Novel integrated Omics based computational approach for drug repurposing for non-muscle invasive bladder cancer (NMIBC).

Non-muscle invasive bladder cancer (NMIBC) refers to a subtype of bladder carcinoma where cancer is localized in the inner lining of bladder. NMIBC consider as one of most costly malignancy and requires significant surgical and therapeutic measure. However, recurrence and progression of tumor is common in treated patients. Here we presented an integrated OMICs approach for the identification and inhibition of NMIBC specific genes. We utilized a case study where three group of patients were compared: 1) Relapsed tumors 2) recurrent tumors and 3) tumor in progression. Common transcriptome signature between patients facing recurrence and progression allowed us to identify three NMIBC specific genes FLT-1, WHSC-1 and CD34. We further utilized novel approach of Co-expressed gene-set enrichment analysis (COGENA) on the differentially expressed genes of this case study. Three drugs (paroxetine, adiphenine and H-89) with role of receptors inhibition were identified and predicted as repurposed drugs for the inhibition NMIBC specific genes. We further tested this hypothesis by performing molecular docking and simulation analysis between cancer specific proteins and drugs. FLT-1 have shown significant stable interaction with both drugs paroxetine and adiphenine whereas WHSC-1 have shown compact interaction with adiphenine and H-89. In the light of these evidence, we suggest that adiphenine could be repositioned as alternate targeted medicine for the treatment of NMIBC. In the future, this study will help for strengthening the strategies development at the molecular level for the control of carcinomas at early as well as detection of active and binding site, receptor-ligand interaction and also make drug repurposing for the early treatment of the carcinomas.Communicated by Ramaswamy H. Sarma.

Identification of potential phytochemical for the inhibition of non-muscle invasive bladder cancer (NMIBC).

Non-muscle invasive bladder cancer (NMIBC) is one of the most common type of bladder cancer. Here, we have utilized an integrated transcriptomic-computational approach to identify alternate treatments to the NMIBC. In this study, we have performed the comprehensive comparative analysis between three groups of 36 patients with non-relapsed (NR), recurrence and progressive symptoms. Differentially expressed genes involved in the pathways associated with the NMIBC were identified. In silico protein-protein interaction (PPI) network was performed to create the network of the hub genes associated with NMIBC. Further, we compared NR individuals with two cohorts of patients with recurrent and progressive symptoms that lead to the identification of three major biomarkers CD34, FLT1 and WHSC1 genes. Concurrently, PPI also suggests that they are significant hub genes responsible for disease recurrence and progression. Furthermore, targeted genes WHSC-1 and FLT-1 were subjected to virtual screening for identification phytochemical inhibitors. Docking and molecular dynamics simulations concluded that the phytochemicals anonymously named 'UNK' and '6-hydroxycyanidin' are suitable for the inhibition of the proteins causing the NMIBC. In the future, this study will help for strengthening the strategies development at the molecular level for the control of carcinomas at early as well as detection of active and binding site, receptor-ligand interaction and also make drug designing for the early treatment of the carcinomas.Communicated by Ramaswamy H. Sarma.

REPercussions: how geminiviruses recruit host factors for replication.

Circular single-stranded DNA viruses of the family Geminiviridae encode replication-associated protein (Rep), which is a multifunctional protein involved in virus DNA replication, transcription of virus genes, and suppression of host defense responses. Geminivirus genomes are replicated through the interaction between virus Rep and several host proteins. The Rep also interacts with itself and the virus replication enhancer protein (REn), which is another essential component of the geminivirus replicase complex that interacts with host DNA polymerases α and δ. Recent studies revealed the structural and functional complexities of geminivirus Rep, which is believed to have evolved from plasmids containing a signature domain (HUH) for single-stranded DNA binding with nuclease activity. The Rep coding sequence encompasses the entire coding sequence for AC4, which is intricately embedded within it, and performs several overlapping functions like Rep, supporting virus infection. This review investigated the structural and functional diversity of the geminivirus Rep.

Evolution of NLR genes in genus Arachis reveals asymmetric expansion of NLRome in wild and domesticated tetraploid species.

