Like film editors and archaeologists biochemists reconstruct the history of the genome.

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Like film editors and archaeologists biochemists reconstruct the history of the genome.

Researchers uncover new evidence for the origin of RNA splicing within human genes

Old-school Hollywood editors cut unwanted images from a film and correct them in the desired images to make a film. The human body does something similar - millions of times a second - through a biochemical editing process called RNA splicing. Rather than cutting a film, it edits the messenger RNA, which is the model for producing the many proteins found in cells.

In their exploration of the evolutionary origins and history of RNA splicing and the human genome, biochemists at UC San Diego Navtej Toor and Daniel Haack combined two-dimensional (2D) images of individual molecules to reconstruct a three-dimensional (3D) image of a portion of RNA, which scientists call Group II introns. In doing so, they discovered a large-scale molecular movement associated with RNA catalysis that proves the origin of RNA splicing and its role in the diversity of life on Earth. Their cutting-edge research is described in the latest edition of Cell.

"We are trying to understand how the human genome evolved from primitive ancestors. Each human gene has unwanted frames that are not coding and must be removed before the gene is expressed. This is the process of splicing RNA," said Toor, associate professor in the Department of Chemistry and Biochemistry, adding that 15% of human diseases are the result of defects in this process.

Toor explained that his team is working to understand the evolutionary origin of 70% of human DNA, a portion composed of two types of genetic elements, both of which would have evolved from Group II introns. More specifically, spliced introns, which represent about 25% of the human genome, are non-coding sequences that must be removed before gene expression. The remaining 45% are sequences derived from so-called retroelements. These are genetic elements that are inserted into DNA and jump around the genome to replicate via an RNA intermediary.

"The study of Group II introns gives us an insight into the evolution of a large part of the human genome," Toor noted.

In collaboration with the Group II intron RNA nanomachine, Toor and Haack, a postdoctoral researcher at UC San Diego and first author of the paper, were able to isolate Group II intronic complexes from a blue-green algae species that lives at high temperatures.

"The use of a Group II intron from a high temperature organism made it easier to determine the structure because of the innate stability of the complex of this species," explains Haack. "The evolution of this type of RNA splicing has probably led to the diversification of life on Earth."

Haack also explained that he and Toor discovered that the Group II intron and spliceosome share a common dynamic mechanism to move their catalytic components during RNA splicing.

"This is the strongest evidence to date that the spiceosome evolved from an intron of the bacterial group II," he said.

In addition, the results reveal how Group II introns are able to insert themselves into DNA through a process called retrotransposition. This copy and paste process has led to the proliferation of selfish retroelements in human DNA to form a large part of the genome.

"The replication of these retroelements has played an important role in the formation of the architecture of the modern human genome and has even been involved in the speciation of primates," Toor noted.

The researchers used electron cryomicroscopy (cryo-EM) to extract a molecular structure from the Group II intron. They froze the RNA in a thin layer of ice and then projected electrons through this sample. According to scientists, the electron microscope can magnify the image 39,000 times. The resulting 2D images of the individual molecules were then assembled to obtain a 3D view of the Group II intron.

"It's like molecular archaeology," Haack described. "Group II introns are living fossils that give us an insight into the evolution of complex life on Earth."