Biology subjects

Jeffares, D. C.

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

13 recordsLinked to original sources

bioRxiv2026

Human settlement drives population divergence of Leishmania guyanensis at the sylvatic-anthropogenic interface

The Amazon is the largest tropical rainforest in the world, and is an important interface between natural rainforest and anthropogenic environments. In the central Amazon region, Leishmania guyanensis is a common agent of cutaneous leishmaniasis (CL), a disfiguring vector-borne disease that circulates between wild mammalian reservoirs and sandfly vectors in sylvatic cycles. People become infected when they interact or disturb this cycle. At present, little is known about the adaptation of Leishmania parasites at the interface between sylvatic and anthropogenic environments. Here, to characterize CL in a transition zone, we conducted a population genomic analysis of 77 Leishmania isolates from human patients living in Manauss outskirts or in highways adjacent to the Brazilian Amazon rainforest. We discovered two L. guyanensis populations; an ancestral sylvatic population occurring in densely forested areas far from the city and a derived population, occurring in areas with lower forest cover closer to the city (the city-proximal population). The genomic divergence between these populations indicates that their separation occurred relatively recently, consistent with human-driven development of a new transmission cycle for CL in the Manaus region. The lack of recent gene flow between these populations indicates that the newer city-proximal population has established a transmission cycle that operates independently from ancestral sylvatic transmission. This provides a striking example of the adaptation of disease transmission to an environment that has been altered by human activity. Significance StatementEmerging infectious diseases often arise at the interface between natural and human-modified environments. One of these important interfaces is the Amazon, the largest rainforest in the world. We analyzed the population genomics of Leishmania guyanensis, the agent of cutaneous leishmaniasis in the Amazon, typically transmitted in sylvatic cycles. Our findings reveal a recent emergence of a L. guyanensis population associated with anthropogenic environment alterations, which is genetically distinct from the ancestral sylvatic lineage. This newly adapted population highlights how landscape change and urban expansion may drive the evolution and emergence of protozoan vector-borne pathogens at the rainforest-urban interface.

evolutionary biology↗

bioRxiv2024

The global dispersal of visceral leishmaniasis occurred within human history

The Leishmania donovani species complex (LdSC) causes visceral leishmaniasis (VL), is present in Africa, Europe, the Middle East, Asia and the Americas, and causes 20-40,000 fatalities per year. Previous analyses concluded that dispersal of this species complex occurred 1-10 million years ago. Using updated methods and data, we show that a ten-thousand year old East African population dispersed globally only within the last 2,000 years, consistent with human migration, war and colonisation as driving factors.

evolutionary biology↗

bioRxiv2024

Estimating the rate of sexual reproduction and the inbreeding rate in Leishmania

Many eukaryotic species undergo sexual reproduction facultatively, either in response to stress or in particular environments. For the remainder of their life cycle they reproduce by mitosis. This facultative sex may be rare, which alters features of their evolutionary dynamics. Both the frequency of sex and the degree of inbreeding have been challenging to estimate from genome-scale polymorphism data. Here, we describe a method to estimate both these parameters based on the Moran model of heterozygous sites. We apply this method to population genomic data from Leishmania parasitic protozoans from the Leishmania donovani species complex, showing that these parasites undergo sexual reproduction approximately once per 10,000 generations and that populations vary considerably in the extent of their inbreeding.

genetics↗

bioRxiv2024

Genome Report: Pseudomolecule-scale genome assemblies of Drepanocaryum sewerzowii and Marmoritis complanata

The Nepetoideae, a subfamily of Lamiaceae (mint family), is rich in aromatic plants, many of which are sought after for their use as flavours and fragrances or for their medicinal properties. Here we present genome assemblies for two species in Nepetiodeae: Drepanocaruym sewerzowii and Marmoritis complanata. Both assemblies were generated using Oxford Nanopore Q20+ reads with contigs anchored to nine pseudomolecules that resulted in 335 Mb and 305 Mb assemblies, respectively, and BUSCO scores above 95% for both the assembly and annotation. We furthermore provide a species tree for the Lamiaceae using only genome derived gene models, complementing existing transcriptome and marker-based phylogenies.

