Endogenous retroviruses are remnants of ancient viral infections that have integrated into the germline DNA of their hosts, becoming a permanent part of the host genome. These viral sequences, once capable of replication, now reside within the human genome, representing a significant portion of our DNA and serving as a fossil record of past viral encounters.
Their persistence and accumulation over millions of years have contributed to the shaping of our genome and have played a critical role in evolution.
But how have endogenous retroviruses shaped the course of genomic evolution, and what are their continuing impacts on human biology, both in health and disease?
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What Are Endogenous Retroviruses?
Endogenous retroviruses originate from ancestral retroviral infections where viral RNA was reverse-transcribed into DNA and integrated into the host's germline DNA, thus becoming a heritable part of the genome.
They can be classified as transposable elements due to their capacity to integrate into diverse genomic loci, mirroring the mobility of other transposable elements.
Thus, similar to other transposable elements, which were once considered solely parasitic but are now recognized for their contributions to host genome evolution and gene function1, endogenous retroviruses warrant analogous consideration. However, endogenous retroviruses are distinct in their origin from ancient retroviral infections that became fixed within the host germline.
Structurally, endogenous retroviruses typically consist of long terminal repeats -like those observed in retrotransposons- flanking internal coding regions that may include classical viral genes such as gag, pol, and env. However, many have accumulated mutations, rendering them non-functional.
Their replication mechanisms, when functional, mirror those of exogenous retroviruses, involving reverse transcription and integration.
These endogenous viral sequences are classified based on sequence homology and structural features, with distinct families showing varying degrees of activity and conservation.
Their distribution is widespread across diverse species, with significant variations in copy number and sequence divergence, reflecting the long history of retroviral infections in evolution.
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The Role of Endogenous Retroviruses in Genomic Evolution
Endogenous retroviruses have profoundly shaped genome structure and function by contributing substantial amounts of DNA and providing versatile genetic elements. They have facilitated genetic innovation by serving as sources of regulatory elements, such as promoters and enhancers, which can alter host gene expression patterns.
Within the human genome, retroviruses played a crucial role in shaping the evolution of innate immunity by acting as independently evolved enhancers for immune genes2.
Endogenous retroviruses-derived sequences have also been co-opted for various cellular functions, including the evolution of novel gene regulatory networks. For instance, endogenous retrovirus long terminal repeats exert tissue-specific regulation of adjacent genes, affecting gene expression in specific tissue types3.
Endogenous Retroviruses in Health and Disease
Endogenous retroviruses possess a complex relationship with the immune system, potentially modulating it through the expression of viral proteins or RNA, and paradoxically, they may contribute to defense against new viral infections by triggering antiviral responses.
However, their aberrant activation has been linked to various diseases, including neurological and autoimmune diseases and cancer4.
For instance, it has been shown that overexpression of Fra-2, a transcription factor that regulates cell growth and differentiation, activates human endogenous retrovirus expression, potentially contributing to the development and chemoresistance of adult T-cell leukemia and lymphoma5.
Current research is exploring endogenous retroviruses as potential therapeutic targets, focusing on strategies to modulate their activity, such as epigenetic drugs that silence their endogenous expression patterns.
The inhibitor of growth family member 3 (ING3), for example, plays a crucial role in the epigenetic silencing of endogenous retroviruses and innate immune regulation in somatic cells, preventing autoimmune responses6.
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Challenges and Future Directions
Studying endogenous retrovirus activity and function presents significant technical challenges due to their repetitive nature, sequence divergence, and complex regulatory landscape.
Advances in genomic sequencing technologies coupled with sophisticated bioinformatics tools for repetitive sequence analysis are enabling deeper insights into retrovirus biology. These advancements are revealing the intricate roles of endogenous retroviruses in gene regulation and cellular processes, opening up potential applications in medicine.
Within the human genome, retroviruses play a role in solid organ malignancy and present important biomarkers or immunologic targets in multiple cancers, highlighting their importance in understanding their transcriptomics and disease treatment strategies7.
Conclusion
Endogenous retroviruses impacted genomic evolution and human health, acting as potent evolutionary catalysts. They have shaped genome structure, influenced gene regulation, and contributed to immune system modulation while also being implicated in various diseases.
This dual nature underscores their complex role, highlighting their capacity to both drive pathological processes and provide raw material for evolutionary innovation. Ultimately, the functional impact of genetic sequences, including those derived from viruses, is context-dependent; thereby a driver of evolutionary adaptation in one environment may prove detrimental in another.
Therefore, further research is crucial to fully understand the intricate functions of endogenous retroviruses, helping to obtain novel insights into human biology and the development of innovative therapeutic strategies that can harness or mitigate their effects.
References
- Vaschetto, L., & Ortiz, N. (2019). The Role of Sequence Duplication in Transcriptional Regulation and Genome Evolution. Current Genomics, 20, 405 - 408. https://doi.org/10.2174/1389202920666190320140721.
- Chuong, E., Elde, N., & Feschotte, C. (2016). Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science, 351, 1083 - 1087. https://doi.org/10.1126/science.aad5497.
- Pavličev, M., Hiratsuka, K., Swaggart, K., Dunn, C., & Muglia, L. (2015). Detecting Endogenous Retrovirus-Driven Tissue-Specific Gene Transcription. Genome Biology and Evolution, 7, 1082 - 1097. https://doi.org/10.1093/gbe/evv049.
- Salavatiha, Z., Soleimani-Jelodar, R., & Jalilvand, S. (2020). The role of endogenous retroviruses‐K in human cancer. Reviews in Medical Virology, 30. https://doi.org/10.1002/rmv.2142.
- Tram, J., Marty, L., Mourouvin, C., Abrantes, M., Jaafari, I., Césaire, R., Hélias, P., Barbeau, B., Mesnard, J., Baccini, V., Chaloin, L., & Peloponese, J. (2024). The Oncoprotein Fra-2 Drives the Activation of Human Endogenous Retrovirus Env Expression in Adult T-Cell Leukemia/Lymphoma (ATLL) Patients. Cells, 13. https://doi.org/10.3390/cells13181517.
- Song, Y., Hou, G., Diep, J., Ooi, Y., Akopyants, N., Beverley, S., Carette, J., Greenberg, H., & Ding, S. (2021). Inhibitor of growth protein 3 epigenetically silences endogenous retroviral elements and prevents innate immune activation. Nucleic Acids Research, 49, 12706 - 12715. https://doi.org/10.1093/nar/gkab1070.
- Grabski, D., Hu, Y., Sharma, M., & Rasmussen, S. (2019). Close to the Bedside: A Systematic Review of Endogenous Retroviruses and Their Impact in Oncology. The Journal of surgical research, 240, 145-155. https://doi.org/10.1016/j.jss.2019.02.009.
Further Reading