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Pandey P.,National Institute of Biomedical Genomics | Acharya M.,National Institute of Biomedical Genomics
Investigative Ophthalmology and Visual Science | Year: 2016

PURPOSE. Capturing organ-specific phenomes in genetic diseases is an uphill task for the eye as it comprises tissue types derived from all three germinal layers. We attempted to deconstruct genetic eye diseases (GEDs) into primary phenotypic features, to understand the complex genome-phenome relationship in GEDs. METHODS. Using phenotype, molecular basis, and gene description features in OMIM as a primary resource, we analyzed gene-phenotype information. All ocular and systemic phenotypes were categorized and ranked based on occurrence. Clustering was performed on shared ocular features to identify genetic interactions and the largest cluster of each phenotype was used for functional analyses. RESULTS. We collected 527 GEDs associated with 440 unique protein-coding genes. We indexed 787 ocular and 3094 systemic features, for an average of 2.17 ocular and 8.14 systemic features, respectively, per disease unit. The most common ocular features included nystagmus, hypertelorism, and myopia, while neurological and skeletal are the most common systemic groups associated with GEDs. Functional analyses revealed pathways relevant to GEDs (e.g., extracellular matrix organization in ONH3 [glaucoma]) and protein metabolism in EOM35 (nystagmus) phenotype clusters. CONCLUSIONS. Our work imparts a structure in dissecting GEDs into unique phenotypes to study the relationship between genes and diseases involving the eye. © 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved.

Dweep H.,University of Heidelberg | Sticht C.,University of Heidelberg | Kharkar A.,University of Heidelberg | Pandey P.,National Institute of Biomedical Genomics | Gretz N.,University of Heidelberg
PLoS ONE | Year: 2013

Autosomal polycystic kidney disease (ADPKD) is a frequent monogenic renal disease, characterised by fluid-filled cysts that are thought to result from multiple deregulated pathways such as cell proliferation and apoptosis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of many genes associated with such biological processes and human pathologies. To explore the possible regulatory role of miRNAs in PKD, the PKD/Mhm (cy/+) rat, served as a model to study human ADPKD. A parallel microarray-based approach was conducted to profile the expression changes of mRNAs and miRNAs in PKD/Mhm rats. 1,573 up- and 1,760 down-regulated genes were differentially expressed in PKD/Mhm. These genes are associated with 17 pathways (such as focal adhesion, cell cycle, ECM-receptor interaction, DNA replication and metabolic pathways) and 47 (e.g., cell proliferation, Wnt and Tgfβ signaling) Gene Ontologies. Furthermore, we found the similar expression patterns of deregulated genes between PKD/Mhm (cy/+) rat and human ADPKD, PKD1L3/L3, PKD1-/-, Hnf1α-deficient, and Glis2lacZ/lacZ models. Additionally, several differentially regulated genes were noted to be target hubs for miRNAs. We also obtained 8 significantly up-regulated miRNAs (rno-miR-199a-5p, -214, -146b, -21, -34a, -132, -31 and -503) in diseased kidneys of PKD/Mhm rats. Additionally, the binding site overrepresentation and pathway enrichment analyses were accomplished on the putative targets of these 8 miRNAs. 7 out of these 8 miRNAs and their possible interactions have not been previously described in ADPKD. We have shown a strong overlap of functional patterns (pathways) between deregulated miRNAs and mRNAs in the PKD/Mhm (cy/+) rat model. Our findings suggest that several miRNAs may be associated in regulating pathways in ADPKD. We further describe novel miRNAs and their possible targets in ADPKD, which will open new avenues to understand the pathogenesis of human ADPKD. Furthermore they could serve as a useful resource for anti-fibrotic therapeutics. © 2013 Dweep et al.

Narang A.,Institute of Genomics and Integrative Biology | Jha P.,Institute of Genomics and Integrative Biology | Rawat V.,Institute of Genomics and Integrative Biology | Mukhopadhayay A.,Institute of Genomics and Integrative Biology | And 3 more authors.
American Journal of Human Genetics | Year: 2011

Identification and study of genetic variation in recently admixed populations not only provides insight into historical population events but also is a powerful approach for mapping disease loci. We studied a population (OG-W-IP) that is of African-Indian origin and has resided in the western part of India for 500 years; members of this population are believed to be descendants of the Bantu-speaking population of Africa. We have carried out this study by using a set of 18,534 autosomal markers common between Indian, CEPH-HGDP, and HapMap populations. Principal-components analysis clearly revealed that the African-Indian population derives its ancestry from Bantu-speaking west-African as well as Indo-European-speaking north and northwest Indian population(s). STRUCTURE and ADMIXTURE analyses show that, overall, the OG-W-IPs derive 58.7% of their genomic ancestry from their African past and have very little inter-individual ancestry variation (8.4%). The extent of linkage disequilibrium also reveals that the admixture event has been recent. Functional annotation of genes encompassing the ancestry-informative markers that are closer in allele frequency to the Indian ancestral population revealed significant enrichment of biological processes, such as ion-channel activity, and cadherins. We briefly examine the implications of determining the genetic diversity of this population, which could provide opportunities for studies involving admixture mapping. © 2011 by The American Society of Human Genetics. All rights reserved.

