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New Technique for Revealing the “Hidden” Genome

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Using an innovative new technique, scientists at Duke-NUS Medical School and their collaborators have identified thousands of previously unknown DNA sequences in the human genome that code for microproteins and peptides potentially critical to human health and disease.

“Much of what we understand about the known two per cent of the genome that codes for proteins comes from looking for long strands of protein-coding nucleotide sequences, or long open reading frames,” explained computational biologist Dr Sonia Chothani, a research fellow with Duke-NUS’ Cardiovascular and Metabolic Disorders (CVMD) Programme and first author of the study. “Recently, however, scientists have discovered small open reading frames (smORFs) that can also be translated from RNA into small peptides, which have roles in DNA repair, muscle formation and genetic regulation.”

Scientists have been trying to identify smORFs and the small peptides they code for, since disruption in these smORFs can cause disease. However, currently available approaches are very limited.

“Much of the current datasets do not provide information that is detailed enough to identify smORFs in RNA,” added Dr Chothani. “The majority also comes from analyses of immortalised human cells that are propagated—sometimes for decades—to study cell physiology, function and disease. However, these cell lines aren’t always accurate representations of human physiology.”

Publishing in Molecular Cell, Chothani and her colleagues in Singapore, Germany, the UK and Australia describe a methodology they developed to address these issues. They screened currently available ribosome profiling datasets for short strands of RNA with periodic three-base sections, covering more than 60 per cent of the RNA’s length. They then conducted their own RNA sequencing and Ribosome profiling to generate a combined data resource of six types of cells and five types of tissue, such as from the heart and the brain, derived from hundreds of patients.

Analyses of these data identified nearly 8,000 smORFs. Interestingly, they were highly specific to the tissues that they were found in, meaning that these smORFs may perform a function specific to their environment. The team also identified 603 microproteins coded by some of these smORFs.

“The genome is littered with smORFs,” said Assistant Professor Owen Rackham, senior author of the study from the CVMD Programme. “Our comprehensive and spatially resolved map of human smORFs highlights overlooked functional components of the genome, pinpoints new players in health and disease and provides a resource for the scientific community as a platform to accelerate discoveries.”

Reference: Chothani SP, Adami E, Widjaja AA, et al. A high-resolution map of human RNA translation. Mol Cell. 2022;82(15):2885-2899.e8. doi: 10.1016/j.molcel.2022.06.023.

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