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Understanding the Genetic Effects of Disease Manifestation by RNA Editing

The combined research effort of experts from mathematical science and life science backgrounds work together using data science to unlock new angles in gene therapy.

The Human Genome Project first completed in 2003 has been a precursor for many studies around the genetic effects of disease development and progression. Genetic causes of disease can be explained through the stages of the central dogma of molecular biology.

For the first time, researchers from the Genomics Research Center of Academia Sinica are exploring the associations between RNA editing activities and the damaging effects of genetic mutations at a population level.

“Prior investigation regarding diseases and DNA mutations never considered the possibility of any down steam RNA editing effects. This study therefore provides a new insight into the role of RNA editing in the pathogenomics studies”, said Prof. Chuang Trees-Juen, form the Genomics Research Center, Acadmia Sinica.

Their research revolved around the premise of “A-to-G” RNA editing, to understand why certain missense mutations are related to disease manifestation and some do not. This RNA editing process is triggered by a protein, adenosine deaminases acting on RNA (ADAR), which is able to swap the “A” nucleotide for a “G” nucleotide. Studies have proven significant relationship between “A-to-G” RNA editing and the development of neurological diseases such as autism, Amyotrophic lateral sclerosis, epilepsy, and Alzheimer’s disease.

Using the tool ICARES they collected and detected “A-to-G” RNA editing events from the DNA and RNA sequencing data from 447 people. The data allow the team to analyse associations between “A-to-G” RNA editing events, damaging effect of A/G mutations, and allele frequency of the mutations in the population. These associations were then used to determine if the patterns were associated with the location of the RNA editing sites.

As a result, for an A/G genomic variant, if G is a minor allele within a population (which implies that G is damaging), then the A allele should be edited less to prevent the conversion of A into G at the RNA level. In contrast, if A is a minor allele (which implies that A is damaging), then editing of the A allele should be promoted to compensate for the deleterious G-to-A change to a certain extent.

They observed that G-to-A missense mutations were much more prevalent than A-to-G ones (and other types of changes) at functionally important sites, in which the differences in the mutational burden of missense changes was significantly positively correlated with the deleteriousness of the changes. Moreover, the deleteriousness of G-to-A changes is significantly positively correlated with the percentage of binding motif of RNA editing enzymes at the variants, also supporting the association between A-to-G RNA editing and the increased burden of G-to-A missense mutations.

For an existing A/G missense variant, if the G-to-A genomic change has severely deleterious effects on protein function, RNA editing at this site with a higher editing level is more likely to neutralize the deleterious effect of the genomic change at the RNA level, making the deleterious effect weaker than expected.

The study was published in December 2019 on Genome Research, a scientific journal by Cold Spring Harbor Laboratory Press. [APBN]