Biology subjects

Jeffares, D.

Publications and source records attributed to Jeffares, D..

6 recordsLinked to original sources

bioRxiv2023

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites

Quiescence and posttreatment relapse constitute an important therapeutic constraint across the microbiological spectrum. This study unveils that Leishmania infantum and L. donovani parasites rapidly enter quiescence after an estimated 4-6 divisions in both mouse and human stem cells of the bone marrow but not in macrophages as primary host cells. Quiescent amastigotes display a reduced size and evidence for a rapid evolutionary adaptation response with genetic alterations. We formally demonstrate that acquisition of a quiescent phenotype endows parasites with a capacity to survive antileishmanial treatment. Transition through quiescence also results in an increased cellular infectivity and high transmission capacity through the sand fly vector. Transcriptional profiling of quiescent and non-quiescent metabolic states identified a limited set of 26 upregulated genes that are of particular interest given their predicted involvement as regulators of cell cycle progression and of gene expression at various levels. The differential gene set constitutes a reliable source for the identification of novel markers and potential drivers of quiescence, a metabolic state bestowing parasites the capacity to escape drug treatment.

microbiology↗

bioRxiv2022

Comparisons between Complete Genomes of the Eukaryotic Extremophile Galdieria sulphuraria Reveals Complex Nuclear Chromosomal Structures

Extremophiles, while typically bacteria and archaea, are also found in the eukaryotic domain of life. The eukaryote Galdieria sulphuraria is a thermoacidophilic red alga belonging to the class Cyanidiophyceae, an especially unique class as it comprises the basal clade of eukaryotic extremophiles. Galdieria species can grow both photosynthetically and heterotrophically on a variety of carbon sources, thriving down to pH 0 and temperatures up to 56 {degrees}C, while tolerating high levels of reactive oxygen species and high levels of heavy metals. Here we report whole-genome sequencing of three G. sulphuraria strains, uncovering a compact (13.1 Mb - 16.0 Mb) nuclear genome with 72-73 chromosomes, dependent on the strain.Comparative analyses of the macro synteny revealed significant structural rearrangement between G. sulphuraria isolates and the genome shows signs of sexual recombination. This, along with the large number of nuclear chromosomes compared to the genome size, reveals a mechanism of intrinsic adaptability in this eukaryotic extremophile, uncovering how G. sulphuraria can thrive in a rapidly changing extreme environment.

genomics↗

bioRxiv2022

Resolving Complexities in Taxonomic Lineages of the Organellar and Nuclear Genomes of Galdieria through Comparative Phylogenomic Analysis

Exploration of life in extreme environments allows the discovery of intriguing organisms with extraordinary biotechnological potential. An example of extreme environments is represented by hot springs, where harsh conditions (pH < 1; Temperature > 50{degrees}C; high concentrations of metals) are prohibitive for most living organisms, except for archaea, bacteria and a few eukaryotes like the unicellular red alga Galdieria. Phylogenetic analysis based on a few plastid and nuclear genes highlighted the intricate genetic structure of Galdieria and the hypothesis of diverging clades within the G. sulphuraria species. To resolve enigmatic relationships between lineages, we used plastid, mitochondrial and nuclear genome-scale data obtained from numerous strains from around the world. The resulting phylogenomic analysis identified: i) the divergence of each of the mitochondrial, plastid, and nuclear genomes into the same six clear lineages; ii) the independent evolution of the lineages; iii) the incongruent interlineages relationships between the three genomes. Differential evolutionary pressure between the strains and the genomes were also highlighted by synonymous and non-synonymous substitutions.

genomics↗

bioRxiv2018

Ancestral admixture and structural mutation define global biodiversity in fission yeast

Mutation and recombination are key evolutionary processes governing phenotypic variation and reproductive isolation. We here demonstrate that biodiversity within all globally known strains of Schizosaccharomyces pombe arose through admixture between two ancestral lineages. Initial hybridization occurred [~]20 sexual outcrossing generations ago consistent with recent, human-induced migration at the onset of intensified transcontinental trade. Species-wide phenotypic variation was explained near-exclusively by strain-specific arrangements of alternating ancestry components with evidence for transgressive segregation. Reproductive compatibility between strains was likewise predicted by the degree of shared ancestry. Over 800 structural mutations segregating at low frequency had overall little effect on the introgression landscape. This study sheds new light on the population history of S. pombe and illustrates the importance of hybridization as a creative force in generating biodiversity.

evolutionary biology↗

bioRxiv2018

Uncovering natural longevity alleles from intercrossed pools of aging fission yeast cells

Quantitative traits often show large variation caused by multiple genetic factors. One such trait is the chronological lifespan of non-dividing yeast cells, serving as a model for cellular aging. Screens for genetic factors involved in ageing typically assay mutants of protein-coding genes. To identify natural genetic variants contributing to cellular aging, we exploited two strains of the fission yeast, Schizosaccharomyces pombe, that differ in chronological lifespan. We generated segregant pools from these strains and subjected them to advanced intercrossing over multiple generations to break up linkage groups. We chronologically aged the intercrossed segregant pool, followed by genome sequencing at different times to detect genetic variants that became reproducibly enriched as a function of age. A region on Chromosome II showed strong positive selection during ageing. Based on expected functions, two candidate variants from this region in the long-lived strain were most promising to be causal: small insertions and deletions in the 5-untranslated regions of ppk31 and SPBC409.08. Ppk31 is an orthologue of Rim15, a conserved kinase controlling cell proliferation in response to nutrients, while SPBC409.08 is a predicted spermine transmembrane transporter. Both Rim15 and the spermine-precursor, spermidine, are implicated in ageing as they are involved in autophagy-dependent lifespan extension. Single and double allele replacement suggests that both variants, alone or combined, have subtle effects on cellular longevity. Furthermore, deletion mutants of both ppk31 and SPBC409.08 rescued growth defects caused by spermidine. We propose that Ppk31 and SPBC409.08 may function together to modulate lifespan, thus linking Rim15/Ppk31 with spermidine metabolism.

genetics↗

bioRxiv2018

Delineating functional sites in the K13 antimalarial resistance protein through evolutionary and structural analyses

K13 is an essential Plasmodium falciparum protein that plays a key role in malaria resistance to artemisinins. Although K13 resembles BTB- and Kelch/propeller-containing proteins involved in ubiquitin ligase complexes, its functional sites remain uncharacterized. Using evolutionary and structural information, we searched for the most conserved K13 sites across Apicomplexa species evolution to identify sub-regions of K13 that are likely functional. An amino acid electropositive patch in the K13 propeller domain has a dense concentration of extraordinarily conserved positions located at a shallow pocket, suggesting a role as binding surface. When applied to experimentally-characterized BTB-Kelch proteins, our strategy successfully identifies the validated substrate-binding residues within their own propeller shallow pocket. Another patch of slowly evolving sites is identified in the K13 BTB domain which partially overlaps the surface that binds to Cullin proteins in BTB-Cullin complexes. We provide candidate binding sites in K13 propeller and BTB domains for functional follow-up studies.

evolutionary biology↗