Molecular Analysis of Genetic Variation in Prions of Saccharomyces cerevisiae

Abstract

Several proteins in the yeast Saccharomyces cerevisiae act as prions, forming infectious amyloids that are transmissible to other cells during division and outcrossed mating. The parallel in‐register β‐sheet structure of yeast prions such as [PSI+] and [RNQ+] provides a template for conversion of normally unstructured prion domains into a β‐sheet with folds at sites determined by the template on the ends of the filament. Prion propagation is highly sequence specific, and polymorphisms can disrupt templating and abrogate prion transmission. To investigate intra‐species barriers for prion transmission in yeast, we sequenced prion genes of 80 wild isolates from a diverse array of geographic locations and ecological niches. Molecular population genetics was used to quantify nucleotide diversity and examine the evolutionary basis for heterogeneity of prion alleles. An array of indels, SNPs and premature stop codons were detected in wild isolates. Many novel prion haplotypes were characterized, and several variants blocked prion propagation, resulting in barriers to transmission between strains. Almost half of the wild strains analyzed were heterozygous at one or more loci, suggesting that outcrossed mating occurs quite frequently in yeast. It is possible that the observed prion sequence heterogeneity is a consequence of natural selection against prion infections in wild yeast populations.