Sarath Janga

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https://hdl.handle.net/1805/25250

Rapid Detection of Viral Based Infectious Diseases

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan (Hubei, China) in December 2019 has been declared a pandemic by the World Health Organization (WHO) due to its easy human to human transmission, making it a global public health concern. Coronaviruses are enveloped single-stranded ribonucleic acid (RNA) viruses with characteristic “crown” like appearance under two-dimensional transmission electron microscopy. Infections caused by these viruses result in severe pneumonia, fever and breathing difficulty. Currently there is a lack of effective vaccines and antiviral medication that has led to a global outbreak of SARS-CoV-2. Due to rapidly evolving nature of coronaviruses, their identification has become increasingly challenging. Therefore, it is important to develop diagnostic methods that can detect the virus rapidly, to prevent its transmission. Currently, most clinical diagnostic tests for viruses depend on detecting a viral antigen or rely on PCR amplification of viral nucleic acid derived from biological samples. These two approaches offer trade-offs in benefits: antigen tests (including current Point-Of-Care Tests [POCT]) are typically rapid but have low sensitivity, while PCR is more time-consuming but also more sensitive. Irrespective of the test used, most clinical diagnostic facilities report a non-quantitative (binary) diagnostic result, and the data generated have limited capacity to inform insights into epidemiological linkage, vaccine efficacy, or antiviral susceptibility. Hence, there is an urgent need to generate new diagnostic tests that combine POCT, speed, sensitivity, detection of coinfection by other viral strains, and generation of quantitative or semi-quantitative data that can be used to identify drug resistance. Such data may also be used to reconstruct phylogeny to inform surveillance, public health strategy, and vaccine design.

Dr. Sarath Janga's lab has been working to employ “third-generation” portable, real-time bench top sequencers which use nanopores, to develop novel experimental protocols and computational algorithms to not only detect the presence of pathogens but also map their variability across clinical samples, to facilitate public health surveillance. More recently, his lab has been combining an efficient, novel and high-throughput viral RNA isolation methods accompanied with nanopore sequencing to develop automated computational software for real time detection of COVID19.

Dr. Janga's research to detect COVID19 virus strains for developing a rapid, real-time and scalable test that can be used in the clinics to help the healthcare workers, who are at the front lines of care and are getting exposed to infections, is another example of how IUPUI's faculty are TRANSLATING their RESEARCH INTO PRACTICE.

