A major enigma in evolutionary biology is that new forms or functions often
require the concerted effects of several independent genetic changes. It i
s unclear how such changes might accumulate when they are likely to be dele
terious individually and be lost by selective pressure. The Saccharomyces c
erevisiae prion [PSI+] is an epigenetic modifier of the fidelity of transla
tion termination, but its impact on yeast biology has been unclear. Here we
show that [PSI+] provides the means to uncover hidden genetic variation an
d produce new heritable phenotypes. Moreover, in each of the seven genetic
backgrounds tested, the constellation of phenotypes produced was unique. We
propose that the epigenetic and metastable nature of [PSI+] inheritance al
lows yeast cells to exploit pre-existing genetic variation to thrive in flu
ctuating environments. Further, the capacity of [PSI+] to convert previousl
y neutral genetic variation to a non-neutral state may facilitate the evolu
tion of new traits.