Miniproteins That May Be Key to Human Evolution Appeared 'Out of Nowhere'

The origins of millions of tiny proteins in our bodies, previously assumed to be useless, have now been discovered.

A study published on February 17 in the journal Molecular Cell describes how these microproteins developed millions of years later in our evolution than larger proteins.

Yet the huge age gap doesn't appear to prevent the proteins from "talking" to each other. "Our lab experiments showed that the young and old proteins can bind to each other—and in doing so possibly influence each other," Jana Schulz, a researcher in the team that published the study, said in a statement.

Contrary to long-held assumptions, the researchers suspect that the microproteins may play a key role in a range of cellular functions

microproteins in the cell
The microprotein in the mitochondria (green) and in the nucleus (blue) was overexpressed in human cells. The yellow and pink areas show that the signal of the microprotein overlaps with the mitochondrial and nuclear signals. Clara Sandmann, Max Delbrück Center

The scientists also found that the genetic code for these tiny proteins is hidden in areas of our DNA that were previously thought to be non-coding, containing random code rather than instructions for building proteins.

These proteins therefore emerged from "out of nowhere—in other words, out of DNA regions that weren't previously tasked with producing proteins," Jorge Ruiz-Orera, an evolutionary biologist at the Max Delbrück Center and the German Center for Cardiovascular Research (DZHK), and co-author of the paper, said in the statement.

The findings open up a lot of new research avenues that are enthusing the biomolecular and medical research communities. One conceivable scenario would be "that these microproteins are involved in cardiovascular disease and cancer, and could therefore be used as new targets for diagnostics and therapies," said Norbert Hübner, lead author of the paper and geneticist at the Max Delbrück Center.

Previously, microproteins had only been thought to form via splitting off from larger precursor proteins.

"In this study we explore the evolution and interactions of the smallest and evolutionary youngest members of the human proteome," Hübner told Newsweek. The proteome is the entire set of proteins that can be expressed by a genome, cell, or organism at a given time.

"We identified previously unknown human microproteins and show that most microproteins (90 percent) are evolutionary young and emerged de novo [anew] in primates," he said.

Microproteins are defined as being fewer than 100 amino acids long. All proteins are long chains of amino acids strung together, the order and type of which is encoded in our DNA. Most proteins that we are familiar with, such as collagen or enzymes, have at least 1,000 amino acids.

dna molecule
Stock illustration of a DNA molecule. The newly discovered microproteins were found to be coded for in areas of our DNA that were previously thought to not code for anything. iStock / Getty Images Plus

In their research into human and primate microproteins, the study authors discovered over 200 super-small proteins, each with fewer than 16 amino acids each. These proteins had not previously been known to exist, let alone studied for their function.

The discovery that these microproteins, despite evolving in humans and primates so much later than other larger proteins, can still interact and signal between the larger proteins, is very significant. This, combined with the fact that these proteins are coded for in DNA that was previously thought not to code for any proteins, implies that the microproteins play a key role in many cell functions where they were previously thought to be functionless, and also might have been a key part of evolutionary development.

"Evolution is a continuous process and the larger proteins that we know today have also started millions of years ago small and evolved into 'today's products' over long periods of time," Hübner said.

The authors hope their findings open up numerous new research opportunities, as these microproteins clearly have functions that have as yet been undiscovered. The researchers plan to expand their experiments further from the 281 microproteins studied in this paper to over 7,000 microproteins in the hope that they will find new functions, and possibly more secrets hidden in our very own DNA where nothing was thought to be.

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