Abstract
The sequences of antibodies from a given repertoire are highly diverse at few sites located on the surface of a genome-encoded larger scaffold. The scaffold is often considered to play a lesser role than highly diverse, non-genome-encoded sites in controlling binding affinity and specificity. To gauge the impact of the scaffold, we carried out quantitative phage display experiments where we compare the response to selection for binding to four different targets of three different antibody libraries based on distinct scaffolds but harboring the same diversity at randomized sites. We first show that the response to selection of an antibody library may be captured by two measurable parameters. Second, we provide evidence that one of these parameters is determined by the degree of affinity maturation of the scaffold, affinity maturation being the process by which antibodies accumulate somatic mutations to evolve towards higher affinities during the natural immune response. In all cases, we find that libraries of antibodies built around maturated scaffolds have a lower response to selection to other arbitrary targets than libraries built around germline-based scaffolds. We thus propose that germline-encoded scaffolds have a higher selective potential than maturated ones as a consequence of a selection for this potential over the long-term evolution of germline antibody genes. Our results are a first step towards quantifying the evolutionary potential of biomolecules.
Highlights
The idea that evolution by natural selection is leading to adaptations but to a propensity to adapt, or “evolvability”, has been repeatedly put forward [1,2,3]
We propose the hypothesis that naïve antibodies which are constructed from germline genes are endowed with a special evolutionary ability to generate selectable diversity, which they lose when undergoing affinity maturation
We introduced an experimental and statistical approach that quantifies the selective potential of antibody scaffolds
Summary
The idea that evolution by natural selection is leading to adaptations but to a propensity to adapt, or “evolvability”, has been repeatedly put forward [1,2,3]. As demonstrated by a number of mathematical models, evolvability can emerge from evolutionary dynamics without any direct selection for it [4,5,6,7]. Theoretical insights have not translated into experimental assays for measuring and controlling evolvability in actual biological systems. Biomolecules as RNAs and proteins are ideal model systems for developing such assays as they are amenable to controlled experimental evolution [8]. In particular, several biophysical and structural features have been proposed to correlate with their evolvability, most notably their thermal stability [9, 10] and the modularity and polarity of their native fold [11]. A major limitation, is the absence of a measurable index of evolvability quantifying evolutionary responses to compare to biophysical or structural quantities
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