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We tend to think of our genomes (or any genome in fact) as immutable stores of vital information, that are cherished, protected and passed on to our children. Of course, we know that some cells change their genomes; B cells provide a striking example of this as they undergo carefully orchestrated genetic rearrangements and rapid focused mutation to achieve antibody diversity and optimisation. However, this behaviour is seen as exceptional, and in animal cells it probably is.

Microorganisms are subject to different pressures and seem much more enthusiastic about risking their genome integrity for adaptive advantage. We have a long running interest in the mechanisms that fungi use to adapt their genomes to the environment – understanding this is incredibly important as not all fungi are as friendly to us as Baker’s yeast… human pathogens like Candida albicans kill more than a million people every year, while plant pathogens like Zymoseptoria tritici destroy more than 10% of food crops worldwide.

We originally discovered how yeast control their ribosomal DNA copy number in response to sugar availability to ensure maximal ribosome synthesis. We don’t tend to think about ribosomes very much but proliferating cells need to make vast numbers of ribosomes, and having many copies of the DNA encoding ribosomal RNAs is a universal strategy to ensure sufficient ribosome synthesis.

 Jack et al

These environmentally-induced copy number variation events are not unique to the ribosomal DNA, and we similarly found that cells actively change the genomic copy number of a gene involved in copper resistance when they detect copper in the environment to make sure that at least some cells have sufficient genomic copies to survive.

 Hull et al

We have looked very carefully at the mechanism allowing cells to change their genomes – we find that transcriptional induction of copper resistance genes leads connects the gene to the nuclear pore creating a partial barrier to replication fork passage. This dramatically accelerates the rate of copy number variation at the locus, forming a wide range of cells with different copy numbers of the copper resistance gene from which cells with higher resistance are then selected.

Whale et al

More recently, we have become interested in extrachromosomal circular DNA (eccDNA or ecDNA). These are circular DNAs carrying copies of chromosomal DNA that can be inherited in a non-Mendelian fashion and rapidly change in copy number, and have been shown to be hugely importance in the acquisition of drug resistance in cancer cells. These eccDNA species are also very abundant and very heterogeneous in fungi, and we have proposed that yeast actively control the behaviour of eccDNA to acquire massive genetic diversity and achieve rapid but transient acquisition of drug resistance phenotypes.

 Hull et al

We have just been awarded funding from the Wellcome Trust to study how eccDNA are used by fungal pathogens to adapt to challenging environments. We think that eccDNAs are a major contributor to the incredible resilience of fungal pathogens against both host immune attacks and anti-fungal drug treatments.

However, this does not result in classic evolution as the adaptive genetic changes are discarded when challenges are removed. In other words, genetic adaptation occurs transiently without any lasting change to the genome.