scholarly journals Identity-by-descent analyses for measuring population dynamics and selection in recombining pathogens

2016 ◽  
Author(s):  
Lyndal Henden ◽  
Stuart Lee ◽  
Ivo Mueller ◽  
Alyssa Barry ◽  
Melanie Bahlo
Keyword(s):  
Drug Resistance ◽  
Positive Selection ◽  
Whole Genome Sequencing Data ◽  
Population Bottlenecks ◽  
Human Pathogens ◽  
Sequencing Data ◽  
Antimalarial Drug Resistance ◽  
Genomic Regions ◽  
Genomic Locations ◽  
Critical Regions

AbstractIdentification of genomic regions that are identical by descent (IBD) has proven useful for human genetic studies where analyses have led to the discovery of familial relatedness and fine-mapping of disease critical regions. Unfortunately however, IBD analyses have been underutilized inanalysis of other organisms, including human pathogens. This is in part due to the lack of statistical methodologies for non-diploid genomes in addition to the added complexity of multiclonal infections. As such, we have developed an IBD methodology, called isoRelate, for analysis of haploid recombining microorganisms in the presence of multiclonal infections. Using the inferred IBD status at genomic locations, we have also developed a novel statistic for identifying loci under positive selection and propose relatedness networks as a means of exploring shared haplotypes within populations. We evaluate the performance of our methodologies for detecting IBD and selection, including comparisons with existing tools, then perform an exploratory analysis of whole genome sequencing data from a global Plasmodium falciparum dataset of more than 2500 genomes. This analysis identifies Southeast Asia as havingmany highly related isolates, possibly as a result of both reduced transmission from intensified control efforts and population bottlenecks following the emergence of antimalarial drug resistance. Many signals of selection are also identified, most of which overlap genes that are known to be associated with drug resistance, in addition to two novel signals observed in multiple countries that have yet to be explored in detail. Additionally, we investigate relatedness networks over the selected loci and determine that one of these sweeps has spread between continents while the other has arisen independently in different countries. IBD analysis of microorganisms using isoRelate can be used for exploring population structure, positive selection and haplotype distributions, and will be a valuable tool for monitoring disease control and elimination efforts of many diseases.

scholarly journals Drug resistance profile and clonality of Plasmodium falciparum parasites in Cape Verde: the 2017 malaria outbreak

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Silvania Da Veiga Leal ◽  
Daniel Ward ◽  
Susana Campino ◽  
Ernest Diez Benavente ◽  
Amy Ibrahim ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Family Members ◽  
Cape Verde ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
High Level

Abstract Background Cape Verde is an archipelago located off the West African coast and is in a pre-elimination phase of malaria control. Since 2010, fewer than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks and sources of infection, including parasite importation. Methods Enrolled subjects involved malaria patients admitted to Dr Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real-time PCR was used to identify SNPs in genes associated with drug resistance (e.g., pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data were generated to investigate the population structure of P. falciparum parasites. Results The study analysed 190 parasite samples, 187 indigenous and 3 from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine-resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%). Conclusions Polymorphisms in pfk13 associated with artemisinin-based combination therapy (ACT) tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and anti-malarial-associated mutations in the the pfcrt and pfdhfr genes. The first whole genome sequencing (WGS) was performed for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.

scholarly journals Drug resistance profile and clonality of Plasmodium falciparum parasites in Cape Verde: The 2017 malaria outbreak

2021 ◽  
Author(s):  
Silvânia da Veiga Leal ◽  
Daniel Ward ◽  
Susana Campino ◽  
Ernest Diez Benavente ◽  
Amy Ibrahim ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Family Members ◽  
Cape Verde ◽  
Whole Genome Sequencing Data ◽  
Cape Verdean ◽  
Sequencing Data ◽  
Drug Resistance Profile ◽  
High Level ◽  
Almost All

