Biology subjects

McShea, H.

Publications and source records attributed to McShea, H..

5 recordsLinked to original sources

bioRxiv2025

Archaeal lineages related to eukaryotes encode functional diterpenoid cyclases

The first eukaryotic cell originated through the union of an archaeon and a bacterium. Phylogenetic evidence suggests that the archaeal partner was a member of phylum Asgardarchaeota, likely within the Heimdallarchaeia clade. Although little is known about the molecular basis of eukaryogenesis, insight can be gained from studying the unique biochemistry of modern Asgardarchaeota. Here, we investigated the potential for Asgards to produce cyclic terpenoids. Phylogenomics coupled with structural prediction revealed that organisms from the clades Hodarchaeales and Kariarchaeaceae encode for diterpenoid cyclases. We tested the functionality of these enzymes in vitro, showing that they cyclize geranylgeranyl pyrophosphate to form bicyclic halimadienyl pyrophosphate. Halimadienyl nucleosides have previously been shown to mediate intracellular persistence of Mycobacterium tuberculosis in host endosomes, and may function similarly in Asgardarchaeota. The characterization of Asgard diterpenoid cyclases provides insight into the biochemistry of an elusive group of microbes that are pivotal in the evolution of complex cellular life.

microbiology↗

bioRxiv2024

The evolutionary history and modern diversity of triterpenoid cyclases

Cyclic terpenoids are a class of lipid compounds containing immense structural and functional diversity, with many cyclic triterpenoids acting as regulators of the physical properties and spatial organization of lipid membranes. Cyclic terpenoids are also readily preserved as terpane fossils, such as steranes and hopanes, forming a rich record of the evolution of life on Earth. Formation of the multiple ring structure of all cyclic terpenoids is catalyzed by terpenoid cyclase enzymes, among which are whole clades of proteins - many from environmental metagenomes and uncultured organisms - whose substrates and products are completely unknown. We investigate the function of these divergent cyclases through biochemical assays, and the evolutionary processes that produced them by testing and applying a variety of evolutionary models. We find deep divergence between the diterpenoid cyclases and triterpenoid cyclases, with other clades branching between the two, rooting the triterpenoid cyclase subtree, between squalene-hopene cyclases and sterol cyclases. Through a simple test of evolutionary rate shifts, we find an elevated evolutionary rate in the enzyme active site on the squalene-hopene cyclase stem, potentially indicative of positive selection. Finally, by testing the activity of divergent cyclases for a variety of substrates, we find a group of early-branching sterol cyclases from bacteria that synthesize arborinols, two of which produce the molecular precursor to a Permian "orphan biomarker." Together, our data present an evolutionary framework for triterpenoid cyclases that can inform both the biochemical potential of these proteins and their products occurrence in the geological record.

evolutionary biology↗

bioRxiv2023

The effectiveness of selection in a species affects the direction of amino acid frequency evolution

Nearly neutral theory predicts that species with higher effective population size (Ne) are better at purging slightly deleterious mutations. We compare evolution in high-Ne vs. low-Ne vertebrates to reveal subtle selective preferences among amino acids. We take three complementary approaches. First, we fit non-stationary substitution models using maximum likelihood, comparing the high-Ne clade of rodents and lagomorphs to its low-Ne sister clade of primates and colugos. Second, we compared evolutionary outcomes across a wider range of vertebrates, via correlations between amino acid frequencies and the codon adaptation index of species, a proxy for Ne. Third, we dissected which amino acids substitutions occurred in human, chimpanzee, mouse, and rat, as scored by parsimony - this also enabled comparison to a historical paper. All three methods agree on amino acid preference under more effective selection. Preferred amino acids are less costly to synthesize and use GC-rich codons, which are hard to maintain under AT-biased mutation. These factors explain 85% of the variance in amino acid preferences. Within highly exchangeable pairs of amino acids, arginine is strongly preferred over lysine, valine over isoleucine, and aspartate over glutamate, consistent with more effective selection preferring a marginally larger free energy of folding. The first two of these preferences, but not the third, match differences between thermophiles and mesophilic relatives. These results reveal the biophysical consequences of mutation-selection-drift balance, and demonstrate the utility of nearly neutral theory for understanding protein evolution. Significance statementAccording to the nearly neutral theory of molecular evolution, selection is less able to distinguish between similar alleles in species with lower population size. We identify which amino acids are subject to such weak preferences - these tend to be less costly to make, to use GC-rich codons easily destroyed by mutation, and to be enriched in thermophiles relative to mesophiles. The latter agrees with theories of marginal protein stability under mutation-selection-drift balance.

evolutionary biology↗

bioRxiv2021

nQMaker: estimating time non-reversible amino acid substitution models

Amino acid substitution models are a key component in phylogenetic analyses of protein sequences. All amino acid models available to date are time-reversible, an assumption designed for computational convenience but not for biological reality. Another significant downside to time-reversible models is that they do not allow inference of rooted trees without outgroups. In this paper, we introduce a maximum likelihood approach nQMaker, an extension of the recently published QMaker method, that allows the estimation of time non-reversible amino acid substitution models and rooted phylogenetic trees from a set of protein sequence alignments. We show that the non-reversible models estimated with nQMaker are a much better fit to empirical alignments than pre-existing reversible models, across a wide range of datasets including mammals, birds, plants, fungi, and other taxa, and that the improvements in model fit scale with the size of the dataset. Notably, for the recently published plant and bird trees, these non-reversible models correctly recovered the commonly known root placements with very high statistical support without the need to use an outgroup. We provide nQMaker as an easy-to-use feature in the IQ-TREE software (http://www.iqtree.org), allowing users to estimate non-reversible models and rooted phylogenies from their own protein datasets.

bioinformatics↗

bioRxiv2019

Reconstructed ancient nitrogenases suggest Mo-specific ancestry

The nitrogenase metalloenzyme family, essential for supplying fixed nitrogen to the biosphere, is one of lifes key biogeochemical innovations. The three isozymes of nitrogenase differ in their metal dependence, each binding either a FeMo-, FeV-, or FeFe-cofactor where the reduction of dinitrogen takes place. The history of nitrogenase metal dependence has been of particular interest due to the possible implication that ancient marine metal availabilities have significantly constrained nitrogenase evolution over geologic time. Here, we reconstructed the evolutionary history of nitrogenases, and combined phylogenetic reconstruction, ancestral sequence inference, and structural homology modeling to evaluate the potential metal dependence of ancient nitrogenases. We find that active-site sequence features can reliably distinguish extant Mo-nitrogenases from V- and Fe-nitrogenases, and that inferred ancestral sequences at the deepest nodes of the phylogeny suggest these ancient proteins most resemble modern Mo-nitrogenases. Taxa representing early-branching nitrogenase lineages lack one or more biosynthetic nifE and nifN genes that both contribute to the assembly of the FeMo-cofactor in studied organisms, suggesting that early Mo-nitrogenases may have utilized an alternate and/or simplified pathway for cofactor biosynthesis. Our results underscore the profound impacts that protein-level innovations likely had on shaping global biogeochemical cycles throughout the Precambrian, in contrast to organism-level innovations that characterize the Phanerozoic Eon.

evolutionary biology↗