Pathogenicity, drug resistance and cancer progression are examples of mutation-driven processes, where increased selective advantage is conferred upon cells carrying new mutations. While these mutations may be beneficial in one specific condition, they may be deleterious in other conditions, a phenomenon known as Antagonistic Pleiotropy (AP). AP is thought to lead to evolutionary trade-offs and the persistence of deleterious alleles. But what is the prevalence of AP? Which genes or pathways are more likely to be involved in AP, and under which conditions? Is there any specific type of mutation that results in AP? One study investigated AP and observed ~14% of non-essential gene deletions display AP (Qian et al., 2012) but the prevalence and nature of AP for beneficial mutations is largely unexplored.
To answer these questions, we are using an experimental system that allows us to track and measure the fitness values of ~500,000 separate lineages within an evolving yeast population via DNA barcodes (Levy et al 2015). We performed evolution on haploid population as well as on diploid population. One preliminary observation is that, diploids arise in the haploid population and have some fitness advantage depending on the growth conditions.
With this barcoding system, we are able to identify lineages that gain a beneficial mutation, based on how their frequencies increase over time. We will select clones that harbor beneficial mutations in order to measure their fitness in alternate conditions. We will infer AP for any clones that carry beneficial mutations in the first environment that now show a fitness lower than wild-type in at least one alternate environment. On clones of interest, we will perform whole genome sequencing to determine the mutation that induces AP in those clones.
These data will result in the largest set of fitness measurements for adaptive mutations ever collected across multiple environments. It will allow us to determine, for example, the extent of AP among new beneficial mutations and any correlations between the magnitude of the beneficial effect a mutation confers in one environment and whether it exhibits AP in other environments. The results will indicate whether beneficial mutations in certain pathways are more likely to exhibit AP and will provide the first insight of how mutation-driven processes can confer selective evolution or why deleterious alleles can be conserved upon evolution.