Biology subjects

Kessler, C.

Publications and source records attributed to Kessler, C..

11 recordsLinked to original sources

bioRxiv2026

Ancient DNA perspectives on North American cervids identify dispersal waves and fluctuations in diversity

North American fauna has experienced major changes over the last two million years. Glacial cycles, animal migrations, peopling waves, and, more recently, European colonisation, caused demographic fluctuations, divergence, and wildlife extinctions. Caribou (Rangifer tarandus), moose (Alces alces), wapiti (Cervus canadensis), white-tailed (Odocoileus virginianus) and mule deer (O. hemionus) are the five extant cervids in Northern America, with unique dispersal patterns and conservation statuses. Here, we used DNA analysis of ancient, historical and modern individuals of these Cervidae to retrace evolutionary processes through time. We show that present-day eastern Canada caribou share ancestry with a 30-thousand-year-old sample from western Canada consistent with the species' complex dispersal history as suggested by literature. Our results suggest rapid expansion of moose following their arrival on the continent ~15 thousand years ago. Data on wapiti shows a recent loss of diversity consistent with its large-scale extirpation after European colonisation. Results on Odocoileus species are in line with their recognised mito-nuclear discordance. Our results exemplify the utility of chronological sampling to gain a better understanding of how external pressures drive genomic changes.

evolutionary biology↗

bioRxiv2025

Ancient DNA from the Toronto subway deer adds to the extinction list of North America's Ice Age megafauna

The late Pleistocene was a time of global megafaunal extinctions that were particularly severe in North America. The continent lost many mammal taxa, but the validity of several remain ambiguous, including a high proportion of Cervidae taxa. Torontoceros hypogaeus is represented by a single specimen (ROMM75974) discovered in 1976 during excavation work for the Toronto subway in Canada. The species was described based on its unique antler morphology, but the variable nature of that trait and the species near absence in the fossil record leads to uncertainty concerning its systematic relationships. We used ancient DNA to clarify the taxonomic relationship and evolutionary history of T. hypogaeus. We performed mitochondrial and whole genome analyses with related cervids and showed that ROMM75974 has a close affinity, but relatively high divergence from the Odocoileus sister species. While some ambiguity remains, ROMM75974 could represent a distinct Odocoileus species to be included in the list of extinct North American taxa. This unique population was likely adapted to open landscape which was rapidly replaced with dense woodland in this region at the end of the Pleistocene, highlighting the role of climate change in the extinction of megafauna biodiversity at the end of the ice age.

paleontology↗

bioRxiv2024

Discovery and chemical optimisation of a Potent, Bi-cyclic (Bicycle(R)) Antimicrobial Inhibitor of Escherichia coli PBP3

Penicillin binding proteins (PBPs) are well validated antimicrobial targets, but the prevalence of {beta}-lactamase driven resistance and, more rarely, target-based mutations, necessitates new classes of PBP-targeting drugs. Here we describe the discovery and optimisation of novel, bicyclic peptide (Bicycle(R)) inhibitors of E. coli PBP3 (EcPBP3) using a proprietary phage display platform, and their conjugation to linear antimicrobial peptides to confer outer membrane permeation. These molecules exhibited high-affinity binding to E. coli PBP3 and a viable spectrum of killing activity against clinically relevant species of the Enterobacterales. X-ray crystallography was used to explore the mode of binding to PBP3, enabling increased target affinity and improvement of in vitro stability. These compounds bind to the transpeptidase active site cleft of PBP3 and represent a novel non-{beta}-lactam chemical class of high affinity, non-covalent penicillin binding protein inhibitors.

biochemistry↗

bioRxiv2024

Natural products from food sources can alter the spread of AMR plasmids in Enterobacterales

