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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ROBUSTNET (Quantitative developmental genetic analysis of phenotypic buffering and cryptic variation)

Teaser

Summary

â€¢ What is the problem/issue being addressed?

We are studying the genetic mechanisms of biological robustness, aiming at deriving broad principles about how animals operate consistently. Biological robustness is a poorly studied phenomenon that has recently attracted a lot of attention both from an experimental and theoretical point of view. We often forget how complicated biological systems are, how many perturbations they constantly face and how much stochasticity there is when looking at the underlying molecular processes. It is therefore rather remarkable that biological systems can operate often with extreme consistency. One such example is development in the simple model nematode Caenorhabditis elegans, which is very stereotypical so that the zygote always produces the same number of 959 cells in a reproducible manner with minimal animal-to-animal variation. The majority of previous studies have been performed in unicellular organisms. We are using a comprehensive system-wide approach using a tractable multi-cellular model organism to break down development robustness of cell numbers and dissect its mechanisms.

â€¢ Why is it important for society?

Although system robustness in non-biology fields such as engineering (e.g. robustness of buildings, bridges, aeroplanes or the internet) is man-made, biological robustness arises from selection or as a by-product of evolution and the underlying mechanisms are very little understood. It is currently unclear whether broad principles can be derived that are important for any type of robustness and whether knowledge from one field can guide thinking or future work in another field (e.g. biologically-inspired engineering). Understanding the basis of biological robustness is a fundamental problem that is relevant to biomedical sciences as a lot of diseases can also be studied within the context of defective homeostasis. New approaches in building synthetic biological networks can be influenced by reaching an understanding on principles of biological robustness.

â€¢ What are the overall objectives?

Our first main objective is to identify a wide-spectrum of genetic determinants of phenotypic robustness and characterise the mechanisms of biological buffering.
Another main objective is to understand how differences in the genetic background within divergent nematode populations affect developmental system traits including their robustness to perturbations.

Work performed

Examples of the work we have performed so far include:

- Extensive genetic screens where we treat nematodes with mutagens and isolate nematode strains showing extensive phenotypic variability.
- Mapping of putative DNA mutations in these strains by whole genome sequencing technologies.
- Experimental validation to establish causality of these mutations for the variable phenotype.
- Phenotypic characterisation of mutant strains using microscopy, imaging and genetics to identify the nature and mechanisms of phenotypic variability.
- Work to introduce mutations we identify (for example using genome editing) in genetically polymorphic C. elegans isolates and find how the background modifies the outcome of these mutations.
- Gene dosage perturbations to study robustness to levels of gene expression.

Final results

This is still an early stage of the project but we now hold a big collection of mutants showing phenotypic variability instead of producing a consistent phenotype as normal. Variable phenotypes are in general more difficult to isolate and study but with the advent of recently available techniques for sequencing and imaging we are hoping to make rapid progress. The characterisation of these mutants in the future is likely to generate impact within our field with potential wider implications as highlighted above.