Biology subjects

Rinker, D.

Publications and source records attributed to Rinker, D..

7 recordsLinked to original sources

bioRxiv2026

Evolutionary origins of protein novelty across an entire yeast subphylum

Novel protein-coding sequences fuel molecular and cellular evolutionary innovations and frequently contribute to species-defining characteristics. They can originate either de novo from previously noncoding sequences or through extreme divergence of already coding ones. How frequently each mechanism occurs and how they shape the structural and functional potential of the resulting proteins remains unclear. Here, we conducted a broad computational investigation of genetic and protein novelty throughout the entire subphylum of Saccharomycotina yeasts. We detected more than 5,000 robust de novo genes across 332 species and compared them to more than 6,000 novel genes resulting from extreme sequence divergence, revealing two quantitatively similar but qualitatively distinct modes of evolution of novelty. A remarkable 40% of de novo proteins are predicted to localize to mitochondria compared to only 20% of divergent, with the latter also being substantially longer and more disordered. A detailed analysis of conservatively predicted tertiary structures of novel proteins shows that ''invention'' of new folds occurs more frequently through de novo emergence. We also illustrate cases of evolutionary ''re-invention'' of existing protein folds from noncoding sequences. Our work deepens our understanding of the origins and importance of novel proteins, opening new directions for further structural and functional characterization.

genomics↗

bioRxiv2026

Opportunistic pathogenicity in fungi can transcend species boundaries

Multiple fungal lineages have independently evolved the ability to opportunistically infect humans, imposing a major burden on public health. Opportunistic pathogenicity requires the confluence of pre-existing fungal traits that facilitate host colonization (e.g., the ability to grow at 37{degrees}C) and host immune filters that permit the survival of some colonizers (e.g., inborn errors of immunity). Numerous studies have shown that fungal pathogens can exhibit extensive strain-to-strain variation in the ability to cause disease. Moreover, it is also well established that non-pathogenic fungi can occasionally cause severe infections. Together, these observations raise the question: What differentiates opportunistic fungal pathogens from non-pathogens? To address this empirically, we compared phenotypic, metabolomic, and genomic variation between Aspergillus fumigatus, an organism responsible for more than 300,000 infections per year, and Aspergillus fischeri, a close relative that is not considered clinically relevant. By examining 26 phenotypic traits across 16 representative strains of A. fumigatus and 16 of A. fischeri, we found that infection-relevant traits measured under in vitro monoculture conditions showed species-specific distributions, whereas traits measured under in vitro coculture with murine macrophages overlapped. Strikingly, strains of the two species also overlapped in their virulence profiles in an immunocompromised murine model of pulmonary aspergillosis; three strains of A. fischeri exhibited lethality rates of >50% while two A. fumigatus strains were among the least virulent of all 32 strains tested. Consistent with this overlap, we could not associate virulence variation with the presence of specific genomic elements, phenotypic traits, or secondary metabolites. Our results raise the hypothesis that opportunistic pathogenicity can extend beyond the boundaries of individual species. We propose a conceptual model in which the opportunistic pathogenic potential of any fungal strain is the product of complex interactions among numerous genomic, ecological, and host immunity factors.

evolutionary biology↗

bioRxiv2025

An integrative genomic and chemical similarity approach linking fungal secondary metabolites and biosynthetic gene clusters

Fungi are well known to biosynthesize structurally complex secondary metabolites (SMs) with diverse bioactivities. These fungal SMs are frequently produced by biosynthetic gene clusters (BGCs). Linking SMs to their BGCs is key to understanding their chemical and biological functions. Reasoning that structural similarity of SMs arises from similarities in the genes involved in their biosynthesis, we developed an integrative approach that leverages known BGC-SM pairs to predict global links across SMs and BGCs in fungi. As proof of concept, we systematically interrogated metabolomes and genomes of 16 strains of the filamentous fungus Aspergillus fischeri, detecting a total of 60 metabolites. Of those, we were able to assign 22 to known BGC-SM pairs and propose specific hypotheses for the remaining 38 metabolites. These results suggest that coupling genomic similarity and chemical structure-based similarity is a straightforward and high-throughput approach for linking fungal SMs to their BGCs.

microbiology↗

bioRxiv2025

Stable hypermutators revealed by the genomic landscape of DNA repair genes among yeast species

Mutator phenotypes are short-lived due to the rapid accumulation of deleterious mutations. Yet, recent observations reveal that certain fungi can undergo prolonged accelerated evolution after losing DNA repair genes. Here, we surveyed 1,154 yeast genomes representing nearly all known yeast species of the subphylum Saccharomycotina to examine the relationship between reduced DNA repair repertoires and elevated evolutionary rates. We identified three distantly related lineages--encompassing 12% of species--with substantially reduced sets of DNA repair genes and the highest evolutionary rates in the entire subphylum. Two of these "faster-evolving lineages" (FELs)--a subclade within the order Pichiales and the Wickerhamiella/Starmerella (W/S) clade (order Dipodascales)--are described here for the first time, while the third corresponds to a previously documented Hanseniaspora FEL. Examination of DNA repair gene repertoires revealed a set of genes predominantly absent in these three FELs, suggesting a potential role in the observed acceleration of evolutionary rates. Genomic signatures in the W/S clade are consistent with a substantial mutational burden, including pronounced A|T bias and signatures of endogenous DNA damage. The W/S clade appears to mitigate UV-induced damage through horizontal acquisition of a bacterial photolyase gene, underscoring how gene loss may be offset by nonvertical evolution. These findings highlight how the loss of DNA repair genes gave rise to hypermutators that persist across macroevolutionary timescales, with horizontal gene transfer as an avenue for partial functional compensation.

