Person:
Neafsey, Daniel

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Neafsey

First Name

Daniel

Name

Neafsey, Daniel
Author's Publications: search.filters.isAuthorOfPublication.22148278-956e-417e-b342-dc242dc51faa

Search Results

Now showing 1 - 10 of 25
  • Thumbnail Image
    Publication
    De Novo Mutations Resolve Disease Transmission Pathways in Clonal Malaria
    (Oxford University Press, 2018) Redmond, Seth N; MacInnis, Bronwyn M; Bopp, Selina; Bei, Amy; Ndiaye, Daouda; Hartl, Daniel; Wirth, Dyann; Volkman, Sarah; Neafsey, Daniel
    Abstract Detecting de novo mutations in viral and bacterial pathogens enables researchers to reconstruct detailed networks of disease transmission and is a key technique in genomic epidemiology. However, these techniques have not yet been applied to the malaria parasite, Plasmodium falciparum, in which a larger genome, slower generation times, and a complex life cycle make them difficult to implement. Here, we demonstrate the viability of de novo mutation studies in P. falciparum for the first time. Using a combination of sequencing, library preparation, and genotyping methods that have been optimized for accuracy in low-complexity genomic regions, we have detected de novo mutations that distinguish nominally identical parasites from clonal lineages. Despite its slower evolutionary rate compared with bacterial or viral species, de novo mutation can be detected in P. falciparum across timescales of just 1–2 years and evolutionary rates in low-complexity regions of the genome can be up to twice that detected in the rest of the genome. The increased mutation rate allows the identification of separate clade expansions that cannot be found using previous genomic epidemiology approaches and could be a crucial tool for mapping residual transmission patterns in disease elimination campaigns and reintroduction scenarios.
  • Thumbnail Image
    Publication
    Host-mediated selection impacts the diversity of Plasmodium falciparum antigens within infections
    (Nature Publishing Group UK, 2018) Early, Angela; Lievens, Marc; MacInnis, Bronwyn L.; Ockenhouse, Christian F.; Volkman, Sarah K.; Adjei, Samuel; Agbenyega, Tsiri; Ansong, Daniel; Gondi, Stacey; Greenwood, Brian; Hamel, Mary; Odero, Chris; Otieno, Kephas; Otieno, Walter; Owusu-Agyei, Seth; Asante, Kwaku Poku; Sorgho, Hermann; Tina, Lucas; Tinto, Halidou; Valea, Innocent; Wirth, Dyann; Neafsey, Daniel
    Host immunity exerts strong selective pressure on pathogens. Population-level genetic analysis can identify signatures of this selection, but these signatures reflect the net selective effect of all hosts and vectors in a population. In contrast, analysis of pathogen diversity within hosts provides information on individual, host-specific selection pressures. Here, we combine these complementary approaches in an analysis of the malaria parasite Plasmodium falciparum using haplotype sequences from thousands of natural infections in sub-Saharan Africa. We find that parasite genotypes show preferential clustering within multi-strain infections in young children, and identify individual amino acid positions that may contribute to strain-specific immunity. Our results demonstrate that natural host defenses to P. falciparum act in an allele-specific manner to block specific parasite haplotypes from establishing blood-stage infections. This selection partially explains the extreme amino acid diversity of many parasite antigens and suggests that vaccines targeting such proteins should account for allele-specific immunity.
  • Thumbnail Image
    Publication
    hmmIBD: software to infer pairwise identity by descent between haploid genotypes
    (BioMed Central, 2018) Schaffner, Stephen; Taylor, Aimee; Wong, Wesley; Wirth, Dyann; Neafsey, Daniel
