Phase Variation

Phase variation for higher education

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What is phase variation?

Phase variation is the switching of protein expression in bacteria from an ON to an OFF phase as a way of responding to rapidly changing environments. Phase variation is caused by reversible mutation in hyper-mutatable DNA sequences whereby mutation can switch off the expression of a gene and conversely mutation can switch it back on again.

Phase variation diagram

Phase variation has been observed in a variety of bacteria, and the University of Leicester has several active research groups studying phase variation in human pathogens. Phase variation has implications in epigenetic control of gene expression, evasion of the immune system and a variety of other processes relevant to infection.

How does phase variation occur?

Bacteria have evolved different mechanisms to vary the expression of their genes, the most common mechanism involved in phase variation is mismatch repair and this can be observed in both C. jejuni and N. meninigitidis.

The text below will explain phase variation with reference to C. jejuni but it is important to remember the same mechanism applies to many other bacteria.

A striking feature of the C. jejuni genome is the presence of a number of short, homonucleotide sequences consisting of a multiple copies (8 to 12) of the same nucleotide in a row (known as a tandem array). In almost every case these sequences have guanine (G) in the protein coding direction. There are 29 such poly-G tracts in the genome of the NCTC11168 strain (which was the first strain to be sequenced) and although this number varies between strains, at least 12 are found in every completely sequenced strain.
These tracts are hypervariable because errors can occur during duplication (see figure below). In normal copying, each base pairs up with its usual partner (G to C, C to G, A to T and T to A) and so an exact complement is formed. However, in slipped-strand mispairing the replication process goes awry and the strands briefly separate and then, when they re-anneal a "kink" can form in either the template strand or the new copy. When the kink forms in the new strand, an extra base is added, whereas when the kink forms in the original strand, one less base is added to the new strand causing a deletion.
Strand slippage mispairing

Note: direct evidence for this mechanism is not yet available but it is widely accepted as the likely mechanism for this change.

Because, in most cases, these poly-G tracts are located in the coding region of the gene, adding or removing a base can cause a frameshift mutation which typically causes the early truncation of the protein, e.g.
PV and Gene Expression
In this example (which is actually sequence from the cj0031/2 gene), deleting a base from the original 10G tract allows translation to continue and the full length, functional gene to be produced. This would be described as going from the OFF state to the ON state but the mutation can just as easily occur in the opposite direction by inserting an extra base into the 9G tract. If a base was deleted from the 9G tract that would also produce an OFF phenotype.
Although, in C. jejuni most phase variable genes work in this way it is also possible for hypervariable tracts to be located in regulator elements where changes in tract prevent binding of the relevant proteins.
Since the discovery of phase variation, mononucleotide repeats have been discovered in a myriad of bacteria.

Overview- single nucleotide insertion/deletions regularly occur in hypermutatable sequences. This can lead to frameshift mutations which results in early protein truncation. This process is reversed by insertion/deletions that shift the frame back to express functional protein.

What are the implications of phase variation?

We touched briefly above on how phase variation is often discussed in the context of immune evasion. Phase variable antigens will often stimulate an immune response in the host, producing inflammation and protective antibodies against the bacterium. If however, the phase variable gene is switched off, then surface protein will not be expressed and the bacterium will not be recognised by the immune system. As these antigens are often also crucial for the progression of infection, the ability to switch them on and off allows for cells to switch between a virulent and a 'silent' state. Take our online tutorial on phase variation in Campylobacter or Neisseria if you want to know more about how phase variation contributes to the ability of these pathogens to cause disease. In addition to evasion of the immune system, phase variation can mediate resistance to infection by phage. You can also take our online tutorial investigating the role of phase variation in phage resistance in Campylobacter through the provided link.

 

Take a look at some of our work on this topic on the 'our research' page.

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