Biology subjects

Rinker, D. C.

Publications and source records attributed to Rinker, D. C..

7 recordsLinked to original sources

bioRxiv2025

Machine learning identifies novel signatures of antifungal drug resistance in Saccharomycotina yeasts

Antifungal drug resistance is a major challenge in fungal infection management. Numerous genomic changes are known to contribute to acquired drug resistance in clinical isolates of specific pathogens, but whether they broadly explain natural resistance across entire lineages is unknown. We leveraged genomic, ecological, and phenotypic trait data from naturally sampled strains from nearly all known species in subphylum Saccharomycotina to examine the evolution of resistance to eight antifungal drugs. The phylogenetic distribution of drug resistance varied by drug; fluconazole resistance was widespread, while 5-fluorocytosine resistance was rare, except in Lipomycetales. A random forest algorithm trained on genomic data predicted drug-resistant yeasts with 54-75% accuracy. In general, frequency of drug resistance correlated with prediction accuracy, with fluconazole resistance being consistently predicted with the highest accuracy (74.9%). Fluconazole resistance accuracy was similar between models trained on genome-wide variation in the presence and number of InterPro protein annotations across Saccharomycotina (74.9% accuracy) and those trained on amino acid sequence alignment data of Erg11, a protein known to be involved in fluconazole resistance (74.3-74.9% accuracy). Interestingly, the top Erg11 residues for predicting fluconazole resistance across Saccharomycotina do not overlap with, are not spatially close to, and are less conserved than those previously linked to resistance in clinical isolates of Candida albicans. In silico deep mutational scanning of the C. albicans Erg11 protein revealed that amino acid variants implicated in clinical cases of resistance are almost universally destabilizing while variants in our most informative residues are energetically more neutral, explaining why the latter are much more common than the former in natural populations. Importantly, previous experimental analyses of C. albicans Erg11 have shown that amino acid variation in our most informative residues, despite having never been directly implicated in clinical cases, can directly contribute to resistance. Our results suggest that studies of natural resistance in yeast species never encountered in the clinic will yield a fuller understanding of antifungal drug resistance.

microbiology↗

bioRxiv2024

Strain heterogeneity in a non-pathogenic fungus highlights factors contributing to virulence

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri, a non-pathogenic close relative of the major pathogen Aspergillus fumigatus. In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.

evolutionary biology↗

bioRxiv2023

Machine learning reveals the diversity of human 3D chromatin contact patterns

Understanding variation in chromatin contact patterns across human populations is critical for interpreting non-coding variants and their ultimate effects on gene expression and phenotypes. However, experimental determination of chromatin contacts at a population-scale is prohibitively expensive. To overcome this challenge, we develop and validate a machine learning method to quantify the diversity 3D chromatin contacts at 2 kilobase resolution from genome sequence alone. We then apply this approach to thousands of diverse modern humans and the inferred human-archaic hominin ancestral genome. While patterns of 3D contact divergence genome-wide are qualitatively similar to patterns of sequence divergence, we find that 3D divergence in local 1-megabase genomic windows does not follow sequence divergence. In particular, we identify 392 windows with significantly greater 3D divergence than expected from sequence. Moreover, 26% of genomic windows have rare 3D contact variation observed in a small number of individuals. Using in silico mutagenesis we find that most sequence changes to do not result in changes to 3D chromatin contacts. However in windows with substantial 3D divergence, just one or a few variants can lead to divergent 3D chromatin contacts without the individuals carrying those variants having high sequence divergence. In summary, inferring 3D chromatin contact maps across human populations reveals diverse contact patterns. We anticipate that these genetically diverse maps of 3D chromatin contact will provide a reference for future work on the function and evolution of 3D chromatin contact variation across human populations.

genomics↗

bioRxiv2022

Reconstructing the 3D genome organization of Neanderthals reveals that chromatin folding shaped phenotypic and sequence divergence

Changes in gene regulation were a major driver of the divergence of archaic hominins (AHs)--Neanderthals and Denisovans--and modern humans (MHs). The three-dimensional (3D) folding of the genome is critical for regulating gene expression; however, its role in recent human evolution has not been explored because the degradation of ancient samples does not permit experimental determination of AH 3D genome folding. To fill this gap, we apply novel deep learning methods for inferring 3D genome organization from DNA sequence to Neanderthal, Denisovan, and diverse MH genomes. Using the resulting 3D contact maps across the genome, we identify 167 distinct regions with diverged 3D genome organization between AHs and MHs. We show that these 3D-diverged loci are enriched for genes related to the function and morphology of the eye, supra-orbital ridges, hair, lungs, immune response, and cognition. Despite these specific diverged loci, the 3D genome of AHs and MHs is more similar than expected based on sequence divergence, suggesting that the pressure to maintain 3D genome organization constrained hominin sequence evolution. We also find that 3D genome organization constrained the landscape of AH ancestry in MHs today: regions more tolerant of 3D variation are enriched for introgression in modern Eurasians. Finally, we identify loci where modern Eurasians have inherited novel 3D genome folding patterns from AH ancestors and validate folding differences in a high-frequency locus using Hi-C, revealing a putative molecular mechanism for phenotypes associated with archaic introgression. In summary, our application of deep learning to predict archaic 3D genome organization illustrates the potential of inferring molecular phenotypes from ancient DNA to reveal previously unobservable biological differences.

