Horn lab discovers a protein that makes random choices to generate cellular diversity

A team lead by WCAIR Principle Investigator Professor David Horn has identified a protein that makes random decisions to allow parasites to survive in their human hosts.

The team have been able to identify a complex that allows genes to switch on and off randomly, changing cell surface characteristics and allowing escape from the defences of the host’s immune system. This behaviour is present in genes within parasites known as trypanosomes, and also in the parasite that causes malaria, which claims hundreds of thousands of lives every year.

David Horn said that the findings had been the culmination of 25 years of work. “I started working with trypanosomes to study this area specifically,” he said. “Survival depends upon large gene families in both humans and parasites. But these genes only work effectively when just one is randomly activated in each cell. Because it was a ‘black box’ problem, there were initially no candidate genes in other systems we could look at, but by developing genetic screens we found that the active gene is sending out a negative signal to turn off the other sequence-related genes. This has been a tough project with no shortcuts, but it has been tremendously exciting for us to make this breakthrough.”

Variant surface glycoprotein (VSG) genes are able to activate what the Dundee team have termed a ‘VSG exclusion’, or VEX-complex, which allows the parasite to change its surface protein coat and escape the immune system defences of its host. The genes involved comprise the largest family in the parasite genome, numbering into the thousands. Unlike most cellular processes, which are precisely controlled, random patterns of activation are essential for these genes, though until now the proteins that allow single gene choice in these parasites have remained unknown.

The breakthrough could benefit research into how other cells make random choices to function effectively. Entire X-chromosomes are randomly inactivated in the cells of female mammals, for example. Cells that make up our immune system make distinct antibodies by activating a different gene in each cell and cells in our noses detect distinct odours by each expressing a different odour receptor. The findings could also assist in developing treatments for diseases that use this type of immune evasion strategy.

Joana Faria, a postdoctoral researcher and the first author on the paper said, “Random choices are important in biology for us and for some of our major foes. The search for the proteins and mechanisms responsible have occupied many researchers over many years and there’s still much to be done to fully understand how random gene choice works.”

The Dundee team now hopes to see an accelerated pace of discovery in this area as a result of their findings.

The work was funded by grant support from the Wellcome Trust.

The paper is published in Nature Communications DOI 10.1038/s41467-019-10823-8