genomics↗

bioRxiv2023

Aneuploidies are an ancestral feature of trypanosomatids, and an ancient chromosome duplication is maintained in extant species

BackgroundAneuploidy is widely observed in both unicellular and multicellular eukaryotes, usually associated with adaptation to stress conditions. Chromosomal duplication stability is a tradeoff between the fitness cost of having unbalanced gene copies and the potential fitness gained from increased dosage of specific advantageous genes. Trypanosomatids, a family of protozoans which include species that cause neglected tropical diseases, are a relevant group to study aneuploidies, as their life cycle has several stressors that would benefit from the rapid adaptation provided by aneuploidies. ResultsBy evaluating the data from 866 isolates covering 7 Trypanosomatids genera, we have observed that aneuploidies are present in the majority of clades, and have a reduced occurrence in a specific monophyletic clade that has undergone large genomic reorganisation and chromosomal fusions. We have also identified an ancient chromosomal duplication that was maintained across these parasites speciations, which has increased sequence diversity, unusual gene structure and expression regulation. ConclusionAneuploidies are an important and ancestral feature in Trypanosomatids. Chromosomal duplication/loss is a constant event in these protozoans, common in Leishmania and Leptomonas and repressed in T. brucei and closely related protozoans. The number of chromosomes with extra copies in a given isolate is usually low, and only one chromosomal duplication was kept for long enough to greatly impact its nucleotide diversity. The thigh control of gene expression in this chromosome suggests that these parasites have adapted to mitigate the fitness cost of having this ancient chromosomal duplication.

genomics↗

bioRxiv2022

Strong effects of parasite genotype on drug susceptibility in the Indian subcontinent

Intracellular parasites of the Leishmania donovani species complex cause visceral leishmaniasis (VL). For parasitic diseases, VL has a mortality rate second only to malaria, and is associated with poverty-stricken areas of the world: primarily Brazil, East Africa and the Indian subcontinent (ISC). Miltefosine (MIL) and the antimonal sodium stibogluconate (SSG) are drugs used in the treatment of leishmaniasis. However, treatment efficacy is variable, and the numbers of reports of parasite resistance to both drugs have risen since their introductions, particularly in the ISC. To assess the level of parasite genotype contribution to drug resistance, we utilised the sequencing and associated drug susceptibility data from Imamura et al. (2016) to estimate heritability and GWAS using LDAK. We obtained strong heritability results, with mainly SNP/indel variations associated with SSG and copy number variants associated with MIL resistance, respectively. However, GWAS results were inconclusive, suggesting that, although the parasite genotype directly influences drug resistance, the effect might be multifactorial.

