Evolution of novel function through retrotransposable element exaptation

About the project

About the Project A 2027 Crick PhD project with George Kassiotis. Project background and description A major force in the evolution of new molecular and cellular functions is the genetic diversity provided by transposable elements (TEs) [1]. Highly abundant in the genome, TEs can be co-opted in new functions that increase host fitness. There are ~4 million individual TE integrations in the human genome, amounting to nearly half of our DNA. The vast majority are fragments of retrotransposable elements (RTEs), including endogenous retroviruses (HERVs), and long and short interspersed nuclear elements (LINEs and SINEs, respectively) [2]. RTE integrations are well annotated at the genome level. However, much less understood is their participation at the more complex transcriptome level. Despite the enormous potential of RTEs to provide alternative promoters, exons, splicing and polyadenylation sites and even intact open reading frames (ORFs) [2], their transcription patterns have remained largely unexplored owing to their repetitive nature. We have previously completed a de novo transcriptome assembly [3], avoiding the bias against repetitive regions of the genome in prior efforts. This assembly doubled the known transcriptome, with substantially increased representation of novel RTE transcripts, and demonstrated much higher transcriptional utilisation of all RTE families than previously appreciated. It also provided the framework for functional studies of RTE utilisation, allowing a higher-resolution definition of disease states and identification of novel cancer-specific antigens and viral mimicry ligands [3, 2]. The focus of this study is the impact of RTEs on the function of genes near or within which they have integrated. Notable recent examples include our discovery of a novel isoform of the common subunit of the heterodimeric type 2 receptor for IL-4 and IL-13, two cytokines pivotal in Th2 adaptive immune responses to invading parasites and allergens. An alternative isoform of the IL-13R?1 chain, encoded by IL13RA1, is created by a primate-specific LOR1A retroelement integration, which creates a decoy receptor for these two cytokines, fine-tuning type 2 immunity [4]. RTE-created alternative isoforms become considerably more prevalent in cancer, due to the altered epigenetic landscape leading to RTE derepression. There, cancer-specific transcriptional activation of RTEs causes frequent reduction or loss of gene function. Contrary to theoretical expectation, transcriptionally activated RTEs affect genes with established tumour-promoting functions, including the common essential RNGTT and the lung cancer-promoting CHRNA5 genes [5]. While these prior findings underscore the gene-disruptive potential of seemingly innocuous germline RTE integrations, unleashed only by their transcriptional utilisation in cancer, they further raise the hypothesis that such metastable RTE integrations are co-opted as sensors of the epigenetic and transcriptional changes occurring during cellular transformation and as executors that disrupt the function of tumour-promoting genes. Testing this hypothesis will be central premise of this project. Many of the RTEs involved in shaping gene function are specific to humans or higher primates, which necessitates their study primarily in human cells ex vivo and in vitro. However, given the complex interaction of the extensive network of cells that participate in cancer evolution or immune reactions, the study may additionally require bespoke genetically-modified in vivo mouse models. Candidate background This project would suit candidates with a background in cell biology, cancer or immunology, and an interest in genetics/genomics and computational approaches. Lab-specific question Which of the most important unanswered questions relating to the biology of transposable elements, particularly in the context of exaptation, would you investigate and how?

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