evolutionary biology↗

bioRxiv2024

VUStruct: a compute pipeline for high throughput and personalized structural biology

Effective diagnosis and treatment of rare genetic disorders requires the interpretation of a patients genetic variants of unknown significance (VUSs). Today, clinical decision-making is primarily guided by gene-phenotype association databases and DNA-based scoring methods. Our web-accessible variant analysis pipeline, VUStruct, supplements these established approaches by deeply analyzing the downstream molecular impact of variation in context of 3D protein structure. VUStructs growing impact is fueled by the co-proliferation of protein 3D structural models, gene sequencing, compute power, and artificial intelligence. Contextualizing VUSs in protein 3D structural models also illuminates longitudinal genomics studies and biochemical bench research focused on VUS, and we created VUStruct for clinicians and researchers alike. We now introduce VUStruct to the broad scientific community as a mature, web-facing, extensible, High-Performance Computing (HPC) software pipeline. VUStruct maps missense variants onto automatically selected protein structures and launches a broad range of analyses. These include energy-based assessments of protein folding and stability, pathogenicity prediction through spatial clustering analysis, and machine learning (ML) predictors of binding surface disruptions and nearby post-translational modification sites. The pipeline also considers the entire input set of VUS and identifies genes potentially involved in digenic disease. VUStructs utility in clinical rare disease genome interpretation has been demonstrated through its analysis of over 175 Undiagnosed Disease Network (UDN) Patient cases. VUStruct-leveraged hypotheses have often informed clinicians in their consideration of additional patient testing, and we report here details from two cases where VUStruct was key to their solution. We also note successes with academic research collaborators, for whom VUStruct has informed research directions in both computational genomics and wet lab studies.

biochemistry↗

bioRxiv2023

Evolutionary origin, population diversity, and diagnostics for a cryptic hybrid pathogen

Cryptic fungal pathogens pose significant identification and disease management challenges due to their morphological resemblance to known pathogenic species while harboring genetic and (often) infection-relevant trait differences. The cryptic fungal pathogen Aspergillus latus, an allodiploid hybrid originating from Aspergillus spinulosporus and an unknown close relative of Aspergillus quadrilineatus within section Nidulantes, remains poorly understood. The absence of accurate diagnostics for A. latus has led to misidentifications, hindering epidemiological studies and the design of effective treatment plans. We conducted an in-depth investigation of the genomes and phenotypes of 44 globally distributed isolates (41 clinical isolates and three type strains) from Aspergillus section Nidulantes. We found that 21 clinical isolates were A. latus; notably, standard methods of pathogen identification misidentified all A. latus isolates. The remaining isolates were identified as A. spinulosporus (8), A. quadrilineatus (1), or A. nidulans (11). Phylogenomic analyses shed light on the origin of A. latus, indicating one or two hybridization events gave rise to the species during the Miocene, approximately 15.4 to 8.8 million years ago. Characterizing the A. latus pangenome uncovered substantial genetic diversity within gene families and biosynthetic gene clusters. Transcriptomic analysis revealed that both parental genomes are actively expressed in nearly equal proportions and respond to environmental stimuli. Further investigation into infection-relevant chemical and physiological traits, including drug resistance profiles, growth under oxidative stress conditions, and secondary metabolite biosynthesis, highlight distinct phenotypic profiles of the hybrid A. latus compared to its parental and closely related species. Leveraging our comprehensive genomic and phenotypic analyses, we propose five genomic and phenotypic markers as diagnostics for A. latus species identification. These findings provide valuable insights into the evolutionary origin, genomic outcome, and phenotypic implications of hybridization in a cryptic fungal pathogen, thus enhancing our understanding of the underlying processes contributing to fungal pathogenesis. Furthermore, our study underscores the effectiveness of extensive genomic and phenotypic analyses as a promising approach for developing diagnostics applicable to future investigations of cryptic and emerging pathogens.

evolutionary biology↗

bioRxiv2021

Transcriptome Profiles of Anopheles gambiae Harboring Natural Low-Level Plasmodium Infection Reveal Adaptive Advantages for the Mosquito

Anopheline mosquitoes are the sole vectors for the Plasmodium pathogens responsible for malaria, which is among the oldest and most devastating of human diseases. The continuing global impact of malaria reflects the evolutionary success of a complex vector-pathogen relationship that accordingly has been the long-term focus of both debate and study. An open question in the biology of malaria transmission is the impact of naturally occurring low-level Plasmodium infections of the vector on the mosquitos health and longevity as well as critical behaviors such as host- preference/seeking. To begin to answer this, we have completed a comparative RNAseq-based transcriptome profile study examining the effect of biologically salient, salivary gland transmission- stage Plasmodium infection on the molecular physiology of Anopheles gambiae s.s. head, sensory appendage, and salivary glands. When compared with their uninfected counterparts, Plasmodium infected mosquitoes exhibit increased transcript abundance of genes associated with olfactory acuity as well as a range of synergistic processes that align with increased fitness based on both anti-aging and reproductive advantages. Taken together, these data argue against the long-held paradigm that malaria infection is pathogenic for anophelines and, instead, suggests there are biological and evolutionary advantages for the mosquito that drive the preservation of its high vectorial capacity.

molecular biology↗