evolutionary biology↗

bioRxiv2022

Parasite genotype is a major predictor of mortality from visceral leishmaniasis

Abstract/SummaryO_ST_ABSBackgroundC_ST_ABSVisceral leishmaniasis (VL) is a potentially fatal disease mainly caused by Leishmania infantum in South America and L. donovani in Asia and Africa. Disease outcomes have been associated with patient genotype, nutrition, age, sex, comorbidities, and co-infections. In this study, we examine the effects of parasite genetic variation on VL disease severity in Brazil. MethodsWe collected and sequenced the genomes of 109 L. infantum isolates from patients in northeast Brazil and retrieved matching patient clinical data from medical records, including mortality, sex, HIV co-infection and laboratory data (creatinine, haemoglobin, leukocyte and platelet counts). We identified genetic differences between parasite isolates, including single nucleotide polymorphisms (SNPs), small insertions/deletions (indels), and variations in genic, intergenic, and chromosome copy numbers (copy number variants, CNVs). To describe associations between the parasite genotypes and clinical outcomes, we applied quantitative genetics methods of heritability and genome-wide association studies (GWAS), treating clinical outcomes as traits that may be influenced by parasite genotype. FindingsMultiple aspects of the genetic analysis indicate that parasite genotype affects clinical outcomes. We estimate that parasite genotype explains 83% chance of mortality (narrow sense heritability, h2 = 0{middle dot}83{+/-}0{middle dot}17), and has a significant relationship with patient sex (h2 = 0{middle dot}60{+/-}0{middle dot}27). Impacts of parasite genotype on other clinical traits are lower (h2 [≤]0{middle dot}34). GWAS analysis identified multiple parasite genetic loci that were significantly associated with clinical outcomes; 17 CNVs that were significantly associated with mortality, two with creatinine and one with bacterial co-infection, jaundice and HIV co-infection; and two SNPs/indels and six CNVs that associate with age, jaundice, HIV and bacterial co-infections, creatinine, and/or bleeding sites. InterpretationParasite genotype is an important factor in VL disease severity in Brazil. Our analysis indicates that specific genetic differences between parasites act as virulence factors, enhancing risks of severe disease and mortality. More detailed understanding of these virulence factors could be exploited for novel therapies. Author SummaryMultiple factors contribute to the risk of mortality from visceral leishmaniasis (VL), including, patient genotype, comorbidities, and nutrition. Many of these factors will be influenced by socio-economic biases 1. Our work suggests that the virulence of the infecting parasite is an important risk factor for mortality. We pinpoint some specific genomic markers that are associated with mortality, which can lead to a greater understanding of the molecular mechanisms that cause severe VL disease, to genetic markers for virulent parasites and to the development of drug and vaccine therapies.

evolutionary biology↗

bioRxiv2021

Genomic taxonomic assignment of individual root-knot nematodes

Root-knot nematodes (RKN; genus Meloidogyne) are polyphagous plant pathogens of great economic importance to agriculturalists globally. These species are small, diverse, and can be challenging for accurate taxonomic identification. Many of the most important crop pests confound analysis with simple genetic marker loci as they are polyploids of likely hybrid origin. Here we take a low-coverage, long-read genome sequencing approach to characterisation of individual root-knot nematodes. We demonstrate library preparation for Oxford Nanopore Technologies Flongle sequencing of low input DNA from individual juveniles and immature females, multiplexing up to twelve samples per flow cell. Taxonomic identification with Kraken 2 (a k-mer-based taxonomic assignment tool) is shown to reliably identify individual nematodes to species level, even within the very closely related Meloidogyne incognita group. Our approach forms a robust, low-cost, and scalable method for accurate RKN species diagnostics.

genomics↗

bioRxiv2021

Multiple targets of balancing selection in Leishmania donovani complex parasites

The Leishmania donovani species complex are the causative agents of visceral leishmaniasis, which cause 20-40,000 fatalities a year. Here, we conduct a screen for balancing selection in this species complex. We used 387 publicly-available L. donovani and L. infantum genomes, and sequence 93 isolates of L. infantum from Brazil to describe the global diversity of this species complex. We identify five genetically-distinct populations that are sufficiently represented by genomic data to search for signatures of selection. We find that signals of balancing selection are generally not shared between populations, consistent with transient adaptive events, rather than long-term balancing selection. We then apply multiple diversity metrics to identify candidate genes with robust signatures of balancing selection, identifying a curated set of 19 genes with robust signatures. These include zeta toxin, nodulin-like and flagellum attachment proteins. This study highlights the extent of genetic divergence between L. donovani complex parasites and provides genes for further study.

evolutionary biology↗

bioRxiv2020

De novo reconstruction of microbial haplotypes by integrating statistical and physical linkage

DNA sequencing technologies provide unprecedented opportunities to analyze within-host evolution of microorganism populations. Often, within-host populations are analyzed via pooled sequencing of the population, which contains multiple individuals or haplotypes. However, current next-generation sequencing instruments, in conjunction with single-molecule barcoded linked-reads, cannot distinguish long haplotypes directly. Computational reconstruction of haplotypes from pooled sequencing has been attempted in virology, bacterial genomics, metagenomics and human genetics, using algorithms based on either cross-host genetic sharing or within-host genomic reads. Here we describe PoolHapX, a flexible computational approach that integrates information from both genetic sharing and genomic sequencing. We demonstrated that PoolHapX outperforms state-of-the-art tools tailored to specific organismal systems, and is robust to within-host evolution. Importantly, together with barcoded linked-reads, PoolHapX can infer whole-chromosome-scale haplotypes from 50 pools each containing 12 different haplotypes. By analyzing real data, we uncovered dynamic variations in the evolutionary processes of within-patient HIV populations previously unobserved in single position-based analysis.

