MSK News - Radiology Side Trip

Features Srihari Sampath, MD PhD, and Srinath Sampath, MD PhD

​Does the human genome contain more information than we think?

Radiologists don't often consider such basic science questions. But in their dual roles as Musculoskeletal Radiologists at UC San Diego and Musculoskeletal Biology Lab heads at the Genomics Institute of the Novartis Research Foundation (GNF), Srihari Sampath, MD PhD, and Srinath Sampath, MD PhD, ask questions like this routinely.

In fact, it was this question that put them on the path to discovering a new gene required for skeletal muscle formation (Zhang et al., Nat Commun. 2017 Jun 1;8:15664).

Researchers have discovered a tiny protein (shown here in red) required for developing muscle progenitors to fuse and form contracting muscle fibers. Image by Qiao Zhang.

​Scientists have believed for some time that the increasing complexity of organisms—from flies to humans, for instance—can't be explained readily by an increase in the number of genes. Sampath and Sampath considered the intriguing possibility that more genes do actually exist in mammals, but that those additional genes have been overlooked due to the convention that defines genes as "protein-encoding" only if they are above a particular (and arbitrary) cutoff size. Recent work has clearly identified important proteins below this cutoff in other species, particularly in fruit flies. Sampath and Sampath wondered if this phenomenon might apply to humans as well, and set out to uncover whether any such "microproteins" exist in mammalian skeletal muscle.

They looked at global gene expression in injured and uninjured mouse skeletal muscle, and were indeed able to identify a new gene encoding a microprotein below the arbitrary size cutoff. To their astonishment, when they genetically deleted this tiny gene via CRISPR/Cas9 gene editing, the mice died at birth. The reason was simple but informative: the gene is essential for formation of all mammalian skeletal muscle, and without it the muscles of respiration never form. Further work showed that this microprotein functions by enabling the fusion of single muscle cell progenitors to form the giant multinucleated cells which we know as myofibers. In honor of the protein's small size but big impact, they named it Minion (Microprotein INducer of FusION).

As physicians, Sampath and Sampath are naturally interested in the translational relevance of these findings. They and others are in fact exploring use of the Minion-based fusion program to accomplish "therapeutic" cell fusion, for instance in oncolytic therapy and cancer vaccine development. Recent work has also indicated that this fusion program is deficient in a human form of congenital myopathy, making the pathway itself a potential therapeutic target. Perhaps the longest term impact, though, is in drawing attention to the many mysteries that still lay hidden in the "dark matter" of our genomes.