Arachis hypogaea is an allotetraploid crop widely grown in the world. Wild relatives of genus Arachis are the rich source of genetic diversity and high levels of resistance to combat pathogens and climate change. The accurate identification and characterization of plant resistance gene, nucleotide binding site leucine rich repeat receptor (NLRs) substantially contribute to the repertoire of resistances and improve production. In the current study, we have studied the evolution of NLR genes in genus Arachis and performed their comparative genomics among four diploids (A. duranensis, A. ipaensis, A. cardenasii, A. stenosperma) and two tetraploid (wild: A. monticola and domesticated: A. hypogaea) species. In total 521, 354, 284, 794, 654, 290 NLR genes were identified from A. cardenasii, A. stenosperma and A. duranensis, A. hypogaea, A. monticola and A. ipaensis respectively. Phylogenetic analysis and classification of NLRs revealed that they belong to 7 subgroups and specific subgroups have expanded in each genome leading towards divergent evolution. Gene gain and loss, duplication assay reveals that wild and domesticated tetraploids species have shown asymmetric expansion of NLRome in both sub-genome (AA and BB). A-subgenome of A. monticola exhibited significant contraction of NLRome while B-subgenome shows expansion and vice versa in case of A. hypogaea probably due to distinct natural and artificial selection pressure. In addition, diploid species A. cardenasii revealed the largest repertoire of NLR genes due to higher frequency of gene duplication and selection pressure. A. cardenasii and A. monticola can be regarded as putative resistance resources for peanut breeding program for introgression of novel resistance genes. Findings of this study also emphasize the application neo-diploids and polyploids due to higher quantitative expression of NLR genes. To the best of our knowledge, this is the first study that studied the effect of domestication and polyploidy on the evolution of NLR genes in genus Arachis to identify genomic resources for improving resistance of polyploid crop with global importance on economy and food security.

Investigation of Resistance Genes in Genus Vigna Reveals Highly Variable NLRome in Parallel Domesticated Member Species.

Vigna is a unique genus that consist of multiple crop species that are domesticated in parallel fashion between 7-10 thousand years ago. Here we studied the evolution of nucleotide-binding site leucine-rich repeat receptor (NLR) genes across five crop species of genus Vigna. In total identified 286, 350, 234, 250, 108 and 161 NLR genes were from Phaseolous vulgaris, Vigna. unguiculata, Vigna mungo, Vigna radiata, Vigna angularis and Vigna umbellata respectively. Comprehensive phylogenetic and clusterization analysis reveals the presence of seven subgroups of Coiled coil like NLRs (CC-NLR) genes and four distinct lineages of Toll interleukin receptor like NLRs (TIR-NLR). Subgroup CCG10-NLR shows large scale diversification among Vigna species suggesting genus specific distinct duplication pattern in Vigna species. Mainly birth of new NLR gene families and higher rate of terminal duplication is the major determinants for expansion of NLRome in genus Vigna. Recent expansion of NLRome in V. anguiculata and V. radiata was also observed which might suggest that domestication have supported their duplication of lineage specific NLR genes. In short, large scale difference in the architecture of NLRome were observed in diploid plant species. Our findings allowed us to hypothesized that independent parallel domestication is the major drivers of highly divergent evolution of NLRome in genus Vigna.

Investigation of NLR Genes Reveals Divergent Evolution on NLRome in Diploid and Polyploid Species in Genus Trifolium.

Crop wild relatives contain a greater variety of phenotypic and genotypic diversity compared to their domesticated counterparts. Trifolium crop species have limited genetic diversity to cope with biotic and abiotic stresses due to artificial selection for consumer preferences. Here, we investigated the distribution and evolution of nucleotide-binding site leucine-rich repeat receptor (NLR) genes in the genus of Trifolium with the objective to identify reference NLR genes. We identified 412, 350, 306, 389 and 241 NLR genes were identified from Trifolium. subterraneum, T. pratense, T. occidentale, subgenome-A of T. repens and subgenome-B of T. repens, respectively. Phylogenetic and clustering analysis reveals seven sub-groups in genus Trifolium. Specific subgroups such as G4-CNL, CCG10-CNL and TIR-CNL show distinct duplication patterns in specific species, which suggests subgroup duplications that are the hallmarks of their divergent evolution. Furthermore, our results strongly suggest the overall expansion of NLR repertoire in T. subterraneum is due to gene duplication events and birth of gene families after speciation. Moreover, the NLRome of the allopolyploid species T. repens has evolved asymmetrically, with the subgenome -A showing expansion, while the subgenome-B underwent contraction. These findings provide crucial background data for comprehending NLR evolution in the Fabaceae family and offer a more comprehensive analysis of NLR genes as disease resistance genes.

