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Humans Have Continued to Evolve New Genes, New Study Finds

NEW YORK — Humans continue to evolve and generate new genes, a new study has found. One such gene that arose since the human and chimpanzee lineage split millions of years ago from that of gorillas is already considered essential.

New genes can arise from preexisting ones through sequence divergence but can also develop de novo. One way is through the emergence of novel open reading frames (ORFs) that code for microproteins. Using a recently published dataset of human microproteins associated with noncanonical ORFs, researchers from Greece and Ireland examined evolutionary origins of such ORFs to find 155 new genes that have arisen in the human lineage, including one that is involved in human heart tissue and others that are linked to diseases like muscular dystrophy.

"This project started back in 2017 because I was interested in novel gene evolution and figuring out how these genes originate," first author Nikolaos Vakirlis, a scientist at the Biomedical Sciences Research Center "Alexander Fleming" in Greece, said in a statement. "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."

This new work was published Tuesday in Cell Reports.

Vakirlis and colleagues drew on a recent ribosomal profiling analysis to identify ORFs that undergo translation and then estimated when in evolution they emerged.

From that dataset, they identified 715 noncanonical ORFs that they could also match to a human transcriptome atlas. By then constructing phylogenetic trees that compared these ORFs across 99 vertebrate species, the researchers found 155 ORFs with a likely de novo origin.

Some of these de novo ORFs and associated microproteins dated back to the origin of mammals, though others emerged more recently, such as among the ancestors of higher primates.

The researcher further noted that some of the microproteins generated at these ORFs appear functionally relevant, as using CRISPR-Cas9 to disrupt 44 of the ORFs led to significant fitness effects.

This suggested to the researchers that there has been ongoing de novo generation of functional microproteins since at least the beginning of the mammalian lineage and that de novo microproteins can become biologically significant and functional within a short span of evolutionary time.

The researchers additionally uncovered three pathogenic or likely pathogenic SNPs — from the dbSNP database — that fell within the boundaries of these ORFs' exons. One pathogenic SNP, for instance, was within an ORF that arose in Simiiformes and is associated with limb-girdle muscular dystrophy, while another has been linked to retinitis pigmentosa and the third to Alazami syndrome, all of which further suggested to the researchers that microproteins could have clinical significance.

Another microprotein, meanwhile, arose around the time the human-chimpanzee ancestor split from the gorilla lineage and now is expressed specifically in human heart tissue. The microprotein seems, the researchers noted, to be an example of a new ORF becoming quickly functional.

"It will be very interesting in future studies to understand what these microgenes might do and whether they might be directly involved in any kind of disease," Vakirlis said.

Senior author Aoife McLysaght from Trinity College Dublin added in a statement that, though these genes are tricky to study, she suspects that "it'll be increasingly recognized that they need to be looked at and considered."

"If we're right in what we think we have here, there's a lot more functionally relevant stuff hidden in the human genome," McLysaght said.