bioinformatics↗

bioRxiv2019

The genome of the zoonotic malaria parasite Plasmodium simium reveals adaptions to host-switching

BackgroundPlasmodium simium, a malaria parasite of non-human primates (NHP) was recently shown to cause zoonotic infections in humans in Brazil. We sequenced the P. simium genome to investigate its evolutionary history and to identify any genetic adaptions that may underlie the ability of this parasite to switch between host species. ResultsPhylogenetic analyses based on whole genome sequences of P. simium from humans and NHPs reveals that P. simium is monophyletic within the broader diversity of South American Plasmodium vivax, suggesting P. simium first infected NHPs as a result of a host-switch of P. vivax from humans. The P. simium isolates show the closest relationship to Mexican P. vivax isolates. Analysis of erythrocyte invasion genes reveals differences between P. vivax and P. simium, including large deletions in the Duffy Binding Protein 1 (DBP1) and Reticulocyte Binding Protein 2a genes of P. simium. Analysis of P. simium isolated from NHPs and humans revealed a deletion of 38 amino acids in DBP1 present in all human-derived isolates, whereas NHP isolates were multi-allelic. ConclusionsAnalysis of the P. simium genome confirmed a close phylogenetic relationship between P. simium and P. vivax, and suggests a very recent American origin for P. simium. The presence of the DBP1 deletion in all human-derived isolates tested suggests that this deletion, in combination with other genetic changes in P. simium, may facilitate the invasion of human red blood cells and may explain, at least in part, the basis of the recent zoonotic infections.

genomics↗

bioRxiv2019

Physiological changes during cellular ageing in fission yeast drive non-random patterns of genome rearrangements

Aberrant repair of DNA double-strand breaks can recombine distant pairs of chromosomal breakpoints. Such chromosomal rearrangements are a hallmark of ageing and compromise the structure and function of genomes. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To gain a better understanding of genome rearrangements during cellular ageing, we focused on a single diagnostic measure - DNA breakpoint junctions - allowing us to interrogate the changing genomic landscape in non-dividing cells of fission yeast (Schizosaccharomyces pombe). Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints on the same or different chromosomes, including the mitochondrial chromosome. An unexpected mechanism of genomic instability caused more local hotspots: age-associated reduction in an RNA-binding protein could trigger R-loop formation at target loci. This finding suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and potential mechanisms of genome rearrangements in non-dividing cells, which can be triggered by ageing-related changes in gene-regulatory proteins.

genomics↗

bioRxiv2018

Fitness Landscape of the Fission Yeast Genome

BackgroundNon-protein-coding regions of eukaryotic genomes remain poorly understood. Diversity studies, comparative genomics and biochemical outputs of genomic sites can be indicators of functional elements, but none produce fine-scale genome-wide descriptions of all functional elements.\n\nResultsTowards the generation of a comprehensive description of functional elements in the haploid Schizosaccharomyces pombe genome, we generated transposon mutagenesis libraries to a density of one insertion per 13 nucleotides of the genome. We applied a five-state hidden Markov model (HMM) to characterise insertion-depleted regions at nucleotide-level resolution. HMM-defined functional constraint was consistent with genetic diversity, comparative genomics, gene-expression data and genome annotation.\n\nConclusionsWe infer that transposon insertions lead to fitness consequences in 90% of the genome, including 80% of the non-protein-coding regions, reflecting the presence of numerous non-coding elements in this compact genome that have functional roles. Display of this data in genome browsers provides fine-scale views of structure-function relationships within specific genes.

genomics↗