Biology subjects

Michael Manhart

Publications and source records attributed to Michael Manhart.

4 recordsLinked to original sources

bioRxiv2016

Separating spandrels from phenotypic targets of selection in adaptive molecular evolution

There are many examples of adaptive molecular evolution in natural populations, but there is no existing method to verify which phenotypic changes were directly targeted by selection. The problem is that correlations between traits make it difficult to distinguish between direct and indirect selection. A phenotype is a direct target of selection when that trait in particular was shaped by selection to better perform a function. An indirect target of selection, also known as an evolutionary spandrel, is a phenotype that changes only because it is correlated with another trait under direct selection. Studies that mutate genes and examine the phenotypic consequences are increasingly common, and these experiments could estimate the mutational accessibility of the phenotypic changes that arise during an instance of adaptive molecular evolution. Under indirect selection, we expect phenotypes to evolve toward states that are more accessible by mutation. Deviation from this null expectation (evolution toward a phenotypic state rarely produced by mutation) would be compelling evidence of adaptation, and could be used to distinguish direct selection from indirect selection on correlated traits. To be practical, this molecular test of adaptation requires phenotypic differences that are caused by changes in a small number of genes. These kinds of genetically simple traits have been observed in many empirical studies of adaptive evolution. Here we describe how to use mutational accessibility to separate spandrels from direct targets of selection and thus verify adaptive hypotheses for phenotypes that evolve by adaptive molecular changes at one or a few genes.

Evolutionary Biology↗

bioRxiv2015

Protein homeostasis imposes a barrier on functional integration of horizontally transferred genes in bacteria

Horizontal gene transfer (HGT) plays a central role in bacterial evolution, yet the molecular and cellular constraints on functional integration of the foreign genes are poorly understood. Here we performed inter-species replacement of the chromosomal folA gene, encoding an essential metabolic enzyme dihydrofolate reductase (DHFR), with orthologs from 35 other mesophilic bacteria. The orthologous inter-species replacements caused a marked drop (in the range 10-90%) in bacterial growth rate despite the fact that most orthologous DHFRs are as stable as E.coli DHFR at 37{degrees} C and are more catalytically active than E. coli DHFR. Although phylogenetic distance between E. coli and orthologous DHFRs as well as their individual molecular properties correlate poorly with growth rates, the product of the intracellular DHFR abundance and catalytic activity (kcat/KM), correlates strongly with growth rates, indicating that the drop in DHFR abundance constitutes the major fitness barrier to HGT. Serial propagation of the orthologous strains for [~]600 generations dramatically improved growth rates by largely alleviating the fitness barriers. Whole genome sequencing and global proteome quantification revealed that the evolved strains with the largest fitness improvements have accumulated mutations that inactivated the ATP-dependent Lon protease, causing an increase in the intracellular DHFR abundance. In one case DHFR abundance increased further due to mutations accumulated in folA promoter, but only after the lon inactivating mutations were fixed in the population. Thus, by apparently distinguishing between self and non-self proteins, protein homeostasis imposes an immediate and global barrier to the functional integration of foreign genes by decreasing the intracellular abundance of their products. Once this barrier is alleviated, more fine-tuned evolution occurs to adjust the function/expression of the transferred proteins to the constraints imposed by the intracellular environment of the host organism.

Systems Biology↗

bioRxiv2014

Scaling properties of evolutionary paths in a biophysical model of protein adaptation

The enormous size and complexity of genotypic sequence space frequently requires consideration of coarse-grained sequences in empirical models. We develop scaling relations to quantify the effect of this coarse-graining on properties of fitness landscapes and evolutionary paths. We first consider evolution on a simple Mount Fuji fitness landscape, focusing on how the length and predictability of evolutionary paths scale with the coarse-grained sequence length and number of alleles. We obtain simple scaling relations for both the weak- and strong-selection limits, with a non-trivial crossover regime at intermediate selection strengths. We apply these results to evolution on a biophysical fitness landscape designed to describe how proteins evolve new binding interactions while maintaining their folding stability. We combine numerical calculations for coarse-grained protein sequences with the scaling relations to obtain quantitative properties of the model for realistic binding interfaces and a full amino acid alphabet.

Evolutionary Biology↗

bioRxiv2014

Protein folding and binding can emerge as evolutionary spandrels through structural coupling

Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and regulation of gene expression. These interactions evolve in response to changes in the protein's chemical or physical environment (such as the addition of an antibiotic), or when genes duplicate and diverge. Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between protein folding and binding -- the fact that most proteins can only bind their targets when folded -- gives rise to evolutionary coupling between the traits of folding stability and binding strength. Using biophysical and evolutionary modeling, we show how these protein traits can emerge as evolutionary "spandrels" even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if misfolding is deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutation events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of fundamental evolutionary principles of both natural and engineered proteins.

Evolutionary Biology↗