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Novel Discovery of "Hidden" Gene Within a Gene in Mammals

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Yousuf Khan is PhD student in molecular and cellular physiology at Stanford School of Medicine. He is the first author on a recent article published in BMC Genetics which outlines the discovery of a novel overlapping coding sequence in the gene POLG. His work, combined with other research in the field, may suggest that there is an abundance of overlapping open reading frames.

Technology Networks recently spoke with Khan to learn more about the research study, how genetics can be likened to cooking up a recipe, and an accidental discovery that could lead to an exciting collaboration in this field.

Molly Campbell (MC): For our readers that may be unfamiliar with genomics, open reading frames and bioinformatics, can you tell us about the background of your research?

Yousuf Khan (YK):
Let’s compare the expression of a genetic sequence with cooking a meal. TheDNA is our mother’s cookbook, it contains every single possible recipe that we would ever need. But when we want to prepare a meal, we don’t want to get our precious cookbook dirty. So instead, we store the cookbook in a different location (genomic DNA in eukaryotes is inside the nucleus). When we want to make something, we make a photocopy of a page in the cookbook (the cell creates a messenger RNA, a temporary copy, of a portion of DNA).

This process of copying a portion of the DNA into mRNA is called transcription. We then take our single sheet of our photocopied recipe (our mRNA) and take it back into the kitchen (the cytoplasm of the cell).

In the kitchen (cytoplasm), we read the photocopied recipe one step at a time. By reading the photocopied recipe from the first step to the last step (the open reading frame), we convert the instructions into our finished, delicious meal. In a similar manner, mRNA is read and translated into a protein by a machine called a ribosome.

In the traditional way we understand biology, cells that want to create different proteins just alternatively splice different mRNAs to be translated. This would be the equivalent of photocopying recipes for scrambled eggs, pancakes, and bacon on Monday morning and then photocopying a different set of recipes (e.g. mashed potatoes, steak, and salad) for dinner.

MC: Can you expand on your recently published study? Have you essentially discovery a "gene within a gene"? If so, does this point towards a potentially "hidden" genome?

In our article, we found that the gene POLG creates an mRNA that contains a very long overlapping open reading frame. Imagine you’re following the instructions of a recipe to make lasagna; you start with step one and you complete every step until you reach the last step. But if you started at step two and then completed steps three, four, five, and six, you would create a hamburger instead. So encoded within a single photocopied recipe, there are multiple meals that can be made.

This study and others that have been published previously may suggest that there are an abundance of these overlapping open reading frames. The real effort is finding them and characterizing them!

MC: What were the key challenges you encountered in this research?

The real challenge is finding these overlapping sequences. They’re tricky to detect and it would not have been possible to do this work without the support of the amazing researchers at Ensembl.

MC: What are your next steps in this space?

I think there are more of these "hidden genes" to be found. The two important questions are i) where exactly are they? and ii) how are they read?

MC: On Twitter, you said "This finding was also made by another group at the exact same time, whose manuscript will be up shortly as well" – Will your research group be looking to collaborate?

This is actually a funny story. I was at a conference in Germany last September and I was sitting in the audience listening to a talk. As my focus began to wane, I started leafing through the abstract book seeing what other research was going to be presented at the conference. Right in front of me on a completely random page I turned to was almost exactly my research. The only difference was that it was done by a completely different group. I panicked. However, after an email of advice from adviser, I decided to approach the group and we ended up agreeing on trying to coordinate our submissions. My work was accepted to a journal faster and hence they uploaded their manuscript to a preprint server after I told them my paper was up. The link for their work is here.

Yousuf Khan, PhD researcher at Stanford School of Medicine, was speaking to Molly Campbell, Science Writer, Technology Networks.

Reference: Khan et al. (2020). Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon. BMC Genetics. DOI: https://doi.org/10.1186/s12863-020-0828-7.