Study shows that genetic diversity influences which adaptive mutations cause antimicrobial resistance.

Researchers have shown that genetic diversity plays a key role in enabling drug resistance to evolve. Scientists at the Wellcome Trust Sanger Institute and the Institute for Research on Cancer and Ageing of Nice in France show that high genetic diversity can prime new mutations that cause drug resistance.

The study published October 17 in the journal Cell Reports has implications for our understanding of the evolution of resistance to antimicrobial and anticancer drugs.

Previous studies had linked high genetic diversity within bacterial infections or in cancers with poor outcomes for patients treated with antimicrobial or chemotherapy drugs. Researchers in this study used budding yeast, creating populations of cells with more than 10 million different randomised genomes, to investigate how genetic diversity affected resistance. They evolved these to grow in antimicrobial drugs over four weeks and then studied the sensitive and resistant yeast cells.

"We found that the degree of diversity within the cell population – known as clonal heterogeneity – played a major role in the acquisition of antimicrobial resistance. By sequencing the genomes of sensitive and resistant cells we showed that some cells were pre-adapted, or primed, while other cells acquired new mutations to gain resistance,” said Dr Ignacio Vazquez-Garcia, the first author from the Wellcome Trust Sanger Institute and University of Cambridge.

By then crossing the evolved strains, the researchers were able to investigate the complex evolutionary processes involved in developing resistance. They were able to see not only which mutations drove resistance – called driver mutations – but also how the background mutations affected these.

They discovered two types of driver mutations. Cells with weak driver mutations needed other background mutations to grow well in antimicrobial drugs, however cells with strong driver mutations developed resistance to drugs regardless of the genetic background.

“We were able to study the evolution in time by combining genome sequences of the cell populations and tracking the growth characteristics of the yeast cells. We found that the genetic background had a major influence on whether or not weaker mutations would confer drug resistance, and in these cases many different cells adapted in a wave. However, with any genetic background, cells with strong driver mutations could “leapfrog” and outcompete other cells growing in the drugs,” said professor Gianni Liti, a senior author on the paper from the Institute for Research on Cancer and Ageing, Nice.