Antimicrobial resistance (AMR) poses a significant threat to global public health. Notably, resistance to carbapenem and extended-spectrum {beta}-lactam antibiotics in Gram-negative bacteria is a major impediment for the treatment of infections. Genes responsible for resistance to these antibiotics are frequently carried on plasmids, which can transfer between bacteria. Therefore, exploring strategies to prevent this transfer and/or the prevalence of AMR plasmids is timely and pertinent. Here, we show that certain natural product extracts and associated pure compounds can reduce the transmission of AMR plasmids into new bacterial hosts. Using our established high-throughput fluorescence-based screen we found that the natural products were more active in reducing transmission of the IncK plasmid pCT in Escherichia coli ST131, compared to Klebsiella pneumoniae Ecl8 carrying the IncFII plasmid pKpQIL. Furthermore, we found that the natural product rottlerin was more active in K. pneumoniae than in E. coli. Importantly, rottlerin was also associated with a reduced number of transconjugant bacteria in a clinical K. pneumoniae isolate harbouring a blaNDM-1 plasmid. Together, these results demonstrate the potential of natural products as promising anti-plasmid agents.

microbiology↗

bioRxiv2023

Island demographics and trait associations in white-tailed deer

When a population is isolated and composed of few individuals, genetic drift is the paramount evolutionary force that results in the loss of genetic diversity. Inbreeding might also occur, resulting in genomic regions that are identical by descent, manifesting as runs of homozygosity (ROHs) and the expression of recessive traits. Likewise, the genes underlying traits of interest can be revealed by comparing fixed SNPs and divergent haplotypes between affected and unaffected individuals. Populations of white-tailed deer (Odocoileus virginianus) on islands of Saint Pierre and Miquelon (SPM, France) have high incidences of leucism and malocclusions, both considered genetic defects; on the Florida Keys islands (USA) deer exhibit smaller body sizes, a polygenic trait. Here we aimed to reconstruct island demography and identify the genes associated with these traits in a pseudo case-control design. The two island populations showed reduced levels of genomic diversity and a build-up of deleterious mutations compared to mainland deer; there was also significant genome-wide divergence in Key deer. Key deer showed higher inbreeding levels, but not longer ROHs, consistent with long-term isolation. We identified multiple trait-related genes in ROHs including LAMTOR2 which has links to pigmentation changes, and NPVF which is linked to craniofacial abnormalities. Our mixed approach of linking ROHs, fixed SNPs and haplotypes matched a high number ([~]50) of a-priori body size candidate genes in Key deer. This suite of biomarkers and candidate genes should prove useful for population monitoring, noting all three phenotypes show patterns consistent with a complex trait and non-Mendelian inheritance.

genomics↗

bioRxiv2023

Genomic analyses unveil unprecedented human-induced demographic collapse and recovery in a wide-ranging cervid

The glacial cycles of the Quaternary heavily impacted species through successions of population contractions and expansions. Similarly, populations have been intensely shaped by human pressures such as unregulated hunting and land use changes. White-tailed and mule deer survived in different refugia through the Last Glacial Maximum, and their populations were severely reduced after the European colonisation. Here, we analysed 73 re-sequenced deer genomes from across their North American range to understand the consequences of climatic and anthropogenic pressures on deer demographic and adaptive history. We found a strong signal of glacial-induced vicariance and demographic decline; notably, there is a severe decline in white-tailed deer effective population size (Ne) at the end of the Last Glacial Maximum. We found robust evidence for colonial overharvest in the form of a recent and dramatic drop in Ne in all analysed populations. Historical census size and restocking data show a clear parallel to historical Ne estimates, and temporal Ne/Nc ratio shows patterns of conservation concern for mule deer. Signatures of selection highlight genes related to temperature, including a cold receptor previously highlighted in woolly mammoth. We also detected immune-genes that we surmise reflect the changing land-use patterns in North America. Our study provides a detailed picture of anthropogenic and climatic-induced decline in deer diversity, and clues to understanding the conservation concerns of mule deer and the successful demographic recovery of white-tailed deer.

genomics↗

bioRxiv2022

Global characterization of the cyclic-di-GMP regulome by bi-directionally evolving a social trait in Pseudomonas fluorescens

