Evolution: from atoms to organisms
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Modern Biology is deeply rooted in Darwinian principles of mutations and selection. Population Genetics aims to address the effects of mutations and selection on populations in a quantitative way within the basic paradigm of ‘’fitness landscape’’, which postulates how genotypicchanges affect phenotype (e.g., fitness or growth rate of an organism or a tissue). No clear connection between the fitness effects of mutations and their effect on molecular properties of proteins has been systematically established – proteins are still treated as ‘’black boxes’’ in most population and organism level studies of evolution. In this talk I will present a systematic theoretical and experimental effort in our lab to go beyond this paradigm by developing multiscale models which relate molecular properties of proteins (their folding, function and interactions) to fitness of carrier organisms. By analyzing such models (both in simulations and analytically) we derived distribution of proteins stabilities which is very close to experimentally observed ones and predict its dependence of mutation rates and population size, linking ecology and molecular biophysics. Further we predicted and found correlation between protein stabilities and their abundances in cells as well as between protein abundances and strength of their interactions with other proteins. We discovered a universal physics-based speed limit on mutation rates in all organisms – ~6 missense mutations per essential part of the genome per replication. Further, we systematically experimentally probe fitness landscape by making controllable biophysical changes in proteins (varying stability and folding rates by mutations and abundances by manipulating upstream regions) with subsequent incorporation of mutant genes into E.coli chromosome and evaluating fitness of mutant strains in competition with wild-type. Our experiments confirm basic features of physics-based fitness landscape and add important new insights on how to make them more comprehensive and accurate.