Jiming Jiang is unlocking the secrets of the centromere, an overlooked region of DNA that holds the key to chromosome engineering - and a new, possibly safer approach to gene therapy
Horticulture professor Jiming Jiang studies centromeres, large regions of DNA that help match up and then separate pairs of chromosomes during cell division. Long ignored by most genome scientists, centromeres now appear to be key in creating artificial chromosomes—complete, self-replicating packages of genetic material that could revolutionize crop improvement in plants and gene therapy in humans.
What is a centromere?
Humans have about 30,000 genes carried by our 46 chromosomes. Each chromosome has one centromere, a stretch of DNA that ensures the accurate transmission of the chromosomes—our genetic material—into daughter cells during cell division.
You can actually see the centromere under the microscope—it looks like a constriction on the chromosome. It’s an extremely complex structure. There’s a lot of protein involved, and the centromere’s DNA—how to describe it? It’s junk DNA, basically. It doesn’t have genes, just a lot of repetitive junk DNA.
When did scientists discover the centromere is full of junk DNA? When they sequenced the human genome?
Scientists say that the human genome has been sequenced, that the mouse genome has been sequenced, but people don’t realize that none of the centromeres have been sequenced. They just don’t count it. And most scientists don’t care because there are no genes [in those regions]. Plus, it’s almost impossible to sequence centromeres with current technology—they are too long and contain too much repetitive DNA.
But rice is a different story. The centromere on rice chromosome 8 is not particularly repetitive, so my team was able to sequence it back in 2004. We were the first team to sequence a centromere from a multicellular species, and, surprisingly, we found genes in it!
How did this rice centromere end up with genes in it?
Let me try to explain what we think is going on in this strange case. In the scientific community, people are starting to believe that centromeres originate somewhere. They don’t just exist, right? And when a new centromere emerges—a neo-centromere—it may look like a regular piece of DNA, with genes in it. Over time, however, as it evolves, the centromere accumulates junk DNA for whatever reason.
So, the rice centromere that we sequenced, we believe, is somewhere in the middle of this evolutionary process. It’s like a caveman. It is starting to accumulate some repetitive, junk DNA, but it still has some genes in it.
It’s interesting to consider that centromeres can evolve.
With funding from the NSF, we are now trying to understand the evolution of this rice centromere over the past 10 million years. To get at this question, we’re sequencing this centromere in five different species of wild rice, which diverged from cultivated rice between 1 million and 10 million years ago. We’ll be able to see what kinds of changes happened over that time—how the genes moved away, how the junk DNA accumulated.
This work will help us figure out the minimum requirements needed to make a centromere. There are a lot of things we don’t know right now, but if we can figure out the answers, this work will ultimately help us design artificial chromosomes. That’s the long-term goal.
What is an artificial chromosome?
It’s a chromosome that’s made from scratch in the lab. It can have one or more genes on it, and it needs a centromere, so it gets replicated and divided up during cell division just like a regular chromosome.
How do you envision artificial chromosomes being used?
I definitely want to see artificial chromosome technology used in agriculture someday. Right now plant biotechnologists add one gene at a time [to plants]. When they made Bt corn, for instance, they put a Bt gene into corn, and that was that. The big argument in favor of the artificial chromosome is that it has a large capacity to carry genes—you can put as many genes on the chromosome as you want. You can put entire pathways.
Let’s say a crop plant doesn’t make vitamin B12, but you’d like it to. To make vitamin B12 you need something like 10 genes. It would be almost impossible to [engineer this plant] with current technology, but with an artificial chromosome it should be possible to do a manipulation like that.
Does your rice research have any implications for human health?
Centromeres exist on all eukaryotic chromosomes, so understanding the structure, function and evolution of centromeres in plants will definitely help on the human side. In humans, artificial chromosomes are seen as a promising way to deliver genes for gene therapy. Let’s say you have a patient who’s colorblind, and they need a single gene to correct the problem.
The basic theory of gene therapy is to put the needed gene into the affected tissue, so that the
gene can produce the protein that’s needed to correct the problem. Currently, doctors use a virus-based vector, which inserts the gene randomly in the genome. It’s already known, however, that this process can actually cause cancer, because sometimes the new gene will insert into the middle of an existing gene that regulates cell division or the cell cycle. But artificial chromosomes carry genes independently. They don’t integrate into the genome, and they don’t interfere with existing chromosomes. So you can express the gene you need, without interfering with the other 30,000 genes that you have. [Human gene therapy] is really the main drive behind artificial chromosome research, and understanding the centromere—how it behaves, how it functions—is the most important part of this effort.
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