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Unravelling the role of copy number variation in host-microbe interactions

Principal Supervisor: Dr Ed Smith

Secondary Supervisor(s): Dr Antonia Sagona

University of Registration: University of Warwick

BBSRC Research Themes: Understanding the Rules of Life (Immunology, Microbiology)

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Deadline: 4 January, 2024


Project Outline

The microbiome is a fundamental mediator of organismal health and has been shown to play essential roles in biological processes ranging from metabolic activity to disease resistance. Although research has shown that the environment plays a strong role in modulating the microbiome, there is also compelling evidence that the host regulates the microbiome. The host’s immune system must simultaneously work to maintain stable associations with beneficial microbes while also mediating susceptibility to invading pathogens. To date, research has highlighted a correlation between host immune gene expression and microbial composition, but the genomic basis for these correlations is poorly understood. However, a more thorough understanding of how host genotype mediates the microbiome will offer exciting new opportunities to further personalised approaches to probiotics and microbiome-based therapeutics.

One mechanism by which the host may regulate microbial composition is through copy number variation (CNV). CNV arises from the duplication of genomic material and genes subject to CNV tend to be enriched in immune functions. These differences in immune gene copy number can result in differential gene expression (i.e., dosage effects). Nevertheless, the effects of CNV-driven changes in immune gene expression on the microbiome are poorly understood as past analyses of CNV across the genome have been hindered by limitations associated with short-read sequencing technologies. Recently, we have taken advantage of long-read sequencing to identify substantial differences in immune gene copy number among genotypes of the sea anemone Nematostella vectensis. This finding presents a unique opportunity to study the effects of CNV in an emerging model system with established state-of-the-art experimental and genomic tools. In this project, you will combine experimental and genomic approaches in the N. vectensis model to investigate how immune gene CNV shapes the microbiome.

Aims

  1. Characterise immune gene family expansions across genotypes.
  2. Quantify the effect of genomic copy number on immune gene expression.
  3. Using experimental crosses, identify the relationship between immune gene copy number and microbiome composition.

Methods

In this project, you will combine molecular, experimental, and ‘omics’-based approaches to investigate the role of CNVs in host-microbe interactions. In particular, you will develop bioinformatics skills and have the chance to analyse genomic, transcriptomic, and microbial community datasets. Furthermore, you will be able to take advantage of existing cutting-edge protocols for studying host-microbe interactions in N. vectensis including microbiome transplantation assays.

Further Reading

  1. Baldassarre, L., Reitzel, A.M. and Fraune, S., 2023. Genotype–environment interactions determine microbiota plasticity in the sea anemone Nematostella vectensis. PLoS Biology, 21(1), p.e3001726.
  2. Smith, E.G., Surm, J.M., Macrander, J., Simhi, A., Amir, G., Sachkova, M.Y., Lewandowska, M., Reitzel, A.M. and Moran, Y., 2023. Micro and macroevolution of sea anemone venom phenotype. Nature Communications, 14(1), p.249.
  3. Zhang, F., Gu, W., Hurles, M.E. and Lupski, J.R., 2009. Copy number variation in human health, disease, and evolution. Annual review of genomics and human genetics, 10, pp.451-481.

Techniques

  • Comparative genomics
  • Transcriptomics
  • Microbial community analyses
  • Molecular biology