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Conservation of adjacency as evidence of paralogous operons
(2004-09) Janga, Sarath Chandra; Moreno-Hagelsieb, Gabriel
Most of the analyses on the conservation of gene order are limited to orthologous genes. However, the organization of genes into operons might also result in the conservation of gene order of paralogous genes. Thus, we sought computational evidence that conservation of gene order of paralogous genes represents another level of conservation of genes in operons. We found that pairs of genes within experimentally characterized operons of Escherichia coli K12 and Bacillus subtilis tend to have more adjacently conserved paralogs than pairs of genes at transcription unit boundaries. The fraction of same strand gene pairs corresponding to conserved paralogs averages 0.07 with a maximum of 0.22 in Borrelia burgdorferi. The use of evidence from the conservation of adjacency of paralogous genes can improve the prediction of operons in E.coli K12 by ∼0.27 over predictions using conservation of adjacency of orthologous genes alone.
Nebulon: a system for the inference of functional relationships of gene products from the rearrangement of predicted operons
(2005-04) Janga, Sarath Chandra; Collado-Vides, Julio; Moreno-Hagelsieb, Gabriel
Since operons are unstable across Prokaryotes, it has been suggested that perhaps they re-combine in a conservative manner. Thus, genes belonging to a given operon in one genome might re-associate in other genomes revealing functional relationships among gene products. We developed a system to build networks of functional relationships of gene products based on their organization into operons in any available genome. The operon predictions are based on inter-genic distances. Our system can use different kinds of thresholds to accept a functional relationship, either related to the prediction of operons, or to the number of non-redundant genomes that support the associations. We also work by shells, meaning that we decide on the number of linking iterations to allow for the complementation of related gene sets. The method shows high reliability benchmarked against knowledge-bases of functional interactions. We also illustrate the use of Nebulon in finding new members of regulons, and of other functional groups of genes. Operon rearrangements produce thousands of high-quality new interactions per prokaryotic genome, and thousands of confirmations per genome to other predictions, making it another important tool for the inference of functional interactions from genomic context.
The partitioned Rhizobium etli genome: Genetic and metabolic redundancy in seven interacting replicons
(2006-03) González, Víctor; Santamaria, Rosa I.; Bustos, Patricia; Hernández-González, Ismael; Medrano-Soto, Arturo; Moreno-Hagelsieb, Gabriel; Janga, Sarath Chandra; Ramírez, Miguel A.; Jiménez-Jacinto, Verónica; Collado-Vides, Julio; Dávila, Guillermo
We report the complete 6,530,228-bp genome sequence of the symbiotic nitrogen fixing bacterium Rhizobium etli. Six large plasmids comprise one-third of the total genome size. The chromosome encodes most functions necessary for cell growth, whereas few essential genes or complete metabolic pathways are located in plasmids. Chromosomal synteny is disrupted by genes related to insertion sequences, phages, plasmids, and cell-surface components. Plasmids do not show synteny, and their orthologs are mostly shared by accessory replicons of species with multipartite genomes. Some nodulation genes are predicted to be functionally related with chromosomal loci encoding for the external envelope of the bacterium. Several pieces of evidence suggest an exogenous origin for the symbiotic plasmid (p42d) and p42a. Additional putative horizontal gene transfer events might have contributed to expand the adaptive repertoire of R. etli, because they include genes involved in small molecule metabolism, transport, and transcriptional regulation. Twenty-three putative sigma factors, numerous isozymes, and paralogous families attest to the metabolic redundancy and the genomic plasticity necessary to sustain the lifestyle of R. etli in symbiosis and in the soil.
Bacterial regulatory networks are extremely flexible in evolution
(2006-05) Lozada-Chávez, Irma; Janga, Sarath Chandra; Collado-Vides, Julio
Over millions of years the structure and complexity of the transcriptional regulatory network (TRN) in bacteria has changed, reorganized and enabled them to adapt to almost every environmental niche on earth. In order to understand the plasticity of TRNs in bacteria, we studied the conservation of currently known TRNs of the two model organisms Escherichia coli K12 and Bacillus subtilis across complete genomes including Bacteria, Archaea and Eukarya at three different levels: individual components of the TRN, pairs of interactions and regulons. We found that transcription factors (TFs) evolve much faster than the target genes (TGs) across phyla. We show that global regulators are poorly conserved across the phylogenetic spectrum and hence TFs could be the major players responsible for the plasticity and evolvability of the TRNs. We also found that there is only a small fraction of significantly conserved transcriptional regulatory interactions among different phyla of bacteria and that there is no constraint on the elements of the interaction to co-evolve. Finally our results suggest that majority of the regulons in bacteria are rapidly lost implying a high-order flexibility in the TRNs. We hypothesize that during the divergence of bacteria certain essential cellular processes like the synthesis of arginine, biotine and ribose, transport of amino acids and iron, availability of phosphate, replication process and the SOS response are well conserved in evolution. From our comparative analysis, it is possible to infer that transcriptional regulation is more flexible than the genetic component of the organisms and its complexity and structure plays an important role in the phenotypic adaptation.
Identification and analysis of DNA-binding transcription factors in Bacillus subtilis and other Firmicutes- a genomic approach
(2006-06) Moreno-Campuzano, Samadhi; Janga, Sarath Chandra; Pérez-Rueda, Ernesto
Background Bacillus subtilis is one of the best-characterized organisms in Gram-positive bacteria. It represents a paradigm of gene regulation in bacteria due its complex life style (which could involve a transition between stages as diverse as vegetative cell and spore formation). In order to gain insight into the organization and evolution of the B. subtilis regulatory network and to provide an alternative framework for further studies in bacteria, we identified and analyzed its repertoire of DNA-binding transcription factors in terms of their abundance, family distribution and regulated genes. Results A collection of 237 DNA-binding Transcription Factors (TFs) was identified in B. subtilis, half of them with experimental evidence. 59% of them were predicted to be repressors, 17% activators, 17% were putatively identified as dual regulatory proteins and the remaining 6.3% could not be associated with a regulatory role. From this collection 56 TFs were found to be autoregulated, most of them negatively, though a significant proportion of positive feedback circuits were also identified. TFs were clustered into 51 regulatory protein families and then traced on 58 genomes from Firmicutes to detect their presence. From this analysis three families were found conserved in all the Firmicutes; fifteen families were distributed in all Firmicutes except in the phyla Mollicutes; two were constrained to Bacillales and finally two families were found to be specific to B. subtilis, due to their specie specific distribution. Repression seems to be the most common regulatory mechanism in Firmicutes due to the high proportion of repressors in the detected collection in these genomes. In addition, six global regulators were defined in B. subtilis based on the number and function of their regulated genes. Conclusion In this work we identified and described the characteristics associated to the repertoire of DNA-binding TFs in B. subtilis. We also quantified their abundance, family distribution, and regulatory roles in the context of Firmicutes. This work should not only contribute to our understanding of the regulation of gene expression in bacteria from the perspective of B. subtilis but also provide us the basis for comprehensive modeling of transcriptional regulatory networks in Firmicutes.
