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Collecting the Clues
CHORI Scientists Link Specific Genetic Sequence to the Emergence of a Novel Centromere

"No one has been able to connect a specific sequence with the emergence of an ENC before. We thought we could use this region to potentially find that correlation."

CHORI scientists Lucia Carbone, PhD, and Pieter de Jong, PhD, of the CHORI Center for Genetics, along with their colleagues at the Department of Genetics and Microbiology at the University of Bari, Italy, have published a new study in Chromosoma reporting the first time association of a specific genetic sequence with the emergence of an evolutionary new centromere, or ENC.

“We were studying the evolutionary history of chromosome 18, comparing it in different primates, and we noticed there was an ENC. When we looked for genomic sequences in that region we noticed there was a clone gap in that family, and we found that intriguing,” says Dr. Carbone.

Centromeres are regions within a chromosome that are necessary for the correct segregation of that chromosome during cell division. Where and how centromeres originally emerge, however, is up for debate, and has resulted in an intense amount of scrutiny on ENCs - new centromeres that suddenly appear in a different region than where it previously had occurred.

"When new centromeres first appear in a chromosome, it's like a seed" says Dr. Carbone. "We don't know why or how, only that once the seeding starts, that centromeric sequence begins to function."

In the latest Chromosoma study, Dr. Carbone and her colleagues were able to identify that a human clone gap - a break in the assembled human genome map for which no sequence is known - corresponded to an ENC in Old World Monkeys (OWM).

"It was very difficult and painstaking, but eventually we were able to partially sequence the clone gap, which indicated a satellite-like, or repeat DNA sequence, that was uncloneable," explains Dr. Carbone.

When Dr. Carbone and her colleagues then compared DNA sequences between OWM and the macaque and the marmoset, they found the same satellite-like sequences occurring in both species, but in different locations.
"When you think about the seeding of a new centromere, why it is there, why in that exact place, we haven't really been able to answer that. There is no explanation, just that the centromere turns off in one place and turns on in another."
"It happens in some species and not others, and in humans as well, as if these regions kind of keep the memory of evolution from generation to generation," says Dr. Carbone.

"Now we believe the most likely hypothesis is that the satellite region may be why the seeding occurred."

With this new evidence in hand, researchers can now investigate why this sequence might be responsible for ENC seeding, and why it functions that one in one species but not another.

"It suggests that researchers could focus on this satellite sequence in more detail, looking for example at possible secondary structures to see what might qualify one sequence and not another to trigger ENC seeding," says Dr. Carbone.

For now, however, Dr. Carbone and her colleagues can enjoy the fruits of their labors, having established this critical clue in the evolutionary puzzle of ENC emergence.
As Dr. Carbone points out, "The mechanisms of mutations are the same when we look at evolutionary changes and when we look at patients. Looking at evolution and comparing different species, though, gives us a wider range of observations and possible mechanisms that had millions of years to get established by processes of trial and errors."

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Tuesday, May 17, 2011 8:19 AM

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