    Background: A number of recent malaria studies have used identity by descent (IBD) to study epidemiological processes relevant to malaria control. In this paper, a software package, hmmIBD, is introduced for estimating pairwise IBD between haploid genomes, such as those of the malaria parasite, sampled from one or two populations. Source code is freely available. Methods: The performance of hmmIBD was verified using simulated data and benchmarked against an existing method for detecting IBD within populations. Code for all tests is freely available. The utility of hmmIBD for detecting IBD across populations was demonstrated using Plasmodium falciparum data from Cambodia and Ghana. Results: Alongside an existing method, hmmIBD was highly accurate, sensitive and specific. It is fast, requiring only 70 s on average to analyse 50 whole genome sequences on a laptop computer, and scales linearly in the number of pairwise comparisons. Treatment of different populations under hmmIBD improves detection of IBD across populations. Conclusion: Fast and accurate software for detecting IBD in malaria parasite genetic data sampled from one or two populations is presented. The latter will likely be a useful feature for malaria elimination efforts, since it could facilitate identification of imported malaria cases. Software is robust to possible misspecification of the genotyping error and the recombination rate. However, exclusion of data in regions whose rates vary greatly from their genome-wide average is recommended. Electronic supplementary material The online version of this article (10.1186/s12936-018-2349-7) contains supplementary material, which is available to authorized users.
  • Thumbnail Image
    Publication
    Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae
    (Nature Publishing Group UK, 2018) Weetman, David; Wilding, Craig S.; Neafsey, Daniel; Müller, Pie; Ochomo, Eric; Isaacs, Alison T.; Steen, Keith; Rippon, Emily J.; Morgan, John C.; Mawejje, Henry D.; Rigden, Daniel J.; Okedi, Loyce M.; Donnelly, Martin J.
    Metabolic resistance to pyrethroid insecticides is widespread in Anopheles mosquitoes and is a major threat to malaria control. DNA markers would aid predictive monitoring of resistance, but few mutations have been discovered outside of insecticide-targeted genes. Isofemale family pools from a wild Ugandan Anopheles gambiae population, from an area where operational pyrethroid failure is suspected, were genotyped using a candidate-gene enriched SNP array. Resistance-associated SNPs were detected in three genes from detoxification superfamilies, in addition to the insecticide target site (the Voltage Gated Sodium Channel gene, Vgsc). The putative associations were confirmed for two of the marker SNPs, in the P450 Cyp4j5 and the esterase Coeae1d by reproducible association with pyrethroid resistance in multiple field collections from Uganda and Kenya, and together with the Vgsc-1014S (kdr) mutation these SNPs explained around 20% of variation in resistance. Moreover, the >20 Mb 2La inversion also showed evidence of association with resistance as did environmental humidity. Sequencing of Cyp4j5 and Coeae1d detected no resistance-linked loss of diversity, suggesting selection from standing variation. Our study provides novel, regionally-validated DNA assays for resistance to the most important insecticide class, and establishes both 2La karyotype variation and humidity as common factors impacting the resistance phenotype.
  • Thumbnail Image
    Publication
    Malaria Life Cycle Intensifies Both Natural Selection and Random Genetic Drift
    (Proceedings of the National Academy of Sciences, 2013) Chang, Hsiao-Han; Moss, Eli L.; Park, Daniel John; Ndiaye, Daouda; Mboup, Souleymane; Volkman, Sarah; Sabeti, Pardis; Wirth, Dyann; Neafsey, Daniel; Hartl, Daniel
    Analysis of genome sequences of 159 isolates of Plasmodium falciparum from Senegal yields an extraordinarily high proportion (26.85%) of protein-coding genes with the ratio of nonsynonymous to synonymous polymorphism greater than one. This proportion is much greater than observed in other organisms. Also unusual is that the site-frequency spectra of synonymous and nonsynonymous polymorphisms are virtually indistinguishable. We hypothesized that the complicated life cycle of malaria parasites might lead to qualitatively different population genetics from that predicted from the classical Wright-Fisher (WF) model, which assumes a single random-mating population with a finite and constant population size in an organism with nonoverlapping generations. This paper summarizes simulation studies of random genetic drift and selection in malaria parasites that take into account their unusual life history. Our results show that random genetic drift in the malaria life cycle is more pronounced than under the WF model. Paradoxically, the efficiency of purifying selection in the malaria life cycle is also greater than under WF, and the relative efficiency of positive selection varies according to conditions. Additionally, the site-frequency spectrum under neutrality is also more skewed toward low-frequency alleles than expected with WF. These results highlight the importance of considering the malaria life cycle when applying existing population genetic tools based on the WF model. The same caveat applies to other species with similarly complex life cycles.
