Biology subjects

Sargison, N.

Publications and source records attributed to Sargison, N..

3 recordsLinked to original sources

bioRxiv2018

Selective sweep and phylogenetic models for the emergence and spread of pyrimethamine resistance mutations in Plasmodium vivax

Pyrimethamine resistance is a major concern for the control of human haemoprotozoa, especially Plasmodium species. Currently, there is little understanding of how pyrimethamine resistance developed in Plasmodium vivax in the natural field conditions. Here, we present first time the evidence of positive selection pressure on a dihydrofolate reductase locus and its consequences on the emergence and the spread of pyrimethamine resistance in P. vivax in the Punjab province of Pakistan. First, we examined the pyrimethamine resistance locus in 38 P. vivax populations to look for evidence of positive selection pressure in human patients. The S58R (AGA)/S117N (AAC) double mutation was most common, being detected in 10/38 populations. Single mutation S117N (AAC), I173L (CTT) and S58R (AGA) SNPs were detected in 8/38, 2/38 and 1/38 populations, respectively. The F57L/I (TTA/ATA) and T61M (ATG) SNPs were not detected in any population examined. Although both soft and hard selective sweeps have occurred with striking differences between populations, there was a predominance of hard sweeps. A single resistance haplotype was present at high frequency in 9/14 populations, providing a strong evidence for the single emergence of these mutations. In contrast, 5/14 populations carried multiple resistance haplotypes at high frequencies, providing an evidence of the emergence of resistance by recurrent mutations, characteristics of soft selective sweeps. Our phylogenetic relationship analysis suggests that S58R (AGA)/S117N (AAC) and S117N (AAC) mutations arose multiple times from a single origin and spread to multiple different cities in the Punjab province through gene flow. Interestingly, the I173L (CTT) mutation was present on a single haplotype, suggesting that it arises rarely and has not spread between cities. Our work shows the need for responsible use of exiting and new antimicrobial drugs and their combinations, control the movement of infected patients and mosquito vector control strategies.

evolutionary biology↗

bioRxiv2018

Emergence and the spread of the F200Y benzimidazole resistance mutation in Haemonchus contortus and Haemonchus placei from buffalo and cattle

Benzimidazoles have been intensively used in the livestock sector, particularly in small ruminants for over 40 years. This has been led to the widespread emergence of resistance in a number of small ruminant parasite species, in particular Haemonchus contortus. In many counties benzimidazole resistance in the small ruminants H. contortus has become severely compromising its control; but there is a little information on benzimidazole resistance in H. contortus infecting buffalo and cattle. Resistance to benzimidazoles have also been reported in the large ruminant parasite, Haemonchus placei, but again there is relatively little information on its prevalence. Hence it is extremely important to understand how resistance-conferring mutations emerge and spread in both parasites in the buffalo and cattle host in order to develop the approaches for the recognition of the problem at an early stage of its development. The present study suggests that the F200Y (TAC) mutation is common in H. contortus, being detected in 5/7 populations at frequencies between 7 to 57%. Furthermore, 6/10 H. placei populations contained the F200Y (TAC) mutation, albeit at low frequencies of between 0.4 to 5%. The phylogenetic analysis suggests that the F200Y (TAC) mutation in H. contortus has emerged on multiple occasions in the region, with at least three independent emergence of resistance alleles across the populations. In contrast, the F200Y (TAC) resistance-conferring mutation in H. placei is only seen on a single haplotype. A high level of haplotype frequency of the susceptible alleles in the region, suggests that the unique resistance conferring-mutation has spread from a single emergence; likely by anthropogenic animal movement. Overall, these results provide the first clear genetic evidence for the spread of benzimidazoles resistance-conferring mutations to multiple different locations from a single emergence in H. placei; while supporting previous small ruminant-based observations of multiple emergence of resistance mutations in H. contortus.

genetics↗

bioRxiv2018

A major locus for ivermectin resistance in a parasitic nematode

BackgroundInfections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved. ResultsHere, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this Q.TL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection. ConclusionsWe have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high quality reference genome in interpreting the signals of selection so identified.

genomics↗