The Evolution of Control and Distribution of Adaptive Mutations in a Metabolic Pathway by ProQuest


More Info
									Copyright Ó 2010 by the Genetics Society of America
DOI: 10.1534/genetics.109.110411

          The Evolution of Control and Distribution of Adaptive Mutations
                             in a Metabolic Pathway

                                             Kevin M. Wright1 and Mark D. Rausher
                                     Department of Biology, Duke University, Durham, North Carolina 27708
                                                   Manuscript received September 29, 2009
                                                 Accepted for publication November 17, 2009

                In an attempt to understand whether it should be expected that some genes tend to be used
             disproportionately often by natural selection, we investigated two related phenomena: the evolution of
             flux control among enzymes in a metabolic pathway and properties of adaptive substitutions in pathway
             enzymes. These two phenomena are related by the principle that adaptive substitutions should occur
             more frequently in enzymes with greater flux control. Predicting which enzymes will be preferentially
             involved in adaptive evolution thus requires an evolutionary theory of flux control. We investigated the
             evolution of enzyme control in metabolic pathways with two models of enzyme kinetics: metabolic control
             theory (MCT) and Michaelis–Menten saturation kinetics (SK). Our models generate two main predictions
             for pathways in which reactions are moderately to highly irreversible: (1) flux control will evolve to
             be highly unequal among enzymes in a pathway and (2) upstream enzymes evolve a greater control
             coefficient then those downstream. This results in upstream enzymes fixing the majority of beneficial
             mutations during adaptive evolution. Once the population has reached high fitness, the trend is reversed,
             with the majority of neutral/slightly deleterious mutations occurring in downstream enzymes. These
             patterns are the result of three factors (the first of these is unique to the MCT simulations while the other
             two seem to be general properties of the metabolic pathways): (1) the majority of randomly selected,
             starting combinations of enzyme kinetic rates generate pathways that possess greater control for the
             upstream enzymes compared to downstream enzymes; (2) selection against large pools of intermediate
             substrates tends to prevent majority control by downstream enzymes; and (3) equivalent mutations in
             enzyme kinetic rates have the greatest effect on flux for enzymes with high levels of flux control, and these
             enzymes will accumulate adaptive substitutions, strengthening their control. Prediction 1 is well supported
             by available data on control coefficients. Data for evaluating prediction 2 are sparse but not inconsistent
             with this prediction.

T   HEORETICAL research on the process of adapta-
      tion has focused primarily on describing the size
and number of genetic changes underlying phenotypic
                                                                          achieved by substitutions in any one of several genes in
                                                                          the pathway. One example is the intensity of floral
                                                                          pigmentation. To a first approximation, final pigment
change (Fisher 1930; Kimura 1983; Orr 1998, 2002,                         concentration, and hence color intensity, can be viewed
2003). By contrast, comparatively little theoretical                      as being determined by the flux rate down the pigment
attention h
To top