be. But for some reason in some individuals, they don't do this. They persist in trying to build the centromere at this variant primary array, and that array is dysfunctional.
So, if your primary bus driver is awake and alert, you'll have a safe trip. If not, the backup driver is always ready to get you where you need to go. But, for some reason, some people have buses in all 37 trillion cells that are driven by the incapacitated primary driver, making the backup driver ride shotgun. Those buses don't always arrive safely.
This defect is passed down from parent to child, and so Dr. Sullivan and her team may have pinpointed a cause of genetically-inherited diseases, like some forms of cancer.
The ultimate aspiration would be to completely switch the centromere location from the bad site to the backup site. But, on a more modest level, our first steps are going to be to try to use this to maybe be predictive of cancer risks.
We think that these gaps need to be filled. There's a wealth of functional information that most people are ignoring because they consider this sequence junk, and they haven't tried to put the puzzle pieces together to see where all these sequences fit. It's the next frontier in genome assembly, and I personally believe that it needs to be completed so that we really understand how our genome works.