ORFpred: A Machine Learning Program to Identify Translatable Small Open Reading Frames in Intergenic Regions of the Plasmodium falciparum Genome

Srinivas, Vivek; Kumar, Mayank; Noronha, Santosh; Patankar, Swati

doi:10.2174/1574893611666160122221757

Cited by 6 publications

(8 citation statements)

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“…Previous studies have used a fixed length of leader sequence (i.e. ~350 nucleotides) for each gene to extract uORFs giving an average of ~4 uORFs per CDS in P. falciparum (Kumar et al ., 2015; Srinivas et al ., 2016). Since the length of leader sequences vary for each gene, hidden Markov model (HMM)-defined leader sequences were used to extract uORFs in this study for more accuracy (Caro et al ., 2014).…”

Section: Methodsmentioning

confidence: 99%

“…Unlike human and mouse genomes, from which ~50% of the transcribed mRNAs would be expected to contain one or more uORFs (Calvo et al ., 2009; Ye et al ., 2015), 96.5% of P. falciparum mRNAs are predicted to contain at least one uORF per coding sequence (CDS) (Srinivas et al ., 2016). An average of ~4 uORFs has been predicted within 350 nucleotides upstream of the start codon of each CDS (Kumar et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

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Messenger RNAs with large numbers of upstream open reading frames are translated via leaky scanning and reinitiation in the asexual stages of Plasmodium falciparum

2020

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The genome of Plasmodium falciparum has one of the most skewed base-pair compositions of any eukaryote, with an AT content of 80–90%. As start and stop codons are AT-rich, the probability of finding upstream open reading frames (uORFs) in messenger RNAs (mRNAs) is high and parasite mRNAs have an average of 11 uORFs in their leader sequences. Similar to other eukaryotes, uORFs repress the translation of the downstream open reading frame (dORF) in P. falciparum, yet the parasite translation machinery is able to bypass these uORFs and reach the dORF to initiate translation. This can happen by leaky scanning and/or reinitiation. In this report, we assessed leaky scanning and reinitiation by studying the effect of uORFs on the translation of a dORF, in this case, the luciferase reporter gene, and showed that both mechanisms are employed in the asexual blood stages of P. falciparum. Furthermore, in addition to the codon usage of the uORF, translation of the dORF is governed by the Kozak sequence and length of the uORF, and inter-cistronic distance between the uORF and dORF. Based on these features whole-genome data was analysed to uncover classes of genes that might be regulated by uORFs. This study indicates that leaky scanning and reinitiation appear to be widespread in asexual stages of P. falciparum, which may require modifications of existing factors that are involved in translation initiation in addition to novel, parasite-specific proteins.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Messenger RNAs with large numbers of upstream open reading frames are translated via leaky scanning and reinitiation in the asexual stages of Plasmodium falciparum

2020

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“…There is evidence for uORFs playing substantive roles in translational control in apicomplexan parasites; this evidence includes high frequencies and a widespread distribution of uORFs among large numbers of genes (Bunnik et al, 2013;Caro et al, 2014;Kumar et al, 2015;Srinivas et al, 2016;Hassan et al, 2017;Holmes et al, 2019;Markus et al, 2021).…”

Section: Translational Regulation Mediated Via Uorfs In Apicomplexan Parasites Plasmodium Falciparum and Toxoplasma Gondiimentioning

confidence: 99%

“…Such features are the Kozak sequence, codon composition, length of the uORF, and the distance between the uORF and the CDS (Kaur et al, 2020). Further, bioinformatics was used to predict translatability of an ORF (therefore, the repressiveness of the uORF) by calculating the probability of translation initiation and elongation of ORFs in the P. falciparum genome (Srinivas et al, 2016). The model utilizes positional features comprising of the Kozak sequence and compositional features comprising of the codon topography of the ORF to predict translation initiation and elongation probabilities of the ORF respectively.…”

Section: High Prevalence Of Uorfs In the P Falciparum Genome Leads To Repression Of Translationmentioning

confidence: 99%

Upstream Open Reading Frames (uORFs) in the Apicomplexan Parasites <em>Plasmodium falciparum</em> and <em>Toxoplasma gondii</em>: Small yet Powerful Regulators of Translation

Kaur¹,

Patankar²

2021

Preprint

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During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.

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“…Unlike human and mouse genomes from which ~50% of the transcribed mRNAs would be expected to contain one or more uORFs (Calvo et al, 2009;Ye et al, 2015), ~98% of P. falciparum mRNAs are predicted to contain an average of ~10 uORFs per coding sequence (CDS) (Caro et al, 2014;Kumar et al, 2015;Srinivas et al, 2016). The presence of such large numbers of uORFs has serious implications for translation.…”

Section: Introductionmentioning

confidence: 99%

Messenger RNAs with large numbers of upstream ORFs are translated via leaky scanning and reinitiation in the asexual stages ofPlasmodium falciparum

Kaur

Kumar

Patankar

2019

Preprint

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The genome of Plasmodium falciparum has one of the most skewed base pair compositions of any eukaryote, with an AT content of 80-90%. As start and stop codons are AT-rich, the probability of finding upstream open reading frames (uORFs) in messenger RNAs (mRNAs) is high and parasite mRNAs have an average of 10 uORFs in their leader sequences. Similar to other eukaryotes, uORFs repress the translation of the downstream gene (dORF) in P. falciparum, yet the parasite translation machinery is able to bypass these uORFs and reach the dORF to initiate translation. This can happen by leaky scanning and/or reinitiation.In this report, we assessed leaky scanning and reinitiation by studying the effect of uORFs on the translation of a dORF, in this case the luciferase reporter gene, and showed that both mechanisms are employed in the asexual blood stages of P.falciparum. Furthermore, in addition to codon usage of the uORF, translation of the dORF is governed by the Kozak sequence and length of the uORF, and intercistronic distance between the uORF and dORF. Based on these features whole genome data was analyzed to uncover classes of genes that might be regulated by uORFs. This study indicates that leaky scanning and reinitiation appear to be widespread in asexual stages of P. falciparum, which may require modifications of existing factors that are involved in translation initiation in addition to novel, parasitespecific proteins.

show abstract

ORFpred: A Machine Learning Program to Identify Translatable Small Open Reading Frames in Intergenic Regions of the Plasmodium falciparum Genome

Cited by 6 publications

References 0 publications

Messenger RNAs with large numbers of upstream open reading frames are translated via leaky scanning and reinitiation in the asexual stages of Plasmodium falciparum

Messenger RNAs with large numbers of upstream open reading frames are translated via leaky scanning and reinitiation in the asexual stages of Plasmodium falciparum

Upstream Open Reading Frames (uORFs) in the Apicomplexan Parasites <em>Plasmodium falciparum</em> and <em>Toxoplasma gondii</em>: Small yet Powerful Regulators of Translation

Messenger RNAs with large numbers of upstream ORFs are translated via leaky scanning and reinitiation in the asexual stages ofPlasmodium falciparum

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