Abstract Background Cape Verde is an archipelago located off the West African coast, and is in a pre-elimination phase of malaria control. Since 2010, less than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks, and sources of infection, including parasite importation.Methods Enrolled subjects involved malaria patients admitted to Dr. Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real time PCR was used to identify SNPs in genes associated with drug resistance (e.g. pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data was generated to investigate the population structure of P. falciparum parasites.Results We analysed 190 parasite samples, 187 indigenous and three from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria, and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%).Conclusions Polymorphisms in pfk13 associated with ACTs tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and antimalarial associated mutations in the the pfcrt and pfdhfr genes. We performed the first WGS for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.

scholarly journals Sensitive, Highly Multiplexed Sequencing of Microhaplotypes From the Plasmodium falciparum Heterozygome

2020 ◽  
Author(s):  
Sofonias K Tessema ◽  
Nicholas J Hathaway ◽  
Noam B Teyssier ◽  
Maxwell Murphy ◽  
Anna Chen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Low Cost ◽  
Dried Blood Spots ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Flexible Tool ◽  
High Coverage ◽  
Targeted Next Generation Sequencing ◽  
Genomic Regions ◽  
High Diversity

Abstract Background Targeted next-generation sequencing offers the potential for consistent, deep coverage of information-rich genomic regions to characterize polyclonal Plasmodium falciparum infections. However, methods to identify and sequence these genomic regions are currently limited. Methods A bioinformatic pipeline and multiplex methods were developed to identify and simultaneously sequence 100 targets and applied to dried blood spot (DBS) controls and field isolates from Mozambique. For comparison, whole-genome sequencing data were generated for the same controls. Results Using publicly available genomes, 4465 high-diversity genomic regions suited for targeted sequencing were identified, representing the P. falciparum heterozygome. For this study, 93 microhaplotypes with high diversity (median expected heterozygosity = 0.7) were selected along with 7 drug resistance loci. The sequencing method achieved very high coverage (median 99%), specificity (99.8%), and sensitivity (90% for haplotypes with 5% within sample frequency in dried blood spots with 100 parasites/µL). In silico analyses revealed that microhaplotypes provided much higher resolution to discriminate related from unrelated polyclonal infections than biallelic single-nucleotide polymorphism barcodes. Conclusions The bioinformatic and laboratory methods outlined here provide a flexible tool for efficient, low-cost, high-throughput interrogation of the P. falciparum genome, and can be tailored to simultaneously address multiple questions of interest in various epidemiological settings.

scholarly journals Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer

2021 ◽  
Author(s):  
Luis Humberto Cisneros ◽  
Kimberly J Bussey ◽  
Charles Vasque
Keyword(s):  
Double Strand Breaks ◽  
Whole Genome Sequencing Data ◽  
Dna Double Strand Breaks ◽  
Sequencing Data ◽  
Single Nucleotide ◽  
Strand Breaks ◽  
Evolutionarily Conserved ◽  
Induced Mutagenesis ◽  
Genomic Locations ◽  
Inherited Mutations

The clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. SIM employs error-prone polymerases resulting in mutations concentrated around DNA double-strand breaks with an abundance that decays with genomic distance. We performed a quantitative study on single nucleotide variant calls for whole-genome sequencing data from 1950 tumors and non-inherited mutations from 129 normal samples. We introduce statistical methods to identify mutational clusters and quantify their distribution pattern. Our results show that mutations in both normal and cancer samples are indeed clustered and have shapes indicative of SIM. We found the genomic locations of groups of close mutations are more likely to be prevalent across normal samples than in cancer suggesting loss of regulation over the mutational process during carcinogenesis.

scholarly journals Systematic Review of Whole-Genome Sequencing Data To Predict Phenotypic Drug Resistance and Susceptibility in Swedish Mycobacterium tuberculosis Isolates, 2016 to 2018

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Theresa Enkirch ◽  
Jim Werngren ◽  
Ramona Groenheit ◽  
Erik Alm ◽  
Reza Advani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Drug Susceptibility Testing ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Second Line ◽  
Sequencing Data ◽  
Phenotypic Drug Resistance

