Study Reveals Key Role of mRNA’s “Fifth Nucleotide” in Sex Determination in Fruit Flies

A team of scientists led by researchers at the University of Birmingham has shown how a common mRNA modification, N6-methyladenosine (m6A), regulates gene expression to determine the sex of fruit flies. The function of m6A, an mRNA modification known as the “fifth nucleotide,” has long been a mystery. But a new study, published online on November 30, 2016 in Nature, has revealed that m6A plays a key role in the regulation of the Sex-lethal (Sxl) gene, which controls sex determination of the fruit fly Drosophila. The Nature article is titled “m6A Potentiates Sxl Alternative pre-mRNA Splicing for Robust Drosophila Sex Determination.” Sxl is a “switch gene,” meaning that Drosophila sex is determined by whether or not Sxl protein is made. The Sxl gene is transcribed into mRNA in both males and females, but through a process called “alternative splicing” only the female mRNA can be made into a functional protein. Alternative splicing is a widespread mechanism of gene expression and occurs in almost all human genes, allowing the synthesis of many more proteins than would be expected from the 20,000 protein-coding genes in our genome. The new study shows that m6A mediates this process for Sxl in Drosophila, ultimately determining whether a fly develops as male or female. The new findings offer an important insight into a classic textbook example of an essential and widely studied process. “Despite sex determination being so fundamental, nature has found many ways of determining sex,” says Dr. Matthias Soller from the School of Biosciences at the University of Birmingham and lead author on the paper. “Our study suggests that m6A-mediated adjustment of gene expression might be an ancient yet unexplored mechanism for the development of this diversity.” The collaboration began after co-author Dr.
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