Title: “Experimental evolution of genetic instability during a yeast model of cancer progression”
Field: Biology, biochemistry, evolution
City: Boston, MA
Supervisor: Miguel Costa Coelho
Affiliation: FAS Center for Systems Biology, Harvard University
Life depends on the faithful transmission of genetic information. During cancer progression, the selection for successive mutations favors the evolution of genetic instability (GI), characterized by increased mutation rates. However, it is not clear how GI defects in DNA repair/replication, chromosome rearrangements or loss arises and evolves. By placing yeast cells under selective pressure to inactivate growth suppression, similarly to what occurs in tumors, we have evolved and quantified GI in three genetic architectures: 1) haploids, 2) diploids heterozygous for the growth suppressor gene, and 3) most similar to cancer – diploids homozygous for the growth suppressor gene.
One mutation is sufficient to cause GI in the evolved clones, but in some clones >1 mutations contribute to GI. Using mutation segregation analysis and whole genome sequencing we identified both lossoffunction and putative gain offunction mutations, also in essential genes, that drive GI. There were 3 prevalent classes of mutations: 1) DNA repair, 2) Protein stability and 3) Mitochondrial genes. To test whether these mutations were causative, we re engineered them back into the ancestor, time traveling to test the origin of instability. For a subset of genes in each class, the reengineered mutation increased GI, proving causality. Conversely, replacing the mutated allele with the wildtype copy in the evolved clone restored genetic stability. The majority of the mutations we discovered lie in genes not previously related to GI in yeast, and half are related to human cancer genes.
In contrast to classic screens where gene deletions were used, to unbiasedly select for increased mutation rate allows evolution to tell us how GI arises. We will proceed to functionally test how protein stability or mitochondrial disfunction affect GI, and analyze the mutational signatures of the evolved GI, focusing on conserved genes to bridge our work with human cancer.