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Natural anitsense transcripts in Plasmodium falciparum clinical isolates

ABSTRACT: Mechanisms regulating gene expression in malaria parasites are not well understood. Little is known about how this parasite regulates its gene expression during transition from one developmental stage to another and in response to various environmental conditions. Parasites in a diseased host face environments which differ from the static, well adapted in vitro conditions in culture. Parasites thus need to adapt quickly and effectively to these conditions by establishing transcriptional states which is best suited for better survival. With the discovery of natural antisense transcripts (NATs) in this parasite and considering the various proposed mechanisms by which NATs might regulate gene expression, it has been speculated that these might be playing a critical role in gene regulation. We report here the diversity of NATs that exist in this parasite, using isolates taken directly from patients with differing clinical symptoms caused by malaria infection. A total of 797 NATs targeted against annotated loci have been detected using a custom designed strand specific microarray. Out of these, 545 are unique to this study. The majority of NATs were positively correlated with the expression pattern of the sense transcript. Many were found to be differentially regulated in response to disease conditions. Antisense transcripts mapped to a wide variety of biochemical/ metabolic pathways, especially pathways pertaining to the central carbon metabolism and stress related pathways. Our data strongly suggests that a large group of NATs detected here are unannotated transcription units antisense to annotated gene models. The results reveal a previously unknown set of NATs that prevails in this parasite, their differential regulation in disease conditions and mapping to functionally well annotated genes. The results detailed here call for studies to deduce the possible mechanism of action, which would help in understanding the in vivo pathological adaptations of these parasites.

ORGANISM(S): Plasmodium falciparum Plasmodium falciparum 3D7

PROVIDER: GSE44921 | GEO | 2014/04/30

SECONDARY ACCESSION(S): PRJNA192674

REPOSITORIES: GEO

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Project description:Mechanisms regulating gene expression in malaria parasites are not well understood. Little is known about how this parasite regulates its gene expression during transition from one developmental stage to another and in response to various environmental conditions. Parasites in a diseased host face environments which differ from the static, well adapted in vitro conditions in culture. Parasites thus need to adapt quickly and effectively to these conditions by establishing transcriptional states which is best suited for better survival. With the discovery of natural antisense transcripts (NATs) in this parasite and considering the various proposed mechanisms by which NATs might regulate gene expression, it has been speculated that these might be playing a critical role in gene regulation. We report here the diversity of NATs that exist in this parasite, using isolates taken directly from patients with differing clinical symptoms caused by malaria infection. A total of 797 NATs targeted against annotated loci have been detected using a custom designed strand specific microarray. Out of these, 545 are unique to this study. The majority of NATs were positively correlated with the expression pattern of the sense transcript. Many were found to be differentially regulated in response to disease conditions. Antisense transcripts mapped to a wide variety of biochemical/ metabolic pathways, especially pathways pertaining to the central carbon metabolism and stress related pathways. Our data strongly suggests that a large group of NATs detected here are unannotated transcription units antisense to annotated gene models. The results reveal a previously unknown set of NATs that prevails in this parasite, their differential regulation in disease conditions and mapping to functionally well annotated genes. The results detailed here call for studies to deduce the possible mechanism of action, which would help in understanding the in vivo pathological adaptations of these parasites. Plasmodium falciparum isolates were collected from patients (n = 11) with differing clinical conditions.The patients exhibited symptoms categorized as un-complicated (n =2) or complicated malaria (n = 9). Criteria for determination of complicated disease were based on World Health Organization year 2000 guidelines. Microarray array based transcriptional profiling was carried out to detect prevalence of natural antisense transcript.

Project description:Plasmodium vivax is the most geographically widespread human malaria parasite causing approximately 130-435 million infections annually. It is an economic burden in many parts of the world and poses a public health challenge along with the other Plasmodium sp. The biology of this parasite is very little understood. Emerging evidences of severe complications due to infections by this parasite provides an impetus to focus research on the same. Investigating this parasite directly from the infected patients is the most feasible way to study its biology and any pathogenic mechanisms which may exist. Gene expression studies of this parasite directly obtained from the patients has provided evidence of gene regulation resulting in varying amount of transcript levels in the different blood stages. However, the mechanisms regulating gene expression in malaria parasites are not well understood. Discovery of natural antisense transcripts (NATs) in P. falciparum has suggested that these might play an important role in regulating gene expression. We report here the genome-wide occurrence of NATs in P. vivax parasites from patients with differing clinical symptoms. A total of 1348 NATs against annotated gene loci have been detected using a custom designed strand specific microarray. Majority of NATs identified from this study shows positive correlation with the expression pattern of the sense transcript. Our data also shows condition specific expression patterns of varying S and AS transcript levels. Genes with AS transcripts enrich to various biological processes. This is the first report detailing the presence of NATs from clinical isolates of P. vivax. The data suggests differential regulation of gene expression in diverse clinical conditions and would lead to future detailed investigations of genome regulation. Plasmodium vivax isolates were collected from patients (n = 8) with differing clinical conditions.The patients exhibited symptoms categorized as un-complicated (n =1) or complicated malaria (n = 7). Criteria for determination of complicated disease were based on World Health Organization year 2010 guidelines. Microarray array based transcriptional profiling was carried out to detect prevalence of natural antisense transcripts.

Project description:The study of rodent malaria parasites has significantly advanced our understanding of malaria parasite biology and host responses to parasite infections. There are four well-characterized rodent malaria parasite species (Plasmodium yoelii, P. chabaudi, P. berghei, and P. vinckei). Each species also has multiple strains that cause different disease phenotypes. P. yoelii nigeriensis N67C and N67, two isogenic parasites, are particularly intriguing as they differ in virulence and incite different immune responses in mice. The genome of the N67 parasite has been assembled recently, but not that of N67C. This study used PacBio HiFi sequencing data to assemble the N67C genome, compared the two genomes, and performed RNA sequencing to identify polymorphisms and differentially expressed genes (DEGs). Results: The assembled N67C parasite genome consisted of 16 scaffolds and three contigs of approximately 22.5 Mb with 100% and 96.6% completeness based on well-characterized single-copy orthologs specific to the Apicomplexa phylum and the Plasmodium genus, respectively. A comparison between the annotated N67C and N67 genomes revealed 133 single nucleotide polymorphisms (SNPs) and 75 indels. Among the polymorphic sites, an S (N67) to N (N67C) amino acid substitution at position 114 (S114N) in the dihydrofolate reductase-thymidylate synthase (DHFR-TS) confers resistance to pyrimethamine in mice. Additionally, 302 differentially expressed genes (DEGs) were detected after comparing mRNA levels between the two parasites. Starting with the predicted and annotated 5,681 N67C and 5,749 N67 genes, we identified 4,641 orthogroups that included at least one gene from the four P. yoelii parasites (N67, N67C, 17X, and YM), whereas 758 orthogroups showed subspecies or strain-specific patterns. Conclusion: The identification of polymorphic sites between the N67 and N67C genomes, along with the detection of the DEGs, may provide crucial insights into the variations in parasite drug responses and disease severity between these two isogenic parasites. The functional characterization of these genetic differences and candidate genes will deepen our understanding of disease mechanisms and pave the way for developing more effective control measures against malaria.

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Natural anitsense transcripts in Plasmodium falciparum clinical isolates

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