Yeast cells can deliberately duplicate or delete specific genes to adapt to heavy metals and other environmental stresses, a process previously assumed to be random. This matters because copy number variation—where sections of DNA are repeated or missing—is a major driver of genetic diversity, disease, and drug resistance. Cancer cells and pathogenic microbes often use CNV to evade treatment. Until now, scientists thought these changes occurred by chance. This research shows cells can actively orchestrate them in response to their surroundings, revealing a hidden layer of genome control. If the team succeeds in working out the molecular mechanism—likely involving replication, non-coding RNAs, and ageing—they could identify drug-like compounds that suppress CNV. That would open a new route to slowing drug resistance in cancer and infections. The work is fundamental science, but the potential payoff is concrete: longer-lasting chemotherapy and antibiotics, and a clearer picture of how genomes tune themselves to hostile environments.
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The aim of this work is to elucidate the mechanisms and consequences of environmentally directed copy number variation (CNV). CNV is rife in eukaryote genomes and imparts much of the genetic diversity in populations. CNV causes certain genetic diseases and has been implicated by genome-wide association studies in many common disorders. CNV can endow growth advantages in adverse environments, allowing drug resistance in cancer cells and pathogenic microorganisms. Therefore understanding CNV is no t only of considerable interest for basic biology but also has far-reaching clinical implications. CNV is thought to occur at random, however our studies of the yeast ribosomal DNA have demonstrated that precise copy number changes can be orchestrated in response to available nutrients. A mechanism by which cells could undergo genome optimisation for current environmental conditions would be of great importance, providing unanticipated pathways for adaptation with clear medical impacts. Indee d, the elements that control ribosomal DNA CNV are not unique and we have identified many candidate sites for environmentally stimulated CNV in the yeast genome. As proof of principle, we have found that exposure to environmental heavy metals stimulates adaptive CNV of a detoxification gene and produces cells with enhanced heavy metal tolerance. We will investigate the mechanism of environmentally stimulated CNV using genetic and molecular approaches, concentrating on the underlying mechanism and predicted roles for replication, non-coding RNAs and ageing. We will apply our findings to understanding CNV-mediated drug resistance in mammalian cells, and to discovering potential pharmaceutical lead compounds for suppressing CNV.
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