We may have parted ways with our primate cousins millions of years ago, but a new study shows just how human beings continue to evolve in ways we never imagined.
Researchers from Biomedical Sciences Research Center “Alexander Fleming” (BSRC Flemming) in Greece and Trinity College Dublin, Ireland, have identified 155 genes in our genome that emerged from small, non-coding sections of DNA. Many appear to play a critical role in our biology, revealing how completely novel genes can rapidly evolve to become essential.
New genes typically arise through well known mechanisms like duplication events, where our genetic machinery accidently produces copies of pre-existing genes that can end up suiting new functions over time.
But the 155 microgenes pinpointed in this study seem to have appeared from scratch, in stretches of DNA that didn’t previously contain the instructions that our bodies use to build molecules.
Since the proteins these new genes are thought to encode would be incredibly tiny, these DNA sequences are hard to find and difficult to study, and therefore are often overlooked in research.
“This project started back in 2017 because I was interested in novel gene evolution and figuring out how these genes originate,” says evolutionary geneticist Nikolaos Vakirlis, from BSRC Flemming in Greece.
“It was put on ice for a few years, until another study got published that had some very interesting data, allowing us to get started on this work.”
That other study, published in 2020 by a team of researchers at the University of California San Francisco, cataloged a stack of microproteins that are produced by non-coding regions once described as ‘junk DNA’.
The team behind this new study subsequently created a genetic ancestral tree to compare those tiny sequences found in our genomes against those in 99 other vertebrate species, tracking the evolution of the genes over time.
Some of the new ‘microgenes’ identified in this new study can be tracked all the way back to the earliest days of mammals, while others are more recent additions. Two of the genes identified by the study seem to have emerged since the human-chimpanzee split, the researchers found.
“We sought to identify and examine cases in the human lineage of small proteins that evolved out of previously noncoding sequences and acquired function either immediately or shortly thereafter,” the team writes in their published paper.
“This is doubly important: for our understanding of the intriguing, and still largely mysterious phenomenon of de novo gene birth, but also for our appreciation of the full functional potential of the human genome.”
Microproteins are already known to have a diverse range of functions from helping to regulate the expressions of other genes to joining forces with larger proteins including our cell membranes. However, while some microproteins perform vital biological tasks, others are plain useless.
“When you start getting into these small sizes of DNA, they’re really on the edge of what is interpretable from a genome sequence, and they’re in that zone where it’s hard to know if it is biologically meaningful,” explains Trinity College Dublin geneticist Aoife McLysaght.
One gene with a role in constructing our heart tissue emerged when an ancestor common to humans and chimps branched off from the gorilla’s ancestry. If indeed this microgene emerged in the last few million years, it’s striking evidence that these evolving parts of our DNA can quickly become essential to the body.
The researchers then probed the sequences’ functions by deleting genes, one by one, in lab-grown cells. Forty-four of the cell cultures went on to show growth defects, confirming those now missing sections of DNA play critical roles in keeping us functioning.
In other comparative analyzes, the researchers also identified in three of the new genes known variants associated with disease. The presence of these happenstance mutations at a single base position in the DNA may suggest some connection to muscular dystrophy, retinitis pigmentosa, and Alazami syndrome, but further research is going to be required to clarify these relationships.
In light of modern technology and medicine, appreciating the scale of biological change humans have experienced as a species at the hand of natural selection can be challenging. But our fitness has been shaped considerably by pressures of diet and disease over the millennia, and will undoubtedly continue to adapt even within a technologically advanced world.
Exactly how the spontaneous creation of new genes within the non-coding region happens is not yet clear, but with our newfound ability to track these genes, we may be closer to finding out.
“If we’re right in what we think we have here, there’s a lot more functionally relevant stuff hidden in the human genome,” says McLysaght.
The research has been published in Cell Reports.