Exploring the Role of Endogenous Retroviruses

The results of a research report recently published in Science offer new insights into the molecular mechanisms governing at least one aspect of genetic innovation in the mammalian immune system. More specifically, this research demonstrates a link between our endogenous retroviruses (ERVs) and the evolution of a transcriptional network that regulates various components of the immune response.

The study was presented by Edward B. Chuong, PhD, a postdoctoral fellow working in the Department of Human Genetics at the University of Utah School of Medicine in Salt Lake City, Utah. While it is known that changes in gene regulatory networks are the underlying cause for a host of biological adaptations, Dr. Chuong et al were interested in a deeper exploration of the potential mechanisms responsible for these changes.

It has been suggested that the unknown mechanisms facilitating the evolution of regulatory networks may involve transposable elements (TEs), including ERVs, as they have been shown not only to contain regulatory elements, but also to amplify in number, move throughout the genome, or both. In an explanation of the need for research to clarify the role of TEs, especially ERVs, in the mechanisms supporting changes in gene regulatory networks, Dr. Chuong and colleagues stated that, "These observations implicate TEs as a potential source of lineage-specific cis-elements capable of rewiring regulatory networks, but the adaptive consequences of this process for specific physiological functions remain largely unexplored."

To study the role of ERVs in the evolution of gene regulatory networks, a network must first be selected. For this study, Dr. Chuong and colleagues selected the network induced by the proinflammatory cytokine interferon-γ (IFNG), an important regulator involved in the innate immune response. The rationale for this decision was described by Dr. Chuong as follows: "Although innate immune signaling pathways are conserved among mammals, the transcriptional outputs of these pathways differ across species, likely reflecting lineage-specific adaptation in response to independent host-pathogen conflicts. Thus, these pathways provide useful systems that allow us to investigate whether TE-derived regulatory elements influence biological outcomes."

Using a variety of cellular and molecular techniques, Dr. Chuong and colleagues ran several separate experiments. These experiments proceeded in an order which built a strong case for the profound role of ERVs in the evolution of the selected gene regulatory network. More specifically, experimental findings revealed dispersion of IFNG-inducible regulatory elements by ERVs, the presence of a MER41 element essential for AIM2 inflammasome activation, the co-option of multiple MER41 elements to regulate the IFNG response, and the pervasive nature of IFNG-inducible ERVs in mammalian genomes including Anthropoidea, Lemuriformes, Rodentia, Vespertilionidae, Pteropus, Carnivora, Perissodactyla, Artiodactyla, and Afrotheria.

Collectively, this suite of results reveals IFN-inducible enhancers introduced and amplified by ERVs in many mammalian genomes. Throughout mammalian evolution, some of these elements have been co-opted to regulate host genes encoding immunity factors. In addressing the larger implications of their findings, Chuong et al state, "We speculate that the prevalence of IFN-inducible enhancers in the LTRs [long terminal repeats] of these ancient retroviruses is not coincidental, but may reflect former viral adaptations to exploit immune signaling pathways promoting viral transcription and replication.” They conclude with, "Regardless of how these sequences originated, our study illuminates how selfish genetic elements have contributed raw material that has been repurposed for cellular innovation."

In addition to providing evidence for the role of ERVs in genetic innovation, these study results and the experimental procedures used to identify them are particularly exciting because they will surely serve as a roadmap for future research on the role of ERVs in the evolution of additional gene regulatory networks in mammals, as well as in phylogenetic classes other than Mammalia.

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.