The significance of detecting and comprehending how variations between tissues and cells influence gene expression without altering the underlying genetic code is discussed in a recent study by University of Kentucky researchers.
Mark Ebbert and his research assistants on August 5th, 2021. Image Credit: Pete Comparoni | UK Photo.
DNA is transcribed into RNA, which is subsequently translated into proteins, according to what is taught in introductory biology courses. However, transcription and translation rates depend on a variety of biological activities. It is possible to determine which genes are active in a tissue or cell by examining the variations in RNA concentrations inside that tissue or cell.
Changes in gene expression can significantly affect various diseases and disease trajectories.”
Justin Miller PhD, Assistant Professor, Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky
Miller, who is also affiliated with the Sanders-Brown Center on Aging and Biomedical Informatics, says that he and his co-workers earlier created the first algorithm to identify ramp sequences from a single gene sequence. Miller and fellow UK scientists Mark Ebbert PhD, and Matthew Hodgman have demonstrated that ramp sequences differ between tissues and cells without altering the RNA sequence by developing an online version of that technique.
A ramp sequence is a portion of the RNA sequence that uses difficult-to-translate codons (sequences of three DNA or RNA nucleotides) to inhibit translation at the start of the gene. Contrary to popular belief, ramp sequences promote overall gene expression by distributing the translational machinery uniformly and avoiding collisions later in the translation process.
The researchers report more than 3,000 genes with ramp sequences that vary between tissues and cell types in their most recent publication in NAR Genomics and Bioinformatics, which corresponds with higher gene expression in those tissues and cells. Researchers also present the first thorough analysis of the tissue- and cell-type-specific ramp sequences.
This research is the first time that variable ramp sequences have been described. Our comprehensive web interface allows other researchers to creatively explore ramp sequences and gene expression.”
Justin Miller PhD, Assistant Professor, Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky
The study team claims that despite the fact that human RNA may encode the same proteins in several ways, the precise RNA sequence is crucial for controlling the quantities of both RNA and protein.
Essentially, a ramp sequence works like an on-ramp to a freeway so that ribosomes do not crash into each other, but the length and speed limit of that onramp can change depending on the cell and the available resources within that cell.”
Justin Miller PhD, Assistant Professor, Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky
Miller claims that he valued working on this project not just with UK colleagues but also with Miller’s brother Kyle Miller at Utah Valley University and his previous colleagues at Brigham Young University. The team developed an online tool that allows users to view how ramp sequences relate to the expression of the COVID-19 and human genes in various tissues and cell types.
According to Miller, this effort will eventually have an effect on patient treatment.
Miller added, “We created an online interface for researchers to query all human genes and see if a specific gene has a ramp sequence in a given tissue and how that gene is expressed within that tissue. We also show that various COVID-19 genes and human entry factors for COVID-19 have ramp sequences that change between different tissues. Ramp sequences are much more likely to occur in tissues where the virus is known to proliferate.”
Because of this, the scientists think that COVID-19 genes feature genetic biases (ramp sequences) that enable them to utilize the cellular machinery at their disposal to raise their expression. “Our research may help us better predict which tissues and cells new viruses will infect and also provides a potential therapeutic target to regulate tissue-specific gene expression without changing the translated protein,” Miller concluded.
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