evolutionary biology↗

bioRxiv2022

The IMD and JNK pathways drive the functional integration of the immune and circulatory systems of mosquitoes

The immune and circulatory systems of animals are functionally integrated. In mammals, the spleen and lymph nodes filter and destroy microbes circulating in the blood and lymph, respectively. In insects, immune cells that surround the heart valves (ostia), called periostial hemocytes, destroy pathogens in the areas of the body that experience the swiftest hemolymph (blood) flow. An infection recruits additional periostial hemocytes, amplifying heart-associated immune responses. Although the structural mechanics of periostial hemocyte aggregation have been defined, the genetic factors that regulate this process remain less understood. Here, we conducted RNAseq in the African malaria mosquito, Anopheles gambiae, and discovered that an infection upregulates multiple components of the IMD and JNK pathways in the heart with periostial hemocytes. This upregulation is greater in the heart with periostial hemocytes than in the circulating hemocytes or the entire abdomen. RNAi-based knockdown then showed that the IMD and JNK pathways drive periostial hemocyte aggregation and alter phagocytosis and melanization on the heart, thereby demonstrating that these pathways regulate the functional integration between the immune and circulatory systems. Understanding how insects fight infection lays the foundation for novel strategies that could protect beneficial insects and harm detrimental ones.

immunology↗

bioRxiv2020

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

BackgroundNearly all Eurasians have [~]2% Neanderthal ancestry due to several events of inbreeding between anatomically modern humans and archaic hominins. Previous studies characterizing the legacy of Neanderthal ancestry in modern Eurasians have identified examples of both adaptive and deleterious effects of admixture. However, we lack a comprehensive understanding of the genome-wide influence of Neanderthal introgression on modern human diseases and traits. ResultsWe integrate recent maps of Neanderthal ancestry with well-powered association studies for more than 400 diverse traits to estimate heritability enrichment patterns in regions of the human genome tolerant of Neanderthal ancestry and in introgressed Neanderthal variants themselves. First, we find that variants in regions tolerant of Neanderthal ancestry are depleted of heritability for all traits considered, except skin and hair-related traits. Second, the introgressed variants remaining in modern Europeans are depleted of heritability for most traits; however, we discover that they are enriched for heritability of several traits with potential relevance to human adaptation to non-African environments, including hair and skin traits, autoimmunity, chronotype, bone density, lung capacity, and menopause age. To better understand the phenotypic consequences of these enrichments, we adapt recent methods to test for consistent directional effects of introgressed alleles, and we find directionality for several traits. Finally, we use a direction-of-effect-aware approach to highlight novel candidate introgressed variants that influence risk for disease. ConclusionOur results demonstrate that genomic regions retaining Neanderthal ancestry are not only less functional at the molecular-level, but are also depleted for variation influencing a diverse array of complex traits in modern humans. In spite of this depletion, we identify traits where introgression has an outsized effect. Integrating our results, we propose a framework for using quantification of trait heritability and direction of effect in introgressed regions to understand how Neanderthals were different from modern humans, how selection acted on different traits, and how introgression may have facilitated adaptation to non-African environments.

evolutionary biology↗

bioRxiv2019

Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck

Neanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes, including immune, skin, and neuropsychiatric diseases. Interpretation of introgressed sequences has focused on alleles derived in the Neanderthal lineage. Here, we demonstrate that Neanderthal introgression also reintroduced thousands of ancestral hominin alleles lost in the Eurasian out of Africa bottleneck. Combining evolutionary simulations, expression quantitative trait loci (eQTL), massively parallel reporter assay (MPRA) data, and in vitro validation, we show that reintroduced alleles (RAs) have different fitness effects than Neanderthal-derived alleles (NDAs) and that some RAs regulate gene expression independent of NDAs. Illustrating the broad potential influence of RAs, we find that over 70% of known phenotype associations with NDAs are equally associated with RAs. Finally, we discover enrichment for RA eQTL activity in several tissues, with strongest enrichment in the brain. In summary, our study reveals that Neanderthal introgression supplied Eurasians with many lost functional variants and demonstrates that RAs must be considered when evaluating the effects of introgression. ONE SENTENCE SUMMARYNeanderthal interbreeding with modern humans restored to Eurasians, hundreds of thousands of ancient alleles that were lost in the out of Africa bottleneck.

evolutionary biology↗