Simulating Hypervariable Genome Sequences

Introduction to the phase variation and microbial simulator

This virtual lesson requires Java. Please ensure that you have the Java runtime environment installed and enabled on your computer.

Java is available from Oracle's website.

Introduction

These pages will teach you about phase variation in the human pathogen Campylobacter jejuni. The core of the learning experience is based around a computer program giving you a visual simulation of how phase variation works.
All reading and exercises should be completable in under an hour.

What is Campylobacter jejuni ?

Campylobacter jejuni and the closely related species Campylobacter coli are the main bacterial species responsible for incidents of food poisoning in the UK, and the rest of the developed world. C. jejuni is so widely implicated in food poisoning - usually resulting in gastroenteritis - because it has formed a mutually harmless relationship with chickens and other birds. It is found living in the guts of the majority of chickens reared for food and is easily transferred onto meat sold for food. As a result most fresh meat from factory farmed chicken, free range or organic chickens contains C. jejuni (a survey in 2007/2008 showed that Campylobacter was present on 65% of fresh chicken samples). Although it is easily killed by proper cooking, poor hygiene in the kitchen can easily transfer the bacteria from raw chicken onto plates, cutlery or uncooked ingredients. This is why it is important to wash your hands after handling raw chicken and to never use the same chopping board for meat and vegetables.

Campy

Scanning electron microscope image of C. jejuni
This false colour image shows the characteristic corkscrew shape of C. jejuni and the flagella (coloured in brown on this image) extending from both ends of each bacterium. (Photo by De Wood; digital colourization by Chris Pooley. Image taken from the Agricultural Research Service).

While gasteroenteritis is unpleasant in its own right what makes food poisoning by C. jejuni particularly worrisome is that in a small number of cases patients go on to develop a condition called Guillain–Barré syndrome (GBS). Although the actual rate of this occurrence is low (fewer than 1 in 5000 campylobacterosis patients develop GBS) because hundreds of thousands of people are affected each year this translates to a significant number of cases. GBS typically occurs two to three weeks after the initial illness and is marked by flaccid paralysis - that is the patient loses the ability to control their body and their muscles become completely relaxed. The initial symptoms are weakness or tingling sensations in the legs which can spread to the arms and upper body and in severe cases to the whole body. Providing the patient can be taken to hospital where they can be maintained by artificial respiration most recover completely over the following months although lasting disability occurs in 20% of cases, with severe disability occurring in 5-10% of cases. The disease is fatal in 2-3% of patients even with complete access to modern medicine.

Campylobacter jejuni...
• is found in almost all poultry
• is the leading cause of food poisoning in the developed world
• in a small number of cases C. jejuni infection leads to Guillain-Barré syndrome - a flaccid, full-body paralysis

 

What is Phase Variation?

The genomes of some bacteria contain hypervariable regions where mutations occur much more commonly than elsewhere in the genome. In some cases these mutations are reversible with high probability meaning that later mutations can reverse the effect of the original mutation. This is called Phase Variation. In C. jejuni most genes affected by phase variation switch between a functional (ON) and non-functional (OFF) state. In the NCTC11168 strain of C. jejuni commonly used in research there are 29 of these phase variable genes and each undergoes phase variation independently.

Phase variation diagram

Diagramatic illustration of phase variation
Phase variation causes genes to alternate between an ON and an OFF state. These changes are caused by physical alterations to the DNA sequence and can go in either direction.

 

Exact measurements of the rate of switching of phase variable genes are extremely hard to obtain and differ between the different phase variable genes in a single species. Roughly speaking however, phase variable genes in C. jejuni will, on average, switch state about every one hundred to one thousand cell divisions. This is a mutation rate between a thousand and a hundred thousand times faster than is normal for the rest of the genome.

This has been a very brief overview of Phase Variation, to learn more about it, follow this link: More on phase variation (optional)

• Some C. jejuni genes are phase variable
• Phase variable genes are hypermutable
• Mutations in phase variable genes switch genes on or off
• These mutations are reversible


Next page: About the simulator

 

This lesson is intended for you to work through in order, but you can jump directly to any page from here:

Teaching aims and prequisites

Simulating hypervariable genome sequences (this page)

More on phase variation (optional)

About the simulator

Simulator exercises

Epilogue

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