Scientists Unlock the Secrets of Fused Chromosomes by Making a Human Model

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Usually each chromosome has just one centromere, which drives chromosome inheritance.

Dicentric chromosomes in model organisms are rarely tolerated and are either lost or kill the organism. But people with dicentric chromosomes can continue to function in a way that does not threaten their overall health. Still some people who have dicentric chromosomes do not fare as well reproductively - they may have infertility, miscarriage and other difficulties. Cancer cells, which are abnormal cells, also may have one or more dicentric chromosomes.

Beth Sullivan, Ph.D., an assistant professor of molecular genetics and microbiology and an Investigator in the Institute for Genome Sciences & Policy at Duke University Medical Center, has studied dicentric chromosomes closely and for the first time has found a way to create specific dicentric chromosome in human cell lines. This technique now can be used by researchers who want to know more about cancer, Down syndrome and other diseases featuring dicentric chromosomes.

The work was published online on Aug. 12 in PLoS Genetics.

Her team, led by Kaitlin Stimpson, a Genetics and Genomics graduate student, found that using a mutant telomere protein (TRF2) to remove the protective ends of the chromosomes (the telomeres) freed the chromosomes to combine in an end-to-end fashion.

What Sullivan and her team didn't expect is that the universe of free chromosomes would combine in the lab in the same way they combine in humans - certain chromosomes are more prone to fusing together - 13, 14, 15, 21, and 22 - creating what are known as Robertsonian fusions.

For example, in experiments, a chromosome 13 would attach to a chromosome 14, to make a 13-14 Robertsonian combination, which also occurs naturally in 1 in 1000 humans.

"This is the first time that dicentric human chromosomes have been engineered in human cells - experimentally induced in the laboratory using a theoretically unbiased approach," Sullivan said. "And, excitingly, this is the first time they have been shown to occur as non-randomly as they do in humans."

Most surprising of all, the lab-made dicentrics remained stable even after many rounds of chromosomal replication and division. "We have shown that these stable dicentric chromosomes remained stable for 150 divisions, many with two functional centromeres," Sullivan said. "The reviewers of our paper made us run many more experiments to show that the chromosomes stayed functionally dicentric, and for how long. I was surprised, too, because I thought in most dicentrics, we would see inactivation of one centromere, like we see in patients. But 50% of the time, that is not what happened."

Stimpson and Sullivan also studied the mechanism by which other of the experimentally-produced dicentrics experienced centromere inactivation. The results highlight similarities and differences in dicentric behavior between humans and model organisms, and provide evidence for one mechanism of centromere inactivation by deletion, the permanent removal of centromeric sequences.

"The ability to create dicentric human chromosomes and to model those that occur naturally in humans now provides a system to test other mechanisms for centromere inactivation, and to learn more about the fate of dicentric chromosomes after formation," Sullivan said.

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