  • Thumbnail Image
    Publication
    Sequence-Based Association and Selection Scans Identify Drug Resistance Loci in the Plasmodium Falciparum Malaria Parasite
    (Proceedings of the National Academy of Sciences, 2012) Park, Daniel John; Lukens, Amanda; Neafsey, Daniel; Schaffner, Stephen; Chang, Hsiao-Han; Valim, Clarissa; Ribacke, Ulf; Van tyne, Daria; Galinsky, Kevin; Galligan, Meghan; Becker, Justin S.; Ndiaye, Daouda; Mboup, Souleymane; Wiegand, Roger; Hartl, Daniel; Sabeti, Pardis; Wirth, Dyann; Volkman, Sarah
    Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite—the deadliest of those that cause malaria—is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites’ in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.
  • Thumbnail Image
    Publication
    Chromerid genomes reveal the evolutionary path from photosynthetic algae to obligate intracellular parasites
    (eLife Sciences Publications, Ltd, 2015) Woo, Yong H; Ansari, Hifzur; Otto, Thomas D; Klinger, Christen M; Kolisko, Martin; Michálek, Jan; Saxena, Alka; Shanmugam, Dhanasekaran; Tayyrov, Annageldi; Veluchamy, Alaguraj; Ali, Shahjahan; Bernal, Axel; del Campo, Javier; Cihlář, Jaromír; Flegontov, Pavel; Gornik, Sebastian G; Hajdušková, Eva; Horák, Aleš; Janouškovec, Jan; Katris, Nicholas J; Mast, Fred D; Miranda-Saavedra, Diego; Mourier, Tobias; Naeem, Raeece; Nair, Mridul; Panigrahi, Aswini K; Rawlings, Neil D; Padron-Regalado, Eriko; Ramaprasad, Abhinay; Samad, Nadira; Tomčala, Aleš; Wilkes, Jon; Neafsey, Daniel; Doerig, Christian; Bowler, Chris; Keeling, Patrick J; Roos, David S; Dacks, Joel B; Templeton, Thomas J; Waller, Ross F; Lukeš, Julius; Oborník, Miroslav; Pain, Arnab
    The eukaryotic phylum Apicomplexa encompasses thousands of obligate intracellular parasites of humans and animals with immense socio-economic and health impacts. We sequenced nuclear genomes of Chromera velia and Vitrella brassicaformis, free-living non-parasitic photosynthetic algae closely related to apicomplexans. Proteins from key metabolic pathways and from the endomembrane trafficking systems associated with a free-living lifestyle have been progressively and non-randomly lost during adaptation to parasitism. The free-living ancestor contained a broad repertoire of genes many of which were repurposed for parasitic processes, such as extracellular proteins, components of a motility apparatus, and DNA- and RNA-binding protein families. Based on transcriptome analyses across 36 environmental conditions, Chromera orthologs of apicomplexan invasion-related motility genes were co-regulated with genes encoding the flagellar apparatus, supporting the functional contribution of flagella to the evolution of invasion machinery. This study provides insights into how obligate parasites with diverse life strategies arose from a once free-living phototrophic marine alga. DOI: http://dx.doi.org/10.7554/eLife.06974.001
  • Thumbnail Image
    Publication
    A genomic and evolutionary approach reveals non-genetic drug resistance in malaria
    (BioMed Central, 2014) Herman, Jonathan D; Rice, Daniel; Ribacke, Ulf; Silterra, Jacob; Deik, Amy A; Moss, Eli L; Broadbent, Kate M; Neafsey, Daniel; Desai, Michael; Clish, Clary B; Mazitschek, Ralph; Wirth, Dyann
    Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0511-2) contains supplementary material, which is available to authorized users.
  • Thumbnail Image
    Publication
    Modeling malaria genomics reveals transmission decline and rebound in Senegal
    (Proceedings of the National Academy of Sciences, 2015) Daniels, Rachel; Schaffner, Stephen; Wenger, Edward A.; Proctor, Joshua L.; Chang, Hsiao-Han; Wong, Wesley; Baro, Nicholas; Ndiaye, Daouda; Fall, Fatou Ba; Ndiop, Medoune; Ba, Mady; Milner, Danny; Taylor, Terrie E.; Neafsey, Daniel; Volkman, Sarah; Eckhoff, Philip A.; Hartl, Daniel; Wirth, Dyann
