As such, we suggest PriA is an ideal candidate to study protein evolution during the process of genome decay. The PriA enzyme is capable of operating in the L-histidine biosynthesis pathway as HisA, while also functioning in the L-tryptophan biosynthesis pathway as TrpF ( Noda-García et al., 2013 Verduzco-Castro et al., 2016 Barona-Gómez and Hodgson, 2003). Furthermore, we have observed that many actinobacterial species lack a trpF gene, while retaining a copy of the potentially bi-functional priA gene. Moreover, within the deep-rooted family Actinomycetaceae, phylogenetic analyses have suggested the occurrence of genome decay ( Zhao et al., 2014). This phylum is known to display significant metabolic specialization, and phylogenomics has been previously applied to correlate genome dynamics with metabolic pathway evolution and enzyme specialization ( Noda-García et al., 2013 Verduzco-Castro et al., 2016 Cruz-Morales et al., 2016). The phylum Actinobacteria, Gram-positive organisms with high (G+C)-content, are ubiquitous and show one of the highest levels of bacterial metabolic diversity ( Barka et al., 2016). We use genome-scale metabolic models to determine when each pathway is lost as well as when they become non-functional ( Henry et al., 2010). To overcome this limitation, we propose to use a bifunctional enzyme to study the evolution of substrate specificity after gene loss, as these enzymes may continue to operate when only one of their associated metabolic pathways becomes dispensable. This is because most proteins are monofunctional, and they are rapidly removed from the bacterial genome once they become dispensable due to gene loss. Second, there is only a brief window of opportunity to study the evolution of most proteins during genome decay in bacteria. As a result, these proteins display higher-than-normal mutation rates, making in vitro analysis of protein function a challenge ( Couñago et al., 2006). First, in genomes that are undergoing decay, there is a relaxation in the selection pressure that increases mutation rates in functioning proteins as these proteins begin to contribute less to cell fitness ( Wernegreen and Moran, 1999 McCutcheon and Moran, 2011). The current bias toward in-depth functional analysis of proteins from genomes that are undergoing gene gain by HGT versus gene loss by decay is likely due to two factors. Here, we propose that bacterial phylogenomics can be similarly applied to study evolution by gene loss ( Albalat and Cañestro, 2016), specifically where enzymes are evolving within bacterial species that are undergoing genome decay ( Adams et al., 2014 Price and Wilson, 2014). Phylogenomics involves the comparative analysis of the gene content of a set of phylogenetically related genomes to expose new insights into genome evolution and function, and this approach has been classically applied to study how gene gain is associated with functional divergence in bacteria ( Treangen and Rocha, 2011). Gene loss has also been implicated in rapid bacterial adaptation after experimental evolution ( Hottes et al., 2013), but this process has not yet been confirmed in natural populations. Acquisition of new functions due to horizontal gene transfer (HGT) or genetic duplications is broadly documented ( Wiedenbeck and Cohan, 2011 Blount et al., 2012). Genome dynamics, or the process by which an organism gains or loses genes, plays a fundamental role in bacterial evolution. Our results show how gene loss can drive the evolution of substrate specificity from retained enzymes. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to a monofunctional, yet not necessarily specialized, inefficient form in genomes undergoing reduction. We observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence of trp and his genes. We apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. The connection between gene loss and the functional adaptation of retained proteins is still poorly understood.
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