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Architects of genomic change: the evolutionary dynamics of transposable elements

Reference	BB/N020146/1
Principal Investigator / Supervisor	Dr Alex Hayward
Co-Investigators / Co-Supervisors
Institution	University of Exeter
Department	Biosciences
Funding type	Research
Value (£)	873,579
Status	Current
Type	Fellowships
Start date	01/03/2017
End date	04/08/2023
Duration	77 months

Abstract

Genomic data have revealed the great extent to which transposable elements (TEs) have infiltrated eukaryotic genomes. Concurrently, a major shift in perspective has occurred, from a view of TEs as mere junk or parasitic DNA to recognition of the considerable roles they have played in the evolution of host genomic complexity. However, understanding of many fundamental aspects of TE biology remains relatively poor. In particular, systematic analyses based within a robust evolutionary framework are required to elucidate on broad-scale TE evolutionary dynamics. I will capitalise on the recent accumulation of eukaryotic genomes, in combination with a novel phylogenetic approach I have developed, to examine the following four important areas of TE biology: 1 Phylogeny and evolution of LTR retrotransposons: I will address outstanding questions of key significance concerning evolution of long terminal repeat TEs that originate from the family Retroviridae, which includes highly important vertebrate viruses such as HIV, and the closely related family Metaviridae. 2 Dynamics of transposable element persistence: A major question in TE biology is how active selfish elements persist in host genomes, while having no direct selective benefit to the host. I will quantify patterns in TE proliferation and host usage to elucidate on this long-standing problem. 3 Transposable elements and the evolution of host genomic complexity: I will explore the features that predispose TEs to being harnessed for host purposes, and examine how TEs interact to contribute to host genomic complexity. 4 Role of transposable elements in speciation: The role of TEs in speciation remains relatively untested. Current developments in genomics offer an opportunity to test the broad hypothesis that gene-flow between host lineages is associated with a reduced capacity for TE repression, reinforcing host reproductive isolation and promoting speciation.

Summary

Recently there have been great breakthroughs in computing and molecular biology. In combination, these have led to a vastly improved ability to generate and analyse large volumes of genetic data. Consequently, near-complete genome sequences are now available for a large variety of organisms. This genomic revolution has revealed many fascinating insights, but one of the most unexpected relates to the abundance of transposable elements (TEs) discovered within the genome. TEs are short DNA sequences with the ability to move around in the genome via a process called transposition. Because of this property, TEs are sometimes referred to as jumping genes. Other names applied to TEs are selfish DNA, parasitic DNA, or even junk DNA, reflecting their perceived lack of contribution to host fitness. To become fixed in the hosts evolutionary lineage, TEs must invade the host germline (i.e. reproductive cells). This has been occurring over great evolutionary periods, leading to the abundance of TE sequences observable in sequenced genomes, the majority of which exist as genomic fossils that have become inactivated due to an accumulation of mutations. Recently, it has emerged that TE sequences have been repeatedly utilised by host genomes for their own purposes during evolution. Indeed, it appears that TEs have played a significant role in the evolution of host genomic complexity via various mechanisms, including direct acquisition of coding sequence, genomic rearrangement, and gene regulatory modification. Despite the widespread abundance of TEs and their important evolutionary contributions across the diversity of life, many questions concerning TE biology remain unanswered. However, the wealth in recently sequenced genomes now provides an exciting opportunity to perform novel large-scale systematic analyses of TE evolution to elucidate on poorly understood aspects of TE biology. In this proposal I will undertake such an analysis to examine the following four important aims: 1 Evolution of the LTR retrotransposons. A particularly diverse and abundant group of TEs with significant impacts on the genomes of a great diversity of organisms are the Long Terminal Repeat (LTR) retrotransposons. Until recently, it was very difficult to estimate evolutionary relationships in this group for methodological reasons, constraining advances. However, I have developed a new method to overcome this problem, offering the possibility to estimate evolutionary history and address questions of key significance in the group, which also includes highly important vertebrate viruses such as HIV. 2 Persistence of TEs in the genome. A major question is how active selfish elements persist in host genomes, while having no direct selective benefit to the host. I will quantify patterns in the proliferation of TEs and their spread across host diversity to elucidate on this long-standing problem. 3 Transposable elements and the evolution of host genomic complexity. I will explore the features that predispose TEs to being harnessed for host purposes, and examine how TEs interact to contribute to host genomic complexity. 4 Role of transposable elements in speciation. Hosts can evolve resistance mechanisms against TEs, but recently invading TEs are typically able to replicate more freely. Consequently, poor-repression of TEs is predicted to result in hybrids between two diverging lineages suffering negative fitness consequences due to increased TE activity, which consequently reinforces reduced gene flow. I will test these ideas to explore the role of TEs as promoters of speciation. Study of the LTR retrotranspsons offers an opportunity to provide insights of relevance to combat disease, since the group contains infectious viruses such as HIV. Meanwhile, given the widespread utilisation of TE sequences for diverse host purposes during evolution, greater knowledge of TE biology will provide insights of potential applied and medical benefit more widely.

Impact Summary

The proposed project will increase understanding of the biology of transposable elements (TEs). This is a topic of considerable interest to scientists and the general public, and contains substantial promise for a wide range of applications. As a result, findings from the project will contribute towards the knowledge and understanding required to move towards a bio-based economy. TEs make up a large proportion of the human genome, and are implicated in a wide range of diseases as well as in normal functioning. Consequently, the findings of this project hold great potential health relevance. In addition, further significance comes from the importance of retroviral disease, and the current vast global HIV epidemic. Research questions examining retroviral evolution, host usage, and the retroviral envelope gene may lead to new insights into retrovirus biology that could be used in new forms of treatment and drug development. Thus, research findings from this project have the capacity to enhance both health and quality of life Results from this project also have the potential to foster economic performance and contribute to the economic competitiveness of the UK. These prospective contributions come predominantly from two sectors: agriculture and biotechnology. TEs are involved with widespread phenotypic traits, a considerable number of which probably influence production traits in domesticated animals. Identifying such inserts offers great scope for improving yields and adding to competitiveness in the farming sector. Meanwhile, a range of retroviruses exert harmful effects on agricultural livestock including poultry, cattle, and sheep. Conducting research that may lead to new methods to control these diseases carries benefits for animal welfare, improving yield and economic margins, and bolstering the resilience of the farming industry. Additionally, novel research on TEs may directly contribute to the development of new tools and methods in the industrial biosciences, which are currently a global growth area. Furthermore, as set out in the pathways to impact, considerable efforts will be made to disseminate research findings among the public, thus fostering enthusiasm and understanding, and a general fluency in science and technology.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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