Journal
VIRUS EVOLUTION
Volume 5, Issue 2, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ve/vez045
Keywords
recombinant virus; genome evolution; genomic deletion; gene expression; genome stability; gene insertion
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Funding
- European Union Horizon 2020 Marie Sklodowska-Curie Research and Innovation Programme grant ONCOGENEVOL [750180]
- VIDI grant from The Netherlands Organisation for Scientific Research [NWO 016.Vidi.171.061]
- Marie Curie Actions (MSCA) [750180] Funding Source: Marie Curie Actions (MSCA)
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Viruses are widely used as vectors for heterologous gene expression in cultured cells or natural hosts, and therefore a large number of viruses with exogenous sequences inserted into their genomes have been engineered. Many of these engineered viruses are viable and express heterologous proteins at high levels, but the inserted sequences often prove to be unstable over time and are rapidly lost, limiting heterologous protein expression. Although virologists are aware that inserted sequences can be unstable, processes leading to insert instability are rarely considered from an evolutionary perspective. Here, we review experimental work on the stability of inserted sequences over a broad range of viruses, and we present some theoretical considerations concerning insert stability. Different virus genome organizations strongly impact insert stability, and factors such as the position of insertion can have a strong effect. In addition, we argue that insert stability not only depends on the characteristics of a particular genome, but that it will also depend on the host environment and the demography of a virus population. The interplay between all factors affecting stability is complex, which makes it challenging to develop a general model to predict the stability of genomic insertions. We highlight key questions and future directions, finding that insert stability is a surprisingly complex problem and that there is need for mechanism-based, predictive models. Combining theoretical models with experimental tests for stability under varying conditions can lead to improved engineering of viral modified genomes, which is a valuable tool for understanding genome evolution as well as for biotechnological applications, such as gene therapy.
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