Modulation of the intracellular cyclic di-guanosine monophosphate (c-di-GMP) pool is central to the formation of structured bacterial communities. Genome annotations predict the presence of dozens of conserved c-di-GMP catalytic enzymes in many bacterial species, but the functionality and regulatory control of the vast majority remain underexplored. Here, we begin to fill this gap by utilizing an experimental evolution system in Pseudomonas fluorescens Pf0-1, which repeatedly produces a unique social trait through bidirectional transitions between two distinct phenotypes converging on c-di-GMP modulation. Parallel evolution of 33 lineages captured 147 unique mutations among 191 evolved isolates in genes that are empirically demonstrated, bioinformatically predicted, or previously unknown to impact the intracellular pool of c-di-GMP. Quantitative chemistry confirmed that each mutation causing the phenotypic shift predictably amplifies or reduces c-di-GMP production. We integrate our mutation, phenotype, and quantification data with current models of known regulatory and catalytic systems, describe a previously unknown relationship between a regulatory component of branched-chain amino acid biosynthesis and c-di-GMP production, and predict functions of unexpected proteins that clearly impact c-di-GMP production. Sequential mutations that continuously disrupt or recover c-di-GMP production across discrete functional elements suggest a complex and underappreciated interconnectivity within the c-di-GMP regulome of P. fluorescens. ImportanceMicrobial communities comprise densely packed cells where competition for space and resources is fierce. In our model system, mutant cells with a dry (D) phenotype are selected from a population with a mucoid (M) phenotype, and vice versa, because M and D cells physically work together to spread away from the overcrowded colony. D cells produce high levels of c-di-GMP and M cells produce low levels, so each mutation impacts c-di-GMP production. C-di-GMP is a second messenger which regulates diverse bacterial phenotypes that cause tremendous clinical and environmental problems. Many bacteria possess dozens of enzymes that are predicted to produce c-di-GMP, but most are considered to be non-functional. Here, we take advantage of the bi-directional selection of M and D phenotypes to identify key residues that could force these enzymes to turn on or off. Several unexpected proteins also participate in this process, but very little is known about them.

microbiology↗

bioRxiv2022

Speciation without gene-flow in hybridizing deer

Under the ecological speciation model, divergent selection acts on ecological differences between populations, gradually creating barriers to gene flow and ultimately leading to reproductive isolation. Hybridisation is part of this continuum and can both promote and inhibit the speciation process. Here, we used white-tailed (Odocoileus virginianus) and mule deer (O. hemionus) to investigate patterns of speciation in hybridising sister species. We quantified genome-wide historical introgression and performed genome scans to look for signatures of four different selection scenarios. Despite ample modern evidence of hybridisation, we found negligible patterns of ancestral introgression and no signatures of divergence with gene flow, rather localised patterns of allopatric and balancing selection were detected across the genome. Genes under balancing selection were related to immunity, MHC and sensory perception of smell, the latter of which is consistent with deer biology. The deficiency of historical gene-flow suggests that white-tailed and mule deer were spatially separated during the glaciation cycles of the Pleistocene and genome wide differentiation accrued via genetic drift. Dobzhansky-Muller incompatibilities and selection against hybrids are hypothesised to be acting, and diversity correlations to recombination rates suggests these sister species are far along the speciation continuum.

evolutionary biology↗

bioRxiv2021

Evolutionary divergence of the Wsp signal transduction system in β- and γ-proteobacteria

