Sign epistasis
Sign epistasis between experimentally evolved adaptive mutations causes a rugged fitness landscape
The fitness landscape captures the relationship between genotype and evolutionary fitness.  On a   rugged fitness landscape, peaks of high fitness are separated by valleys of lower fitness.    Theoretical studies have shown that these valleys are created by reciprocal sign epistasis, where   negative interactions between two mutations result in a fitness that is less than each individual   mutation’s fitness.  However, little molecular work has been done to test this theory.  Here we   demonstrate reciprocal sign epistasis between two adaptive mutations in the genes mth1 and   HXT6/HXT7 that arose in different lineages during experimental evolution of an asexual   population of Saccharomyces cerevisiae.  This epistasis causes the two mutations to be mutually   exclusive.  This is the first example in an experimental evolution of a rugged, two-peaked   molecular fitness landscape, where the adaptive mutations in mth1 and HXT6/HXT7 are at the   two fitness peaks, and the mutant carrying both the mth1 and HXT6/HXT7 mutations is in a   fitness valley.  The constraint caused by the reciprocal sign epistasis has far-reaching   evolutionary implications, including the maintenance of biodiversity, the evolution of sex, and   speciation.  Our study draws some surprising parallels with cancer, where mutually exclusive   mutations in the Ras pathway have been identified in colorectal cancers.