Abstract
Cells cultured in a nutrient-limited environment can undergo adaptation,
which confers improved fitness under long-term energy limitation. We
have previously shown how a recombinant S. cerevisiae strain,
producing a heterologous insulin product, under glucose-limited
conditions adapts over time at the average population level.
In this paper, we investigated this adaptation at the single-cell level
by application of FACS and showed that three apparent phenotypes
underlie the adaptive response observed at the bulk level: (1) cells
that drastically reduced insulin production (23 %), (2) cells with
reduced enzymatic capacity in central carbon metabolism (46 %), (3)
cells that exhibited pseudohyphal growth (31 %). We speculate that the
phenotypic heterogeneity is a result of different mechanisms to increase
fitness. Cells with reduced insulin productivity have increased fitness
by reducing the burden of the heterologous insulin production and the
populations with reduced enzymatic capacity of the central carbon
metabolism and pseudohyphal growth have increased fitness towards the
glucose-limited conditions.
The results highlight the importance of considering population
heterogeneity when studying adaptation and evolution.