TY - JOUR T1 - A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection JF - bioRxiv DO - 10.1101/083469 SP - 083469 AU - Johanna Rhodes AU - Mathew A. Beale AU - Mathieu Vanhove AU - Joseph N. Jarvis AU - Shichina Kannambath AU - John A. Simpson AU - Anthea Ryan AU - Graeme Meintjes AU - Thomas S. Harrison AU - Matthew C. Fisher AU - Tihana Bicanic Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/10/26/083469.abstract N2 - Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis. Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, whilst the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5 and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and non-synonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in Cryptococcus neoformans and represent a novel pathway for rapid within-host adaptation and evolution of resistance to firstline antifungal drugs. ER -