Health, Canada (Commonwealth Union) – New research published in Nature today provides insights into a fraction of the “dark genome,” constituting the 98% of the human genome with largely unknown biological functions. The study, conducted by an international multidisciplinary team, unveils high-resolution images and structural details of LINE-1, a genetic element implicated in diseases such as cancer, autoimmune disorders, neurodegeneration, and aging.
The paper characterizes LINE-1 as an “ancient genetic parasite” with approximately 100 potentially active copies in each individual. The activity of LINE-1 is frequently associated with various diseases. In contrast to the typical flow from DNA to RNA and then proteins, retrotransposons like LINE-1 operate in reverse, generating DNA from RNA and integrating it into the genome. The crucial enzyme facilitating this process is LINE-1 reverse transcriptase, also known as LINE-1 RT.
Matthias Götte, professor and chair of the Department of Medical Microbiology and Immunology at the University of Alberta and one of the eight co-corresponding authors, clarifies, Retrotransposons are commonly known as ‘jumping genes’ because they insert themselves into our chromosomes using a copy-and-paste mechanism. In this study, they identified the critical stages of this process, paving the way for potential strategies to inhibit the enzyme and ultimately address these diseases.
The team comprised scientists from institutions across the United States and Europe, in addition to biotechnology partners. Götte’s laboratory stood as the sole Canadian contributor to the study, which was spearheaded by investigators from Harvard Medical School and the Boston-based biotechnology company ROME Therapeutics.
“Our integrated analyses reveal the inner workings of the molecular machine that has written nearly half of the human genome,” the researchers report. “Understanding LINE-1 structure and function is important both in evolution and, increasingly, in human disease.”
The Götte laboratory played a crucial role in generating much of the biochemical data presented in the paper. Explaining their contribution, Götte indicated that they expressed and purified LINE-1 RT in the lab and conducted biochemical experiments to elucidate the process by which it synthesizes new DNA from RNA and reintegrates it into the genome.”
As an expert in polymerases and reverse transcriptases (RTs) – the replication engines of viruses like HIV and HCV – Götte has shifted his focus to viruses with high epidemic potential, including Ebola, Lassa, and SARS-CoV-2.
Götte added that they observed both similarities and differences between LINE-1 RT and HIV-1 RT, permitting to develop drugs that are more tailored to the specific characteristics of the LINE-1 enzyme.
“It was a large team effort with world-class structural biologists, and that’s why the science is absolutely fantastic,” he said. “Effective treatments for important human diseases can only be developed with a very strong scientific foundation.”
Earlier, Götte collaborated with a comparable scientific team to publish research on the human endogenous retrovirus-K RT enzyme, another enzyme implicated in disease.
Götte acknowledges the significant contributions of his research associate, Egor Tchesnokov, who dedicated four years to conducting experiments for this paper pointing out that he possesses exceptional skills, and he is truly grateful to have his presence in the lab.
The research undertaken by Götte on this project was funded by ROME Therapeutics. Additionally, he holds equity in the company and has received consulting fees from ROME Therapeutics.
The unveiling of LINE-1’s high-resolution images and structural details marks a significant leap forward in deciphering the complexities of the dark genome. This research not only deepens our understanding of LINE-1 but also opens new doors for potential therapeutic interventions in diseases linked to this intriguing genetic element. As scientists continue to explore the vast landscapes of the dark genome, LINE-1 remains a focal point, promising discoveries that could reshape the landscape of genetic medicine.
