Biology subjects

Shea, T.

Publications and source records attributed to Shea, T..

7 recordsLinked to original sources

bioRxiv2025

Complex exchanges among plasmids and clonal expansion of lineages shape the population structure and virulence of Borrelia burgdorferi

The many plasmids (commonly >20 per strain) of Borrelia burgdorferi (Bb) pose challenges for studies of Lyme disease. The genetic content of most plasmids cannot be resolved using short-read sequencing. We generated long-read assemblies (LRA) of 183 isolates of human-derived Bb and analyzed patterns of genome variation in the Lyme spirochete. LRAs confirm that populations consist of strongly-structured genotypes with nearly-clonal structure and tight-knit blocks of accessory genome elements. Notably, these patterns of linkage were statistical but not physical, with linkage blocks distributed across multiple plasmids. A consequence of this structure is that plasmid name and/or plasmid subtype does not capture strain-specific genetic content. We used network methods to characterize patterns of genetic linkage. We demonstrate that co-occurring gene networks, here termed genetic modules, are the fundamental unit of genome variation in Bb and designate genetic modules consisting of co-occurring genes. We linked genetic modules to Bb phenotype by identifying modules that influence dissemination in humans. This modular decomposition clarifies previously observed associations between strain and virulence. For example, virulent RST1/OspC type A strains are distinguished by the presence of virulence-associated modules containing gene content from lp28-1, lp56, and the chromosome along with the absence of gene content on lp28-1 and lp28-4 associated with localized disease. LRAs also demonstrate that the well-established statistical linkage between physical unlinked genetic markers (e.g. RST and OspC) is a general pattern among accessory genome elements. In summary, genetic modules containing genes linked across multiple replicons, rather than strain-defining plasmids, organize the Bb accessory genome and the strain-specific variation responsible for differences in human virulence.

microbiology↗

bioRxiv2025

Insights into global antimicrobial resistance dynamics through the sequencing of enteric bacteria from U.S. international travelers

Antimicrobial resistance (AMR) is an urgent threat to public health, but gaps in surveillance limit the detection of emergent novel threats and knowledge about the global distribution of AMR genes. International travelers frequently acquire AMR organisms, and thus may provide a window into AMR dynamics in otherwise poorly monitored regions and environments. To assess the utility of travelers as global AMR sentinels, we collected pre- and post-travel stool samples from 608 travelers, which were screened for the presence of extended-spectrum beta-lactamase producing Enterobacterales, carbapenem-resistant Enterobacterales, and mcr-mediated colistin-resistant Enterobacterales. A total of 307 distinct AMR organisms were sequenced in order to determine genotypic patterns and their association with travel region and behavior. Travel-associated AMR organisms were overwhelmingly E. coli, which exhibited considerable phylogenetic diversity regardless of travel region. However, the prevalence of resistance genes varied by region, with blaCTX-M-55 and blaCTX-M-27 significantly more common in travelers returning from South America and South-Eastern Asia, respectively. Hybrid assembly and plasmid reconstruction revealed the genomic neighborhood of blaCTX-M-55 frequently matched a motif previously linked to animal populations. Contact with animals was also associated with virulence factors in acquired AMR organisms, including carriage of the ColV plasmid, a driver of avian pathogenic E. coli. We identified novel variants of the mcr-1 gene in strains acquired from Western Africa, highlighting the potential for traveler surveillance to detect emerging clinical threats. Ongoing efforts to track travel-acquired organisms could complement existing global AMR surveillance frameworks. ImportanceWe collected pre- and post-travel stool samples from 608 U.S. international travelers, which were screened for the presence of three clinically relevant antimicrobial-resistant organisms, with the goal of understanding the utility of travelers as sentinels for emerging AMR and identifying regional resistance patterns. We sequenced 307 organisms and uncovered significant diversity and geographic heterogeneity in AMR organisms. We found significant differences in certain resistance gene alleles of travelers returning from South America and South-Eastern Asia, traveler contact with animals associated with virulence factors, including a plasmid that is a known driver of avian pathogenic E. coli, and novel variants of the colistin resistance mcr-1 gene in strains acquired from Western Africa. This work emphasizes the value of monitoring international travelers as a proxy for understanding AMR patterns globally and could be an important addition to existing global AMR surveillance frameworks.