Bacteria rapidly adapt to their environment by integrating external stimuli through diverse signal transduction systems. Pseudomonas aeruginosa, for example, senses surface-contact through the Wsp signal transduction system to trigger the production of cyclic di-GMP. Diverse mutations in wsp genes that manifest enhanced biofilm formation are frequently reported in clinical isolates of P. aeruginosa, and in biofilm studies of Pseudomonas spp. and Burkholderia cenocepacia. In contrast to the convergent phenotypes associated with comparable wsp mutations, we demonstrate that the Wsp system in B. cenocepacia does not impact intracellular cyclic di-GMP levels unlike that in Pseudomonas spp. Our current mechanistic understanding of the Wsp system is entirely based on the study of four Pseudomonas spp. and its phylogenetic distribution remains unknown. Here, we present the first broad phylogenetic analysis to date to show that the Wsp system originated in the {beta}-proteobacteria then horizontally transferred to Pseudomonas spp., the sole member of the {gamma}-proteobacteria. Alignment of 794 independent Wsp systems with reported mutations from the literature identified key amino acid residues that fall within and outside annotated functional domains. Specific residues that are highly conserved but uniquely modified in B. cenocepacia likely define mechanistic differences among Wsp systems. We also find the greatest sequence variation in the extracellular sensory domain of WspA, indicating potential adaptations to diverse external stimuli beyond surface-contact sensing. This study emphasizes the need to better understand the breadth of functional diversity of the Wsp system as a major regulator of bacterial adaptation beyond B. cenocepacia and select Pseudomonas spp. ImportanceThe Wsp signal transduction system serves as an important model system for studying how bacteria adapt to living in densely structured communities known as biofilms. Biofilms frequently cause chronic infections and environmental fouling, and they are very difficult to eradicate. In Pseudomonas aeruginosa, the Wsp system senses contact with a surface, which in turn activates specific genes that promote biofilm formation. We demonstrate that the Wsp system in Burkholderia cenocepacia regulates biofilm formation uniquely from that in Pseudomonas species. Furthermore, a broad phylogenetic analysis reveals the presence of the Wsp system in diverse bacterial species, and sequence analyses of 794 independent systems suggest that the core signaling components function similarly but with key differences that may alter what or how they sense. This study shows that Wsp systems are highly conserved and more broadly distributed than previously thought, and their unique differences likely reflect adaptations to distinct environments.

microbiology↗

bioRxiv2020

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories toward type 2 diabetes

Existing studies do not sufficiently describe the molecular changes of pancreatic islet beta cells leading to their deficient insulin secretion in type 2 diabetes (T2D). Here we address this deficiency with a comprehensive multi-omics analysis of metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum from normoglycemia to T2D. Islet pools isolated from surgical samples by laser-capture microdissection had remarkably heterogeneous transcriptomic and proteomic profiles in diabetics, but not in non-diabetic controls. Transcriptomics analysis of this unique cohort revealed islet genes already dysregulated in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive but disharmonic remodeling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or trans-differentiation stages in T2D. Further, integration of islet transcriptomics and pre-operative blood plasma lipidomics data enabled us to define the relative importance of gene co-expression modules and lipids positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.

bioinformatics↗

bioRxiv2020

A robust sequencing assay of a thousand amplicons for the high-throughput population monitoring of Alpine ibex immunogenetics

Genetic variation is a major factor determining susceptibility to diseases. Polymorphism at the major histocompatibility complex (MHC) and other immune function loci can underlie health and reproductive success of individuals. Endangered species of low population size could be severely compromised to evolve disease resistance due to reduced adaptive variation. A major impediment to screen adaptive genetic variation in wild species is the difficulty to comprehensively genotype immune-related loci based on low input material. Here, we design and validate a targeted amplicon sequencing assay to parallelize the analysis of a thousand loci of the MHC, other immunity-related genes, and genome-wide markers for the assessment of population structure. We apply the approach to Alpine ibex, one of the most successful examples of restoration of a large mammal in Europe. We used 51 whole genome sequenced individuals to select representative target SNPs. We integrated SNP call data from four related species for amplification robustness and genotyped 158 Alpine ibex individuals for validation. We show that the genome-wide markers perform equally well at resolving population structure as RAD-seq or low-coverage genome sequencing datasets with orders of magnitude more markers. The targeted amplicon sequencing assay is robust to >100-fold variation in input DNA quantity and generates useful genotype information from fecal samples. The amplicon marker set also identified recent species hybridization events with domestic goats. The immune loci show unexpectedly high degrees of differentiation within the species. Our assay strategy can realistically be implemented into population genetic surveys of a large range of species.

genomics↗