Science, discussed.

Probability of finding fitter promiscuous mutants (Evolvability) as a function of purifying selection

Recently, in an opinion article, Dr. Shelley Copley, had an interesting view on evolvability..

".. promiscuity may exist simply because it is impossible to 
exclude all potential substrates .."
Copley SD
An evolutionary biochemist’s perspective on promiscuity 
Trends in Biochemical Sciences.Feb 2015.

In nature, organisms are selected by gradual changes in environmental conditions to which they respond by keeping their native-optimal-fitness by tinkering with two properties robustness (with no change in function) and evolvability (by acquiring new functions, innovability).

Relationship between robustness and evolvability and role of selection strength

Relationship between robustness and evolvability and role of selection strength

If two types of purifying selections involve catalysis of two different substrates which are structural analogs of each other, the fitness of mutants in both conditions would be roughly the same. This is because both types of substrates would bind roughly similarly to active sites. In such a case, at lower selection strengths, larger populations would have native-like-optimal-fitness also called robustness (may that be through mutational buffering). While at higher selection strengths, purifying selection would act upon and only those individuals which higher fitness (excess activity) in one type of selection and thusly also having higher fitness in other type of selection would most likely to exhibit evolvability.

A recent paper in Cell systematically investigates the evolvability aspect of molecular evolution of TEM-1 β-Lactamase and find that it is a function of strengths of selection.

Evolvability) as a Function of Purifying Selection in TEM-1 
Michael A. Stiffler, Doeke R. Hekstra, Rama Ranganathan
Cell Feb 2014

Authors analyse the evolvability of TEM-1 β-Lactamase which natively catalzes ampicilin to catalyze a related (beta lactam scaffold), rather poor substrate – cefotaxime. To uncover this, the authors used a comprehensive single site mutation library of TEM-1 b-Lactamase. After a bulk competition in different conditions, survival count was done by Illumina 75 bp paired-end (shotgun) sequencing. This approach is better known as ‘Deep mutational scanning’, pioneered and popularised by Fowler DM et al.

Deep mutational scanning: a new style of protein science
Fowler DM, Fields S. 
Nature Methods 2014.
Measuring the activity of protein variants on a large scale 
using deep mutational scanning.
Fowler DM, Stephany JJ, Fields S. 
Nature Protocols 2014.

The relative fitness among conditions is calculated by following equation,

Relative fitness= Log(SEL1/UNSEL1)-Log(SEL2/UNSEL2) 
Where, SEL and UNSEL are survival counts under different 
antibiotic selections and that without.

They find a non-linear phenotype-fitness relationship in which fitness tends to saturate at distinct levels of enzyme activities with respect to concentration of applied ampilicin. They find that evolvability is exhibited more at the higher selection strengths dosages. Whereas robustness is exhibited more at the lower selection strengths dosages. Through modelling, they shows that excessive intracellular enzymatic activity at a particular strength of selection might be the cause for robustness and evolvability to arise. Hence knowing the modulation of robustness and evolvability by environmental factors has the potential to uncover the historical cues in molecular evolution of proteins.

For very similar types of selections, the probability of finding fitter-promiscuous mutants would definitely be dependent on the strength of purifying selection as discussed above. But would this model be conserved in case of evolvability for other unrelated substrates?


This entry was posted on 15/03/2015 by in Molecular Evolution, Papers and Reviews, postprintreview and tagged , , .


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