Trevino J.G.,H. Lee Moffitt Cancer Center and Research Institute | Trevino J.G.,University of Florida | Pillai S.,H. Lee Moffitt Cancer Center and Research Institute | Pillai S.,National Institute of Biomedical Genomics | And 6 more authors.
Neoplasia (United States) | Year: 2012

Smoking is a significant risk factor for pancreatic cancer, but the molecular mechanisms by which tobacco smoke components promote the growth and progression of these cancers are not fully understood. While nicotine, the addictive component of tobacco smoke, is not a carcinogen, it has been shown to promote the growth of non-small cell lung and pancreatic cancers in a receptor-dependent fashion. Here, we show that stimulation of pancreatic cancer cells with nicotine concentrations that are within the range of human exposure results in activation of Src kinase, which facilitated the induction of the inhibitor of differentiation-1 (Id1) transcription factor. Depletion of Id1 prevented nicotine-mediated induction of proliferation and invasion of pancreatic cancer cells, indicating that it is a major mediator of nicotine function. Nicotine could promote the growth and metastasis of pancreatic cancers orthotopically implanted into SCID mice; in addition, cells stably expressing a short hairpin RNA for Id1 did not grow or metastasize in response to nicotine. Nicotine could also confer resistance to apoptosis induced by gemcitabine in pancreatic cancer cells in vitro and depletion of Src or Id1 rendered the cells sensitive to gemcitabine. Further, nicotine could effectively inhibit the chemotherapeutic effects of gemcitabine on pancreatic tumors xenografted into mice. Clinical analyses of resected pancreatic cancer specimens demonstrated a statistically significant correlation between Id1 expression and phospho-Src, tumor grade/differentiation, and worsening overall patient survival. These results demonstrate that exposure to tobacco smoke components might promote pancreatic cancer progression, metastasis, and chemoresistance and highlight the role of Id1 in these processes. © 2012 Neoplasia Press, Inc. All rights reserved.

Singh S.,H. Lee Moffitt Cancer Center and Research Institute | Singh S.,National Institute of Biomedical Genomics | Trevino J.,H. Lee Moffitt Cancer Center and Research Institute | Trevino J.,University of Florida | And 5 more authors.
Molecular Cancer | Year: 2012

Background: Cancer stem cells are thought to be responsible for the initiation and progression of cancers. In non-small cell lung cancers (NSCLCs), Hoechst 33342 dye effluxing side population (SP) cells are shown to have stem cell like properties. The oncogenic capacity of cancer stem-like cells is in part due to their ability to self-renew; however the mechanistic correlation between oncogenic pathways and self-renewal of cancer stem-like cells has remained elusive. Here we characterized the SP cells at the molecular level and evaluated its ability to generate tumors at the orthotopic site in the lung microenvironment. Further, we investigated if the self-renewal of SP cells is dependent on EGFR mediated signaling.Results: SP cells were detected and isolated from multiple NSCLC cell lines (H1650, H1975, A549), as well as primary human tumor explants grown in nude mice. SP cells demonstrated stem-like properties including ability to self-renew and grow as spheres; they were able to generate primary and metastatic tumors upon orthotopic implantation into the lung of SCID mice. In vitro study revealed elevated expression of stem cell associated markers like Oct4, Sox2 and Nanog as well as demonstrated intrinsic epithelial to mesenchymal transition features in SP cells. Further, we show that abrogation of EGFR, Src and Akt signaling through pharmacological or genetic inhibitors suppresses the self-renewal growth and expansion of SP-cells and resulted in specific downregulation of Sox2 protein expression. siRNA mediated depletion of Sox2 significantly blocked the SP phenotype as well as its self-renewal capacity; whereas other transcription factors like Oct4 and Nanog played a relatively lesser role in regulating self-renewal. Interestingly, Sox2 was elevated in metastatic foci of human NSCLC samples. Conclusions: Our findings suggest that Sox2 is a novel target of EGFR-Src-Akt signaling in NSCLCs that modulates self-renewal and expansion of stem-like cells from NSCLC. Therefore, the outcome of the EGFR-Src-Akt targeted therapy may rely upon the expression and function of Sox2 within the NSCLC-CSCs. © 2012 Singh et al.; licensee BioMed Central Ltd.

