Rapidly Reversible Microhomology-mediated Tandem Duplications Drive Clonal Genome Diversity And Evolvability

Most genetic changes have negligible reversion rates.As most mutations that confer resistance to an adversary condition(e.g.,drug treatment)also confer a growth defect in its absence,it is challenging for cells to genetically adapt to transient environmental changes.Here we identify a set of rapidly reversible drug resistance mutations in S.pombe that are caused by Microhomology mediated Tandem Duplication(MTD),and reversion back to the wild-type sequence.Using 10,000 x coverage whole-genome sequencing we identify near 6000 subclonal MTDs in single a clonal population.The frequency of any single MTD will depend on the rate of MTD formation,the rate of reversion and the fitness.Using machine learning and high temperature(36?)screening to determine how MTD frequency is encoded.We annotated the S.pombe genome and identified 25 million MHPs,providing multiple potential MTD sites,and find that sequences with the highest predicted MTDs rates tend to generate insertions that maintain the correct reading frame,indicating that MTD formation has shaped the evolution of coding sequences.Our study reveals a mechanism of reversible genetic variation that is beneficial for adaptation to environmental fluctuations and facilitates evolutionary divergence.