Retrotransposable element co-option in the evolution of immune networks
File(s)
Author(s)
Plowman, Tobias William
Type
Thesis
Abstract
Retrotransposable elements (RTEs) are, or derive from, retrovirus-like genomic parasites which represent almost half of human DNA and can be exonised to provide coding material. In research they have largely been ignored as their repetitive nature creates a significant technical challenge. However, RTEs can provide a powerful source of genetic variation. Indeed, several show evidence for positive selection many millions of years after their integration, suggesting important functions. Here, we have studied the effect of RTE integrations adjacent to the IL13RA1 gene, which encodes a central receptor subunit in type 2 immunity. Two of these integrations (LOR1a and L1MD1) have led to the production of an IL13RA1 transcript with an alternative terminal exon, referred to here as IL13RA1-LOR1a. In the primate genome lineage that contains LOR1a elements, all showed evidence for retention of important motifs necessary for IL13RA1-LOR1a transcript production, and primate lines in culture were positive for expression. As a terminal exon replacement, IL13RA1-LOR1a was subject to a different profile of 3′UTR-mediated regulation, for instance it was resistant to the RNA degrading protein tristetraprolin, which is known to target IL13RA1. In addition, canonical IL13RA1 was found to be sensitive to downregulation by oestrogen, while IL13RA1-LOR1a was not. As a protein, IL-13Rα1-LOR1a’s ligand-binding and transmembrane domains were entirely intact, but its cytoplasmic signalling domain was altered, and experimentally it was signalling defective. When co-expressed, IL-13Rα1-LOR1a was dominant negative over canonical IL-13Rα1, downregulating cellular responses to type 2 immune cytokines. These data therefore suggest balancing the ratio of IL13RA1 isoforms informs overall cellular type 2 immune signalling responses. It is also another example of how RTEs can significantly contribute to evolving immune function.
Version
Open Access
Date Issued
2025-08-28
Date Awarded
01/01/2026
License URL
Advisor
Kassiotis, George
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)