In a large-scale study of more than 8,500 human samples and hundreds of primate and mouse samples, A*STAR researchers have investigated how RNA editing allows for the variable expression of genes in different human organs, and those of other mammals. The mammalian atlas will help scientists determine what genes and cell types are important in various diseases.
Almost every cell in your body contains nearly identical copies of your DNA, which is why DNA profiling is so useful in forensic analysis. But how that DNA is expressed varies greatly in different kinds of cells, resulting in the diversity of body tissues.
A cell produces RNA by copying stretches of its DNA, and then RNA is subjected to various kinds of processing which gives rise to some of the variability observed between different types of cells. It also goes some of the way toward explaining the complexity of humans despite the fact that we do not have vastly more protein-coding genes than other mammals.
“RNA editing diversifies the transcriptome,” explains Meng How Tan of the A*STAR Genome Institute of Singapore. “If every variation of a transcript was genetically encoded, our genome would be enormous.”
By drawing on the resources of the Genotype-Tissue Expression (GTEx) Consortium, Tan and his colleagues have conducted a survey of RNA editing in more than 8,500 human samples (corresponding to 53 tissue types in 552 individuals). They also analyzed hundreds of samples from the mouse and four other primates: chimpanzee, macaque, baboon and marmoset. The team focused on the RNA editing process that converts the nucleotide adenosine to inosine, the most common kind of RNA editing in animals.
The results revealed several surprises. For a start, the greatest amount of editing of RNA that codes for proteins was found to occur in the arteries, and not in the brain, as previously thought. Also, the comparison between species revealed that RNA editing profiles are more similar between different organs in a single species than they are between the same organ in different species.
The team is now exploring how diseases occur when RNA editing goes wrong. “There are over a million editing sites in humans, but for the most part, no-one knows what their functions are,” says Tan. “We are now actively investigating how RNA editing is dysregulated in various diseases, and we have ongoing collaborations with clinicians in Singapore.”
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.