genomics↗

bioRxiv2023

Comparative genomics of Cryptococcus and Kwoniella reveals pathogenesis evolution and contrasting modes of karyotype evolution via chromosome fusion or intercentromeric recombination

A large-scale comparative genomic analysis was conducted for the global human fungal pathogens within the Cryptococcus genus, compared to non-pathogenic Cryptococcus species, and related species from the sister genus Kwoniella. Chromosome-level genome assemblies were generated for multiple species of both genera, resulting in a dataset encompassing virtually all of their known diversity. Although Cryptococcus and Kwoniella have comparable genome sizes (about 19.2 and 22.9 Mb) and similar gene content, hinting at pre-adaptive pathogenic potential, our analysis found evidence in pathogenic Cryptococcus species of specific examples of gene gain (via horizontal gene transfer) and gene loss, which might represent evolutionary signatures of pathogenic development. Genome analysis also revealed a significant variation in chromosome number and structure between the two genera. By combining synteny analysis and experimental centromere validation, we found that most Cryptococcus species have 14 chromosomes, whereas most Kwoniella species have fewer (11, 8, 5 or even as few as 3). Reduced chromosome number in Kwoniella is associated with formation of giant chromosomes (up to 18 Mb) through repeated chromosome fusion events, each marked by a pericentric inversion and centromere loss. While similar chromosome inversion-fusion patterns were observed in all Kwoniella species with fewer than 14 chromosomes, no such pattern was detected in Cryptococcus. Instead, Cryptococcus species with less than 14 chromosomes, underwent chromosome reductions primarily through rearrangements associated with the loss of repeat-rich centromeres. Additionally, Cryptococcus genomes exhibited frequent interchromosomal translocations, including intercentromeric recombination facilitated by transposons shared between centromeres. Taken together, our findings advance our understanding of genomic changes possibly associated with pathogenicity in Cryptococcus and provide a foundation to elucidate mechanisms of centromere loss and chromosome fusion driving distinct karyotypes in closely related fungal species, including prominent global human pathogens.

genomics↗

bioRxiv2022

Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex

Sexual reproduction is a ubiquitous and ancient trait of eukaryotic life. While sexual organisms are usually faced with the challenge of finding a compatible mating partner, species as diverse as animals, plants, and fungi have repeatedly evolved the ability to reproduce sexually without an obligate requirement for another individual. Here, we uncovered the underlying mechanism of self-compatibility (homothallism) in Cryptococcus depauperatus, a fungal species sister to the clinically relevant human fungal pathogens Cryptococcus neoformans and Cryptococcus gattii species complexes. In contrast to C. neoformans or C. gattii, which grow as a yeast in the asexual stage, and produce hyphae, basidia, and infectious spores during the sexual stage, C. depauperatus grows exclusively as hyphae decorated with basidia and abundant spores and appears to be continuously engaged in sexual reproduction. By combining the insights from comparative genomics and genetic analyses of mutants defective in key mating and meiosis genes, we demonstrate the sexual cycle of C. depauperatus involves meiosis, and reveal that self-compatibility is orchestrated by the expression, in the same cell, of an unlinked mating receptor (Ste3a) and pheromone ligand (MF) pair seemingly derived from opposite mating types of a heterothallic (self-sterile) ancestor. We identified a putative mating-type (MAT) determining region containing genes phylogenetically aligned with MATa alleles of other species, and a few MAT gene alleles scattered and unlinked throughout the genome, but no homologs of the mating-type homeodomain genes SXI1 (HD1) and SXI2 (HD2). Comparative genomic analyses suggested a dramatic remodeling of the MAT locus possibly owing to reduced selective constraints to maintain mating-type genes in tight linkage, associated with a transition to self-fertility. Our findings support C. depauperatus as an obligately sexual, homothallic fungal species and provide additional insight into the repeated transitions between modes of sexual reproduction that have occurred throughout the fungal kingdom.

microbiology↗

bioRxiv2019

Chromosomal rearrangements and loss of subtelomeric adhesins linked to clade-specific phenotypes in Candida auris

