Abstract
Recent laboratory evolution experiments have identified surprising
properties in the evolution of trimethoprim resistance in E.coli through
mutation of the drug's target, DHFR: (1) mutations are acquired in a
reproducibly ordered manner; (2) multiple resistant endpoints exist; and
(3) some pathways include mutation reversion or conversion. Here we
investigate how these properties emerge from the fitness landscape of
DHFR by characterizing all combinations of observed DHFR mutations. We
see that the effects of mutations are so profoundly dependent on other
mutations that sign-epistasis is nearly maximised, and the distributions
of most mutations' effects are indistinguishable from randomly
increasing or decreasing resistance. This almost `maximally-rugged'
fitness landscape contains multiple separated peaks in drug resistance,
and 20% of favourable mutational steps are the loss or conversion of a
previously acquired mutation. Select pathways through the rugged
landscape avoid a common tradeoff between growth and resistance.
Empirical characterization of this fitness landscape has identified that
ordered but sometimes indirect mutational pathways to multiple endpoints
arises from near-maximal levels of sign epistasis.
| Original language | English |
|---|---|
| Title of host publication | American Physical Society, APS March Meeting 2012, February 27-March 2, 2012 |
| Volume | 57 |
| Edition | 1 |
| State | Published - 2012 |