Climate-Resilient Crops · Data Tutorial

Mechanistic Modelling of a Gene Regulatory Network

By the end of this practical you will be able to:

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0 What is a mechanistic model, and why bother?

In the earlier practicals you used data-driven methods: clustering and genomic selection look at a pile of measurements and let patterns emerge, without any built-in idea of why genes behave as they do. A mechanistic model works the other way around. You start from biological knowledge that already exists, such as "gene A switches gene B on" or "hormone X represses gene C", and you write those cause-and-effect rules down as equations. The computer then simulates what happens over time when you turn a knob.

Think of it as a flight simulator for a cell. Nobody is guessing from data whether the plane will stall; the simulator encodes the physics and lets you try things. That is exactly why this approach is useful:

Keep in mind that a model is only as good as the rules and numbers you put in. It is a deliberate simplification of a far messier reality: useful for reasoning and prediction, but never a substitute for real experiments.

1 The network we will play with

We will use a mechanistic model inspired by this paper (also discussed in the Plant Science lecture). It models how tobacco responds to drought stress, and how that response changes the plant's ability to defend itself against a biotic attacker (white flies). Building models like this normally takes years of experiments and prior knowledge; here that work is already baked in, so you can just explore.

The diagram below is the gene regulatory network. Drought is an external input that feeds into the hormone ABA. From there the signal travels through the network. Green solid arrows mean one gene activates another; red dashed arrows mean one gene represses another. Drag the nodes around to untangle it.

activates represses

Hover a gene for its name. The chain ICS1 → SA → BGL2 is the plant's salicylic-acid defence pathway.

❓ Questions
  • Have a look at the paper. Which gene(s) are important for drought resistance, and which for white-fly resistance?
  • Follow the arrows: how do you think the network will respond when there is no drought stress at all?

2 A plant at rest: no drought

Let's simulate the network when nothing is stressing the plant. Each line is the expression level of one gene over time. Watch especially the defence readout BGL2 (drawn thick).

Gene expression over time with drought = 0 the whole way through.

❓ Questions
  • In this case, does the plant have white-fly resistance? Why does it, or why doesn't it?
  • What do you think will happen when we give the plant a brief pulse of drought stress?

3 A brief drought pulse

Now we switch drought on for a single short moment (from time 10 to 11) and then off again. The grey band marks when it is on. Run it and compare with the resting plant above.

The grey band is the drought pulse. Notice which genes react, and which barely move.

❓ Questions
  • Can you explain this behaviour, using what you know about gene regulation and the network diagram?
  • Why would it make sense for a plant to have such a mechanism?
  • What do you expect will happen to white-fly resistance if we make the drought pulse longer? Try it in the next step.

4 Make the drought last longer

Here you control the drought yourself. Slide the start and end of the drought pulse and the simulation re-runs live. Try a long drought and keep your eye on BGL2.

The grey band is the drought. Widen it and watch the defence pathway.

❓ Questions
  • Can you explain why the response is different when the drought lasts longer? Why would this make biological sense?
  • Does this model reflect the true underlying biology? In what ways does it, and in what ways doesn't it?
  • Which gene(s) do you think you could knock out to change the response? Test your idea in the next step.

5 Knock out genes and redesign the response

A knockout silences a gene: its expression decays to zero and it can no longer pass its signal on. Tick a gene to knock it out and the simulation re-runs. A drought pulse (10 → 30) is applied so you can see the effect on defence.

Knocked-out genes are greyed out in the legend. Drought is on from 10 to 30.

❓ Questions
  • Which combination(s) of knocked-out genes give the plant the "best" phenotype according to this model, keeping its defence even under a long drought?
  • Would doing this be realistic biologically? What could go wrong that this model doesn't capture? Before you answer, look up what else the hormone ABA does in a plant.
  • What experiment would you propose next to test the model's prediction, and how would you explain your finding to a plant biologist?

If you have time left, open this link and click Genome Editor to build your own gene regulatory network and try to grow the prettiest possible plant. While you do, notice how such "simple" networks can produce strikingly complex, emergent behaviour.

✓ Check your understanding