At the core of the study was detailed screening of the yeast's entire genome, some 6,000 genes in all. Conducted by graduate research assistant Yu Zhang, the exhaustive assay identified 33 genes associated with the repeats fragility and expansions.
The connection between genomic expansion and genes that initiate transcription came as a surprise.
"We found that these repeats can recruit transcription initiation factors and induce transcription," said Lobachev. "The repeats seem to work as non-traditional promoters for an abnormal type of transcription. It turns out that this ability to drive transcription is a significant factor in their instability. That makes this a more complicated story for sure, however, it also opens new avenues to examine the repeats."
The ability of the repeats to affect the activity of genes may indicate a broader effect on the genome, and if the effect is also seen in humans, could account for some of the subtle differences between individuals.
"By some estimates, there may be a thousand locations in our chromosomes where these repeats can expand," said Lobachev. "Probably each person differs in the number of repeats in specific locations. This is important because of their ability to change gene expression."
Among the next steps in the research is to determine how the expansions occur in cells that aren't dividing, such as neurons. The genetic mechanisms involved in cell replication offer clear opportunities for repeat expansions, but the mechanism for repeat amplification in non-dividing cells remains a mystery. The researchers believe the finding that GAA/TTC repeats can promote transcription provides clues f
|Contact: John Toon|
Georgia Institute of Technology Research News