Do stubborn drug resistant fungal infections circumvent the rules of adaptive evolution?
Lead Research Organisation:
Babraham Institute
Department Name: Epigenetics
Abstract
Fungal infections in mammals and plants are stubbornly resistant to eradication by host defences and exogenous treatments. I propose that much of this resilience arises from an undiscovered transient genetic adaptation system that contravenes our understanding of the Rules of Adaptive Evolution.
DNA repair mechanisms guarding chromosomal genome integrity limit genetic heterogeneity, but rare genetic changes that yield highly advantageous traits (such as drug resistance) become rapidly fixed in the population. These properties render adaptive evolution of the chromosomal genome slow but irreversible.
I hypothesise that fungi use extrachromosomal circular DNA (eccDNA) to generate massive genetic heterogeneity in the form of gene copy number variation, but resistance traits selected from this genetic heterogeneity are transient as the eccDNA is expunged once the challenge subsides. This fast, reversible mode of adaptive evolution would render pathogenic fungal infections almost impossible to eradicate, yet the genetic changes mediating survival would often disappear during laboratory analysis.
Fungal pathogens kill >1.5 million people per year and destroy food crops that could otherwise feed 8.5% of the global population. Understanding active genetic mechanisms used by fungal infections to resist eradication will reveal new treatment strategies and drug targets to specifically block adaptation.
DNA repair mechanisms guarding chromosomal genome integrity limit genetic heterogeneity, but rare genetic changes that yield highly advantageous traits (such as drug resistance) become rapidly fixed in the population. These properties render adaptive evolution of the chromosomal genome slow but irreversible.
I hypothesise that fungi use extrachromosomal circular DNA (eccDNA) to generate massive genetic heterogeneity in the form of gene copy number variation, but resistance traits selected from this genetic heterogeneity are transient as the eccDNA is expunged once the challenge subsides. This fast, reversible mode of adaptive evolution would render pathogenic fungal infections almost impossible to eradicate, yet the genetic changes mediating survival would often disappear during laboratory analysis.
Fungal pathogens kill >1.5 million people per year and destroy food crops that could otherwise feed 8.5% of the global population. Understanding active genetic mechanisms used by fungal infections to resist eradication will reveal new treatment strategies and drug targets to specifically block adaptation.
