Biology subjects

Grace, C. A.

Publications and source records attributed to Grace, C. A..

5 recordsLinked to original sources

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↗

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

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↗