The distinctive signatures of promoter regions and operon junctions across prokaryotes
(2006-08) Janga, Sarath Chandra; Lamboy, Warren F.; Huerta, Araceli M.; Moreno-Hagelsieb, Gabriel
Here we show that regions upstream of first transcribed genes have oligonucleotide signatures that distinguish them from regions upstream of genes in the middle of operons. Databases of experimentally confirmed transcription units do not exist for most genomes. Thus, to expand the analyses into genomes with no experimentally confirmed data, we used genes conserved adjacent in evolutionarily distant genomes as representatives of genes inside operons. Likewise, we used divergently transcribed genes as representative examples of first transcribed genes. In model organisms, the trinucleotide signatures of regions upstream of these representative genes allow for operon predictions with accuracies close to those obtained with known operon data (0.8). Signature-based operon predictions have more similar phylogenetic profiles and higher proportions of genes in the same pathways than predicted transcription unit boundaries (TUBs). These results confirm that we are separating genes with related functions, as expected for operons, from genes not necessarily related, as expected for genes in different transcription units. We also test the quality of the predictions using microarray data in six genomes and show that the signature-predicted operons tend to have high correlations of expression. Oligonucleotide signatures should expand the number of tools available to identify operons even in poorly characterized genomes.
Prediction and evolution of transcription factors and their evolutionary families in prokaryotes
(2007-05) Janga, Sarath Chandra
Transcription factors (TFs) play an important role in the genetic regulation of transcription in response to internal and external cellular stimulus even in a simple bacterium like Escherichia coli [1]. However little is known about their functional roles, expression dynamics and evolutionary scenarios on a large scale, even in a well studied model organisms. In this short tutorial, I will first talk about the prediction of transcription factors, which form the core of the regulatory repertoires in prokaryotes, responsible for controlling the expression of genes/transcription units by binding to their cis-regulatory regions. I will present different commonly used sequenced-based approaches to predict TFs in prokarya and discuss a simple rule of thumb to identify the putative regulatory role played by a TF based on its protein sequence alone [2-6]. I will discuss on some important properties of prokaryotic TFs which distinguish them apart from rest of the protein coding genes. The second part of the talk would concentrate on the evolutionary conservation of TFs and TF families across genomes and the implications of the observations on the phenotypic adaptation of species to different niches [3,7,8]. Finally, I will discuss some future perspectives in this area of research.
Conservation of transcriptional sensing systems in prokaryotes: A perspective from Escherichia coli
(2007-07) Salgado, Heladia; Martínez-Antonio, Agustino; Janga, Sarath Chandra
The activity of transcription factors is usually governed by allosteric physicochemical signals or metabolites, which are in turn produced in the cell or obtained from the environment by the activity of the products of effector genes. Previously, we identified a collection of more than 110 transcription factors and their corresponding effector genes in Escherichia coli K-12. Here, we introduce the notion of “triferog”, which relates to the identification of orthologous transcription factors and effector genes across genomes and show that transcriptional sensing systems known in E. coli are poorly conserved beyond Salmonella. We also find that enzymes that act as effector genes for the production of endogenous effector metabolites are more conserved than their corresponding effector genes encoding for transport and two-component systems for sensing exogenous signals. Finally, we observe that on an evolutionary scale enzymes are more conserved than their respective TFs, suggesting a homogenous cellular metabolism across genomes and the conservation of transcriptional control of critical cellular processes like DNA replication by a common endogenous signal. We hypothesize that extensive variation in the domain architecture of TFs and changes in endogenous conditions at large phylogenetic distances could be the major contributing factors for the observed differential conservation of TFs and their corresponding effector genes encoding for enzymes, causing variations in transcriptional responses across organisms.
Coordination logic of the sensing machinery in the transcriptional regulatory network of Escherichia coli
(2007-10) Janga, Sarath Chandra; Salgado, Heladia; Martínez-Antonio, Agustino; Collado-Vides, Julio
The active and inactive state of transcription factors in growing cells is usually directed by allosteric physicochemical signals or metabolites, which are in turn either produced in the cell or obtained from the environment by the activity of the products of effector genes. To understand the regulatory dynamics and to improve our knowledge about how transcription factors (TFs) respond to endogenous and exogenous signals in the bacterial model, Escherichia coli, we previously proposed to classify TFs into external, internal and hybrid sensing classes depending on the source of their allosteric or equivalent metabolite. Here we analyze how a cell uses its topological structures in the context of sensing machinery and show that, while feed forward loops (FFLs) tightly integrate internal and external sensing TFs connecting TFs from different layers of the hierarchical transcriptional regulatory network (TRN), bifan motifs frequently connect TFs belonging to the same sensing class and could act as a bridge between TFs originating from the same level in the hierarchy. We observe that modules identified in the regulatory network of E. coli are heterogeneous in sensing context with a clear combination of internal and external sensing categories depending on the physiological role played by the module. We also note that propensity of two-component response regulators increases at promoters, as the number of TFs regulating a target operon increases. Finally we show that evolutionary families of TFs do not show a tendency to preserve their sensing abilities. Our results provide a detailed panorama of the topological structures of E. coli TRN and the way TFs they compose off, sense their surroundings by coordinating responses.
Highlights from the Third International Society for Computational Biology Student Council Symposium at the Fifteenth Annual International Conference on Intelligent Systems for Molecular Biology
(2007-11) Gehlenborg, Nils; Corpas, Manuel; Janga, Sarath Chandra
In this meeting report we give an overview of the 3rd International Society for Computational Biology Student Council Symposium. Furthermore, we explain the role of the Student Council and the symposium series in the context of large, international conferences.

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