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Selective Impact of Transposable Elements in Drosophila melanogaster

Reference	BB/P00685X/1
Principal Investigator / Supervisor	Dr Andrea Betancourt
Co-Investigators / Co-Supervisors
Institution	University of Liverpool
Department	Institute of Integrative Biology
Funding type	Research
Value (£)	453,254
Status	Completed
Type	Research Grant
Start date	15/05/2017
End date	14/01/2021
Duration	44 months

Abstract

Understanding the forces that maintain fitness variation is a central question in evolutionary biology. Some is due to a form of balancing selection, in which alleles deleterious in some environments are preserved due to their positive effects in others. The rest is due to mutation, which recurrently introduces deleterious alleles later removed by selection. Most work quantifying the contribution of deleterious mutation comes from the study of point mutations. But work in Drosophila shows that these alone do not explain the observed fitness variation. Here, we propose to quantify the contribution of a neglected source of mutation: transposable element (TE) insertions. In Drosophila, TE insertions underlie the majority of spontaneous classical mutations. Nevertheless, there have been no systematic attempts to quantify their deleterious impact, independent of that from point mutations. We will remedy this neglect. Specifically, we will test whether TE insertions explain fitness variation in Drosophila. To do this, we will perform two experiments. In the first, we will use targeted sequencing in wild flies to cost-effectively count low frequency insertions. With these data, we will use population genetic inference to obtain maximum likelihood estimates of the transposition rate. In the second, we will take advantage of genetic tools available in Drosophila to perform a mutation accumulation experiment limited to TE insertions. We will then use targeting sequencing to locate and count the insertions, and measure fitness components in the mutation accumulation lines, obtaining an estimate of their deleterious effects. Combining data from these experiments, we will test whether the "missing fitness variation" can be explained by TEs, or if some other source, such as rare, large-effect point mutations, must be invoked. Although the work will be done in Drosophila, it has implications for understanding the maintenance of fitness variation generally.

Summary

The genetic material that contains our genes is not always copied faithfully from parent to offspring. Mistakes in this transmission-- mutations-- are important; without them, there would be no way for organisms evolve, as there would be no mechanism by which organisms could be genetically different from their ancestors. But this ability to change comes at a cost: most mutation are much more likely to damage genes than improve them. These deleterious mutations happen to all organisms, and can be disastrous for them: they can cause genetic disease in individuals, and accumulate in small populations due to inbreeding, endangering the future of some species. Deleterious mutations also contribute to the genetic load, or the degree to which populations suffer from imperfect health due to genetic causes. Genetic load impacts populations through a few individuals suffering from severe genetic disease, as well as through many individuals with less-than-perfect health. Because of its impact on the health of organisms, and conservation of endangered species, it is crucial to understand the nature of genetic load. To do this, we need to know how often deleterious mutations occur, and how severely they affect their victims. In fact, there has been a lot of attention paid to the rates and effects of deleterious mutations, often using the fly, Drosophila melanogaster, as a genetic model. Flies are convenient models for understanding mutation as their genes are already well described. Further, thousands of flies can be grown up easily, in order to inexpensively test the effects of hundreds of mutations, with few ethical concerns. But, in spite of all the attention paid to deleterious mutation, the most important source of them may have been neglected. A century of collecting mutations in flies has shown that selfish genes, or "transposable elements", cause more spontaneous mutations than the simple DNA substitutions. In spite of transposable elements numerous costs, simple substitutions have received most of the attention. Transposable elements are genomic parasites, pieces of DNA that integrate themselves into genomes in one location, and then reproduce by inserting copies of themselves in new locations, usually to the hosts detriment. In fact, TE insertions have been shown to have unpredictable effects, including possibly causing cancer and schizophrenia. Transposable elements are not rare; in fact, they comprise large fractions of the genome of most eukaryotes (e.g.,~45% of that of humans). In Drosophila, transposable element insertions are such a reliable source of deleterious mutations that they are routinely used to disrupt genes for genetic study. Here, we aim to remedy this neglect of transposable elements as a source of deleterious mutation, by performing two sets of experiments in Drosophila. In one, we will measure how often these mutations occur in natural populations, using the power of modern sequencing technology and statistical inference. In the other, we will measure how deleterious these transposable element insertions typically are. To do this, we will use genetic tools that are readily available only in flies, to induce new transposable element insertions. Then, we can measure their effects under controlled conditions, allowing us to ask how much harm they usually do. Together, these experiments will shed light on one of the most important, and most neglected, sources of deleterious mutation.

Impact Summary

Who might benefit from this research? Members of the public. While this is a basic research programme, the work addresses the underlying cause of several topics with wide impacts, such as genomic parasitism, genetic disease and public health, ageing, the preservation of endangered species, and the evolution of sex. Public health and medical workers. This proposal addresses the harmful impacts of genomic parasites, which will improve our quantitative understanding of the sources of deleterious genetic variation. In particular, the structure of this underlying variation has important implications for the search for 'disease genes' undertaken by genome wide association studies. These genes may be difficult to detect because they are due to alleles with individually small effects; in humans, active transposable elements and endogenous retroviruses are one possible source of this fitness variation. Alternatively, this work may show that a large fraction of fitness variation appears to be due to large effect mutations, with different implications for the search for disease genes. In both cases, these deleterious mutations may be poorly tagged by the SNP markers usually used to search for the basis of genetic disease. Further, this work will yield insights into the proximate mechanisms by which genomic parasites lead to deleterious mutation, for example, via gene expression. How might they benefit from this research? Members of the public will benefit from insights into 'selfish genes', one of the clearest examples of Darwinian evolution, into the evolution of sex, and into understanding why we suffer from disease and senescence. These insights will improve the engagement of the general public with science and scientific research, resulting in an enhanced quality of life. This represents an immediate outcome of the research programme, realizable within the time-frame of the proposed work. In the long-term, this research programme has the potential to impact the conservation of endangered species, by leading to insights that may affect breeding programs, increasing the cost-effectiveness of this public service. This represents long-term potential impacts of this work, not expected to be realised during the lifetime of the grant. Public health and medical workers, will benefit from insights into the nature of deleterious fitness variation, which may lead to improved methods for detecting disease alleles. Similarly, understanding of how genomic parasites result in deleterious variation can yield insights that may, in the long-term, lead to effective treatment for particular genetic diseases. In both cases, these are long-term potential impacts of this work, not expected to be realised during the lifetime of the grant.

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	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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