Abstract
BackgroundTreatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana—exposed to more than a decade of regular ivermectin treatment—have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Methodology/Principal findingsPooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.Conclusions/SignificanceThis study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations.
Highlights
Onchocerca volvulus is a filarial nematode pathogen responsible for causing human onchocerciasis
This is evident in the data from the study conducted in Ghana in which all palpable nodules had been excised and phenotyped (Fig A in S1 Text); some hosts classified as sub-optimal responder (SOR) contained only female worms with a good responder (GR) phenotype, whereas from a few hosts classified as GR, only SOR adult worms were in palpable nodules
The data presented suggest that the evolution of SOR to ivermectin in O. volvulus is via soft selective sweeps of pre-existing quantitative trait loci (QTL) rather than via a hard selective sweep of a relatively rare resistance-conferring mutation
Summary
Onchocerca volvulus is a filarial nematode pathogen responsible for causing human onchocerciasis. Population genomics of sub-optimal ivermectin response by Onchocerca volvulus have motivated large-scale disease control programmes in the foci located in South and Central America, Yemen and throughout Sub-Saharan Africa, where more than 99% of the global at-risk population, estimated at 100 million people, live. Annual CDTI (expanded to biannual CDTI in some cases) and/or vector control have or are likely to have eliminated onchocerciasis in a number of endemic areas in Africa [13,14,15,16,17,18,19]. Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana—exposed to more than a decade of regular ivermectin treatment—have raised concern that sub-optimal responses to ivermectin’s anti-fecundity effect are becoming more frequent and may spread
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
