RNA-editing events can reveal the genetic basis of many human diseases

Scientists from Children’s Hospital of Philadelphia (CHOP) have detected RNA-editing events that affect the expression of genes and, consequently, the phenotypic manifestation of that specific expression.

The researchers made this discovery by combining experimental laboratory testing with computational mining of big data.

During the analysis of the so-called A-to-I RNA editing, where the adenosine of an RNA molecule is chemically changed into inosine, the investigators explained how a single nucleotide modification caused by RNA editing can have massive downstream effects. The study results were recently published in the Genome Biology journal.

Millions of A-to-I RNA editing sites have been identified across the human transcriptome, but the functions of most RNA editing events are unknown. Understanding how RNA editing affects gene expression and phenotype could help us unravel the genetic basis to many human conditions.”

Dr Yi Xing, PhD, Study Senior Author and Director of Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia

Along with his research team, Dr. Xing examined the functions of RNA editing through the lens of human genetic variation, or the variations that occur among individuals in around 1 in 1,000 base pairs of DNA, including the expression of genes and also the way messenger RNAs (mRNAs) are processed.

The investigators examined the corresponding transcriptomic and genetic data of 49 tissues across 437 people, totaling about 8,000 human specimens from the NIH Genotype-Tissue Expression (GTEx) project, searching for the so-called A-to-I RNA-editing events linked to genetic variation among people.

The team used a new approach that involves molecular quantitative trait loci (QTL) mapping, which identifies genetic effects on gene regulation by mapping the molecular traits to genotypes. Molecular QTL analyses can offer clues about the genetic mechanisms that control biological processes.

Through this method, the team was able to detect as many as 3,117 exclusive RNA-editing events linked to genetic changes. Most significantly, 14% of these RNA-editing QTLs were also linked to genetic changes in gene expression.

When the researchers compared their data with the existing genome-wide association study data, they observed that a subset of these RNA-editing QTLs was also linked to complex diseases or traits in the human population.

To figure out why RNA-editing changes can be combined with gene-expression changes, the team targeted microRNAs—a group of tiny noncoding RNAs that can control the expression of genes by attaching to complementary mRNAs sequences and causing the degradation of the bound mRNA molecules.

The researchers observed that specific microRNAs either degrade or do not degrade their target mRNAs, based on whether a specified RNA-editing location in the mRNA is edited to inosine (I) or remains unedited as adenosine (A).

If human genetic variation controls this RNA-editing site, this mechanism can activate a cascade of downstream events by altering the abundance and stability of crucial mRNA molecules and, thus, the phenotypes affected by these mRNA molecules.

What is so useful about this approach is that it is disease agnostic. Future research can use this strategy to study specific diseases and look at the impact of RNA editing events from a disease perspective.”

Dr Yi Xing, PhD, Study Senior Author and Director of Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia

Source:
Journal reference:

Park, E., et al. (2021) Genetic variation and microRNA targeting of A-to-I RNA editing fine tune human tissue transcriptomes. Genome Biology. doi.org/10.1186/s13059-021-02287-1.

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