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Unstable shapes: A repeated three-nucleotide sequence (yellow) in the FMR1 gene triggers hybrid loops of RNA (red) and DNA (blue), as well as hairpin-like structures in the unpartnered DNA strand.
A repeated sequence within the gene mutated in fragile X syndrome forms unusual loops of genetic material, reports a study published 17 April in PLoS Genetics1. The loops may trigger a cascade of genetic changes that push a precursor mutation into one that causes the disorder.
Fragile X syndrome is the most common inherited cause of autism. It arises from the abnormal expansion of a three-nucleotide repeat — the sequence CGG — in part of the FMR1 gene. More than 200 repeats silence the gene, resulting in a loss of the FMRP protein.
However, a smaller number of repeats, called a premutation, boosts the rate at which the gene is transcribed into RNA. The premutation is also associated with a late-onset neurodegenerative condition called fragile X-associated tremor/ataxia syndrome.
Until now, researchers did not know exactly how the repeated sequence expands from the premutation or shuts down FMR1 expression once more than 200 repeats exist. The new study confirmed suspicions that the expanded region can form strange hybrid DNA-RNA structures. These so-called R-loops are created when a strand of RNA remains attached to one strand of the DNA during transcription. The hybrid genetic material that arcs out from the DNA molecule can further twist and cause instability in the gene.
In particular, strands of DNA rich in C and G, such as the expansion region, tend to form R-loops. The loops form at multiple points throughout the expansion; the more repeats there are, the more loops they form.
R-loops are part of the normal function of some genes — they can help keep a gene activated. But the long loops the new study found tend to introduce contortions in the DNA that can activate a cell’s DNA-repair response. This can lead to more mutations and changes in the way genes are regulated, and may explain how the repeat expands and silences FMR1, the researchers suggest.
References:
1. Loomis E.W. et al. PLoS Genet. 10, e1004294 (2014) PubMed
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