Dynamic Evolution of NLR Genes in Dalbergioids.

Dalbergioid is a large group within the family Fabaceae that consists of diverse plant species distributed in distinct biogeographic realms. Here, we have performed a comprehensive study to understand the evolution of the nucleotide-binding leucine-rich repeats (NLRs) gene family in Dalbergioids. The evolution of gene families in this group is affected by a common whole genome duplication that occurred approximately 58 million years ago, followed by diploidization that often leads to contraction. Our study suggests that since diploidization, the NLRome of all groups of Dalbergioids is expanding in a clade-specific manner with fewer exceptions. Phylogenetic analysis and classification of NLRs revealed that they belong to seven subgroups. Specific subgroups have expanded in a species-specific manner, leading to divergent evolution. Among the Dalbergia clade, the expansion of NLRome in six species of the genus Dalbergia was observed, with the exception of Dalbergia odorifera, where a recent contraction of NLRome occurred. Similarly, members of the Pterocarpus clade genus Arachis revealed a large-scale expansion in the diploid species. In addition, the asymmetric expansion of NLRome was observed in wild and domesticated tetraploids after recent duplications in the genus Arachis. Our analysis strongly suggests that whole genome duplication followed by tandem duplication after divergence from a common ancestor of Dalbergioids is the major cause of NLRome expansion. To the best of our knowledge, this is the first ever study to provide insight toward the evolution of NLR genes in this important tribe. In addition, accurate identification and characterization of NLR genes is a substantial contribution to the repertoire of resistances among members of the Dalbergioids species.

CAULIFINDER: a pipeline for the automated detection and annotation of caulimovirid endogenous viral elements in plant genomes.

Plant, animal and protist genomes often contain endogenous viral elements (EVEs), which correspond to partial and sometimes entire viral genomes that have been captured in the genome of their host organism through a variety of integration mechanisms. While the number of sequenced eukaryotic genomes is rapidly increasing, the annotation and characterization of EVEs remains largely overlooked. EVEs that derive from members of the family Caulimoviridae are widespread across tracheophyte plants, and sometimes they occur in very high copy numbers. However, existing programs for annotating repetitive DNA elements in plant genomes are poor at identifying and then classifying these EVEs. Other than accurately annotating plant genomes, there is intrinsic value in a tool that could identify caulimovirid EVEs as they testify to recent or ancient host-virus interactions and provide valuable insights into virus evolution. In response to this research need, we have developed CAULIFINDER, an automated and sensitive annotation software package. CAULIFINDER consists of two complementary workflows, one to reconstruct, annotate and group caulimovirid EVEs in a given plant genome and the second to classify these genetic elements into officially recognized or tentative genera in the Caulimoviridae. We have benchmarked the CAULIFINDER package using the Vitis vinifera reference genome, which contains a rich assortment of caulimovirid EVEs that have previously been characterized using manual methods. The CAULIFINDER package is distributed in the form of a Docker image.

Insertion of Badnaviral DNA in the Late Blight Resistance Gene (R1a) of Brinjal Eggplant (Solanum melongena).

Endogenous viral elements (EVEs) are widespread in plant genomes. They result from the random integration of viral sequences into host plant genomes by horizontal DNA transfer and have the potential to alter host gene expression. We performed a large-scale search for co-transcripts including caulimovirid and plant sequences in 1,678 plant and 230 algal species and characterized 50 co-transcripts in 45 distinct plant species belonging to lycophytes, ferns, gymnosperms and angiosperms. We found that insertion of badnavirus EVEs along with Ty-1 copia mobile elements occurred into a late blight resistance gene (R1) of brinjal eggplant (Solanum melongena) and wild relatives in genus Solanum and disrupted R1 orthologs. EVEs of two previously unreported badnaviruses were identified in the genome of S. melongena, whereas EVEs from an additional novel badnavirus were identified in the genome of S. aethiopicum, the cultivated scarlet eggplant. Insertion of these viruses in the ancestral lineages of the direct wild relatives of the eggplant would have occurred during the last 3 Myr, further supporting the distinctiveness of the group of the eggplant within the giant genus Solanum.