The mutation police

Scientists at the EMBL-European Bioinformatics Institute (EMBL-EBI) and the MRC Laboratory of Molecular Biology in the UK have discovered how our genome keeps the effects of mutations in check. The discovery, published in the journal Cell, will help in the study of diseases such as cancer and neurodegeneration. The findings also explain how new proteins are created, providing useful insights into the evolution of the human genome.

Our genes are made up of stretches of DNA called exons, which code for proteins, and introns, which do not. When genes get ready to make protein, exons are spliced together much like pieces of rope, removing introns in the process. Most introns also contain short DNA segments that closely resemble the ends of exons. These segments are often called “pseudo-exons” because there is always a chance they will be mistaken for exons and wrongly made into protein – a potentially dangerous but sometimes evolutionarily interesting scenario for the organism.

One of the most common sources of pseudo-exons are Alu transposons: they are a common cause of harmful genetic mutations, and there are about 650 000 of them within our genes.

Nicholas Luscombe from EMBL-EBI together with Jernej Ule from the MRC Laboratory of Molecular Biology have now discovered how the organism keeps the activity of the Alu transposons in check.

Using a technique called iCLIP that helps to study interactions between proteins and RNA, the scientists were able to show that an extremely abundant protein called hnRNP C has a crucial role in suppressing the Alu transposons.

“We were amazed to find that hnRNP C dedicates a full quarter of its binding sites to suppressing Alu exons,” says Nicholas Luscombe, “Cells missing hnRNP C activate thousands of Alu pseudo-exons, and the proteins they produce are damaged.”

These findings were supported when the scientists looked into genes linked to disease: “We found that, actually, many of these ‘disease exons’ occur because a binding site for hnRNP C has been lost. Once the Alu gets expressed it creates a problem,” says Jernej Ule.

So why do Alus play such a dangerous game? “Every so often a hnRNP C binding site is lost and something new will be expressed,” says Nick Luscombe. “Most of the time the mechanism we discovered keeps mutations from being expressed, but it has also allowed for evolutionary innovation, for example differences in sporting ability.”

Mutations involving Alu transposons are thought to be involved in diseases such as cancer and neurodegeneration. The researchers believe that discovering how hnRNP C works may lead to mitigating the effects of potentially harmful mutations.

Tags: genome, mutation, protein, transposon