ABSTRACT In this retrospective study, whole-genome sequencing (WGS) data generated on an Ion Torrent platform was used to predict phenotypic drug resistance profiles for first- and second-line drugs among Swedish clinical Mycobacterium tuberculosis isolates from 2016 to 2018. The accuracy was ∼99% for all first-line drugs and 100% for four second-line drugs. Our analysis supports the introduction of WGS into routine diagnostics, which might, at least in Sweden, replace phenotypic drug susceptibility testing in the future.

scholarly journals Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence

2017 ◽  
Author(s):  
Jakob M. Goldmann ◽  
Vladimir B. Seplyarskiy ◽  
Wendy S.W. Wong ◽  
Thierry Vilboux ◽  
Dale L. Bodian ◽  
...  
Keyword(s):  
De Novo ◽  
Underlying Mechanism ◽  
Strand Break ◽  
De Novo Mutation ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Induced Mutations ◽  
Cancer Genomes ◽  
Oocyte Aging ◽  
Genomic Regions

Clustering of mutations has been found both in somatic mutations from cancer genomes and in germline de novo mutations (DNMs). We identified 1,755 clustered DNMs (cDNMs) within whole-genome sequencing data from 1,291 parent-offspring trios and investigated the underlying mutational mechanisms. We found that the number of clusters on the maternalallele was positively correlated with maternal age and that these consist of more individual mutations with larger intra-mutational distances compared to paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in regions with an overall increased maternal mutation rate. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G mutations. Finally, we found that maternal clusters associate with processes involving double-stranded-breaks (DSBs) such as meiotic gene conversions and de novo deletions events. These findings suggest accumulation of DSB-induced mutations throughout oocyte aging as an underlying mechanism leading to maternal mutation clusters.

scholarly journals Drug Resistance Profile and Clonality of Plasmodium Falciparum Parasites in Cape Verde: The 2017 Malaria Outbreak

2020 ◽  
Author(s):  
Silvânia da Veiga Leal ◽  
Daniel Ward ◽  
Susana Campino ◽  
Ernest Diez Benavente ◽  
Amy Ibrahim ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Family Members ◽  
Cape Verde ◽  
Whole Genome Sequencing Data ◽  
Cape Verdean ◽  
Sequencing Data ◽  
Drug Resistance Profile ◽  
High Level ◽  
Almost All

Abstract BackgroundCape Verde is an archipelago located off the West African coast, and is in a pre-elimination phase of malaria control. Since 2010, less than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks, and sources of infection, including parasite importation.MethodsEnrolled subjects involved malaria patients admitted to Dr. Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real time PCR was used to identify SNPs in genes associated with drug resistance (e.g. pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data was generated to investigate the population structure of P. falciparum parasites.ResultsWe analysed 190 parasite samples, 187 indigenous and three from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria, and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%).ConclusionsPolymorphisms in pfk13 associated with ACTs tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and antimalarial associated mutations in the the pfcrt and pfdhfr genes. We performed the first WGS for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.

scholarly journals Introgression patterns between house mouse subspecies and species reveal genomic windows of frequent exchange

2017 ◽  
Author(s):  
Kristian Karsten Ullrich ◽  
Miriam Linnenbrink ◽  
Diethard Tautz
Keyword(s):  
Genetic Material ◽  
Innate Immune ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Mus Spretus ◽  
Coding Regions ◽  
Genomic Conflict ◽  
Frequent Exchange ◽  
Genomic Regions ◽  
Active Genes

AbstractBased on whole genome sequencing data, we have studied the patterns of introgression in a phylogenetically well defined set of populations, sub-species and species of mice (Mus m. domesticus, Mus m. musculus, Mus m. castaneus and Mus spretus). We find that many discrete genomic regions are subject to repeated and mutual introgression and exchange. The majority of these regions code for genes that are involved in parasite defense or genomic conflict. They include genes involved in adaptive immunity, such as the MHC region or antibody coding regions, but also genes involved in innate immune reactions of the epidermis. We find also clusters of KRAB zinc finger proteins that control the spread of transposable elements and genes that are involved in meiotic drive. These findings suggest that even well separated populations and species maintain the capacity to exchange genetic material in a special set of evolutionary active genes.

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