Candida auris is an emerging fungal pathogen of rising concern due to its increasing incidence, its ability to cause healthcare-associated outbreaks and antifungal resistance. Genomic analysis revealed that early cases of C. auris that were detected contemporaneously were geographically stratified into four major clades. Clade II, also termed East Asian clade, consists of the initial isolates described from cases of ear infection, is less frequently resistant to antifungal drugs and to date, the isolates from this group have not been associated with outbreaks. Here, we generate nearly complete genomes (\"telomere-to-telomere\") of an isolate of this clade and of the more widespread Clade IV. By comparing these to genome assemblies of the other two clades, we find that the Clade II genome appears highly rearranged, with 2 inversions and 9 translocations resulting in a substantially different karyotype. In addition, large subtelomeric regions have been lost from 10 of 14 chromosome ends in the Clade II genomes. We find that shorter telomeres and genome instability might be a consequence of a naturally occurring loss-of-function mutation in DCC1 exclusively found in Clade II isolates, resulting in a hypermutator phenotype. We also determine that deleted subtelomeric regions might be linked to clade-specific adaptation as these regions are enriched in Hyr/Iff-like cell surface proteins, novel candidate cell surface proteins, and an ALS-like adhesin. The presence of these cell surface proteins in the clades responsible for global outbreaks causing invasive infections suggests an explanation for the different phenotypes observed between clades.\n\nIMPORTANCECandida auris was unknown prior to 2009 and since then it has quickly spread around the world, causing outbreaks in healthcare facilities and representing a high fraction of candidemia cases in some regions. The emergence of C. auris is a major concern, since it is often multidrug-resistant, easily spread between patients, and causes invasive infections. While isolates from three global clades cause invasive infections, isolates from Clade II primarily cause ear infections and have not been implicated in outbreaks, though cases of Clade II infections have been reported on different continents. Here, we describe genetic differences between Clade II and Clades I, III and IV, including a loss-of-function mutation in a gene associated with telomere length maintenance and genome stability, and the loss of cell wall proteins involved in adhesion and biofilm formation, that may suggest an explanation for the lower virulence and potential for transmission of Clade II isolates.

genomics↗

bioRxiv2019

Transmission of human-associated microbiota along family and social networks

The human microbiome, described as an accessory organ because of the crucial functions it provides, is composed of species that are uniquely found in humans1,2. Yet, surprisingly little is known about the impact of routine interpersonal contacts in shaping microbiome composition. In a relatively closed cohort of 287 people from the Fiji Islands, where common barriers to bacterial transmission are absent, we examine putative bacterial transmission in individuals gut and oral microbiomes using strain-level data from both core SNPs and flexible genomic regions. We find a weak signal of transmission, defined by the inferred sharing of genotypes, across many organisms that, in aggregate, reveals strong transmission patterns, most notably within households and between spouses. We find that women harbor strains more closely related to those harbored by their familial and social contacts than men; and that transmission patterns of oral- and gut-associated microbiota need not be the same. Using strain-level data alone, we are able to confidently predict a subset of spouses, highlighting the role of shared susceptibilities, behaviors or social interactions that distinguish specific links in the social network.

microbiology↗

bioRxiv2018

Whole genome analysis illustrates global clonal population structure of the ubiquitous dermatophyte pathogen Trichophyton rubrum

Dermatophytes include fungal species that infect humans, as well as those which also infect other animals or only grow in the environment. The dermatophyte species Trichophyton rubrum is a frequent cause of skin infection in immunocompetent individuals. While members of the T. rubrum species complex have been further categorized based on various morphologies, the population structure and ability to undergo sexual reproduction are not well understood. In this study, we analyze a large set of T. rubrum and Trichophyton interdigitale isolates to examine mating types, evidence of mating, and genetic variation. We find that nearly all isolates of T. rubrum are of a single mating type, and that incubation with T. rubrum morphotype megninii isolates of the other mating type failed to induce sexual development. While the region around the mating type locus is characterized by a higher frequency of SNPs compared to other genomic regions, we find that the population is remarkably clonal, with highly conserved gene content, low levels of variation, and little evidence of recombination These results support a model of recent transition to asexual growth when this species specialized to growth on human hosts.\n\nData access: Genome sequence data is available in NCBI under the Umbrella BioProject PRJNA186851.

genetics↗