    To study the effects of malaria-control interventions on parasite population genomics, we examined a set of 1,007 samples of the malaria parasite Plasmodium falciparum collected in Thiès, Senegal between 2006 and 2013. The parasite samples were genotyped using a molecular barcode of 24 SNPs. About 35% of the samples grouped into subsets with identical barcodes, varying in size by year and sometimes persisting across years. The barcodes also formed networks of related groups. Analysis of 164 completely sequenced parasites revealed extensive sharing of genomic regions. In at least two cases we found first-generation recombinant offspring of parents whose genomes are similar or identical to genomes also present in the sample. An epidemiological model that tracks parasite genotypes can reproduce the observed pattern of barcode subsets. Quantification of likelihoods in the model strongly suggests a reduction of transmission from 2006-2010 with a significant rebound in 2012-2013. The reduced transmission and rebound were confirmed directly by incidence data from Thiès. These findings imply that intensive intervention to control malaria results in rapid and dramatic changes in parasite population genomics. The results also suggest that genomics combined with epidemiological modeling may afford prompt, continuous, and cost-effective tracking of progress toward malaria elimination.
  • Thumbnail Image
    Publication
    COIL: a methodology for evaluating malarial complexity of infection using likelihood from single nucleotide polymorphism data
    (BioMed Central, 2015) Galinsky, Kevin; Valim, Clarissa; Salmier, Arielle; de Thoisy, Benoit; Musset, Lise; Legrand, Eric; Faust, Aubrey; Baniecki, Mary Lynn; Ndiaye, Daouda; Daniels, Rachel; Hartl, Daniel; Sabeti, Pardis; Wirth, Dyann; Volkman, Sarah K; Neafsey, Daniel
    Background: Complex malaria infections are defined as those containing more than one genetically distinct lineage of Plasmodium parasite. Complexity of infection (COI) is a useful parameter to estimate from patient blood samples because it is associated with clinical outcome, epidemiology and disease transmission rate. This manuscript describes a method for estimating COI using likelihood, called COIL, from a panel of bi-allelic genotyping assays. Methods: COIL assumes that distinct parasite lineages in complex infections are unrelated and that genotyped loci do not exhibit significant linkage disequilibrium. Using the population minor allele frequency (MAF) of the genotyped loci, COIL uses the binomial distribution to estimate the likelihood of a COI level given the prevalence of observed monomorphic or polymorphic genotypes within each sample. Results: COIL reliably estimates COI up to a level of three or five with at least 24 or 96 unlinked genotyped loci, respectively, as determined by in silico simulation and empirical validation. Evaluation of COI levels greater than five in patient samples may require a very large collection of genotype data, making sequencing a more cost-effective approach for evaluating COI under conditions when disease transmission is extremely high. Performance of the method is positively correlated with the MAF of the genotyped loci. COI estimates from existing SNP genotype datasets create a more detailed portrait of disease than analyses based simply on the number of polymorphic genotypes observed within samples. Conclusions: The capacity to reliably estimate COI from a genome-wide panel of SNP genotypes provides a potentially more accurate alternative to methods relying on PCR amplification of a small number of loci for estimating COI. This approach will also increase the number of applications of SNP genotype data, providing additional motivation to employ SNP barcodes for studies of disease epidemiology or control measure efficacy. The COIL program is available for download from GitHub, and users may also upload their SNP genotype data to a web interface for simple and efficient determination of sample COI. Electronic supplementary material The online version of this article (doi:10.1186/1475-2875-14-4) contains supplementary material, which is available to authorized users.