Adaptation of a retroviral family to its host

We only turn the light on in the rooms we use when we are awake. Similarly, the genes in our genome are only expressed when needed in a given cell in the body. Each gene also harbours regulatory regions in the genome. Those regulatory regions are akin to light switches in a room, waiting to be engaged. All cells express their cell type specific transcriptional regulatory proteins which bind to the genomic switch regions and modulate gene expression, similar to the finger that flicks a light- switch ON or OFF. Retroviruses, like the Human Immunodeficiency Virus (HIV), lack their own transcriptional regulators. Instead, retroviruses adapted their own, very short regulatory or switch sequence to abuse its hosts cellular transcriptional regulators. This allows retroviral expression specifically in those cells the viruses indeed infect. Today, we understand little how retroviral switch regions adapted during evolution. Retroviruses are prevalent in the genome of fruit flies. These fly retroviruses emerged when a noninfective transposable element, related to retroviruses, stole the sequence encoding an envelope protein from another virus. Like this, it acquired the means to infect another cell. Our previous data shows that this novel retrovirus effectively spread and diversified into at least 27 highly related, retroviral and retroviral-like species. In specific conditions, ten different fly retrovirus species (encoding an envelope) are expressed in at least eight distinct subsets of ovarian somatic support cells. From there, they infect the developing germline. In contrast, several other retroviruses during evolution have independently lost their envelope, and hence also their infectivity. These derived retrovirus-like elements have concurrently adapted their expression to the germline tissue in the fly ovary where they replicate intracellularly. Like HIV, fly retroviruses highjack their hosts transcriptional regulators for their own expression. The size of this retroviral family and their diversification of expression patterns - via adapting their short switch regions - provides a unique and profound model system to study the evolution and function of viral switch regions. With the evolutionary pedigree of the retroviruses as a context, we seek to identify the essential switch regions in the viral DNA, to uncover which transcriptional host regulatory proteins are essential for viral expression and whether viral DNA and host regulatory proteins indeed interact directly in living fly ovarian cells. Our work will highlight how a viral family tapped into its hosts transcriptional regulation. Deciphering the combinatorial logic of the viral switch regions will provide fundamental insights into retroviral evolution and may be instrumental to understand the much larger regulatory regions controlling the host gene expression.

The genome of most organisms consists not only of the sequences necessary for the execution of all organismal functions, but unintentionally also harbors genomic parasites known as transposable elements (TEs). In the evolution of many organisms, including humans, TE diversity has contributed to genetic innovations of their hosts. We showed how TE diversity itself arose from an evolutionary conflict and its race of innovations. TEs replicate by generating new insertions of themselves in the germline genome, compromising its integrity. To counteract this, host organisms have developed defense mechanisms that suppress the expression of TEs. These mutually antagonistic goals triggered an evolutionary conflict between hosts and TEs, forcing both sides to constantly innovate in order to survive. Nevertheless, it was largely unknown how evolutionary innovations diversified both TEs and the host defenses against them. We chose the genetic model organism of the fruit fly to study this conflict. Flies have a well-understood defense system against transposable elements, conserved among animals, which can be experimentally disrupted. In addition, their genome harbors a wide variety of TEs, including long terminal repeat (LTR) retroelements and endogenous LTR retroviruses, which are structurally related to pathogenic retroviruses such as the human immunodeficiency virus (HIV). To unravel this evolutionary conflict, we analyzed the sequences of different TE lineages, their phylogenetic relationships, their expression in flies with and without functional defense systems, and the host's own defense mechanisms. This complex correlation revealed how different LTR retroelements and infectious LTR retroviruses are expressed and how the host's defense has adapted in response to this over the course of evolution. We uncovered several retroviral evolutionary adaptations of LTR elements, how they function mechanistically, and how they have enabled the diversification of TEs and the defense mechanisms of the fruit fly. Two LTR retroelement lineages evolved separately into LTR retroviruses by acquiring two different foreign sequences that enabled them to move from cell to cell using viral-like infection mechanisms. At the same time, they also tailored their own transcriptional regulatory sequences to be expressed in different tissues. Later in evolution, some retrovirus-like elements lost their infectivity modules again and also reset their transcriptional regulatory switches, strongly suggesting that these two traits co-evolve in a coordinated manner. Furthermore, the host's defense systems adapted cell-type-specific innovations to suppress these new threats. In the future, we will seek to understand how the transcriptional regulatory switches of TEs function in detail and how TEs replicate in their adapted niches. Our work highlights the flexibility of repeated coevolutionary innovations that drive the race between TEs and host control. It reveals the mechanistic basis of these molecular changes and how each TE is highly adapted to replication in a specific cellular environment in the germline.