News Article | March 4, 2016
Site: www.nature.com

An ambitious plan to turn India into a world-class centre for genomics research and commercialization received a modest boost on 29 February when the government announced its annual budget. A big winner in the budget was India’s main science funding agency, the Department of Science and Technology, which received 44.7 billion rupees (US$650 million), a 17% hike on last year’s allocation. The Department of Biotechnology (DBT), meanwhile, received 18.2 billion rupees, a 12% rise on the previous year — an indication of how the National Biotechnology Development Strategy, which the department unveiled last December, is likely to evolve. The budget brought mixed news for other departments engaged in scientific research (see ‘Budget allocations’). The Department of Health Research’s budget represented a 12% rise in funding compared with the money pledged in 2015–16, for instance, whereas the Department of Space got an increase of less than 2%. The DBT’s allocation is roughly half of what Krishnaswamy VijayRaghavan, the department’s secretary, estimated was needed when the strategy was released — but he is confident that the remainder can be made up from other sources. The allocation is “very good” in terms of implementing the strategy, he told Nature. The DBT’s strategy aims to ramp up India’s total biotech revenues by more than tenfold since the industry started up two decades ago, to $100 billion by 2025. The idea is to kick-start the economy by replicating the success of the information-technology boom that has fuelled economic growth for more than 20 years. “Biotechnology can be another vibrant model for growth that India can offer,” said the science minister, Harsh Vardhan, back in December. India’s pharmaceutical industry is largely confined to the production of ‘generic’ copies of existing drugs, and to contract research organizations, which conduct clinical trials of drugs and vaccines on behalf of pharmaceutical companies. Both have grown into successful industries, says VijayRaghavan, but the nation “is now ready to upgrade its biotech capabilities”. The DBT received an encouraging sign last year, when its budget allocation for 2015 was not subsequently slashed during mid-term budget revisions, as often happens. The latest 12% increase builds on that good news, says VijayRaghavan. Ahead of this year’s budget, however, VijayRaghavan said that this figure would need to rise to 25–30% annually over the next five years to implement the strategy.  He now says that the DBT could make up the difference with funds from elsewhere, including a national innovation mission launched in January, which identified biotechnology as a key area — in particular, to bolster the parts of the strategy aimed at nurturing biotech start-ups and supporting entrepreneurs. The DBT could also tap into the science department’s budget. Department secretary Ashutosh Sharma, who described the increase as “fantastic”, says that his department’s plans include a rise in the number and quality of start-ups and business incubators, support for scientists undertaking high-risk research, the promotion of industry-relevant research at academic institutes and new research programmes on, among other things, biomedical devices. Some of these plans overlap with the DBT’s strategy. Ahead of the budget announcement, VijayRaghavan told Nature that the strategy revolves around three core activities. The first is the creation of new infrastructure. India already hosts several genomics research institutes, such as the Institute of Genomics and Integrative Biology (IGIB) and the National Institute of Plant Genome Research, both in New Delhi, and the National Institute of Biomedical Genomics near Kolkata. The DBT’s strategy aims to create five more centres, each dedicated to a different field, including drug discovery, marine biology and infection, as well as several centres of excellence based on narrower, high-priority areas such as genetically modified organisms, vaccines and marine bioproducts. The second activity is the provision of training in the analysis of big data. Indian geneticists have previously discovered mutations in breast-cancer genes that are unique to the Indian population (M. T. Valarmathi et al. Hum. Mutat. 23, 205; 2004) and sequenced the genomes of several crops, including chickpea (R. K. Varshney et al. Nature Biotechnol. 31, 240–246; 2013). The DBT’s strategy aims to train researchers in the scanning and analysis of large numbers of genomes. VijayRaghavan notes that the country’s existing expertise in computing and biology will help this. “We need to bring the two skill sets together,” he says. The strategy also aims to create 150 technology-transfer organizations to help to commercialize discoveries made in publicly funded research laboratories, together with 40 technology and business incubators, which will provide equipment and guidance for new firms, and facilitate networking opportunities. Together, these all comprise the third core activity, says VijayRaghavan, and will build on the activities of the DBT’s Biotechnology Industry Research Assistance Council, which was set up in 2012. Lipi Thukral, a computational structural biologist at the IGIB, sees the DBT’s goal of creating a genomics hub as an opportunity for India to enter the emerging field of precision medicine, which uses genomic, physiological and other data to tailor treatments to the individual. Achieving that will require clinicians to gather extensive data and to interact better with academics to analyse the data, says Thukral. To succeed, the strategy will also need a feedback mechanism between the biotech corporate sector and academic institutions, policies to protect scientists undertaking high-risk, high-reward research and a reorientation of academia towards more industry-relevant research, she adds. Others have reservations about the scale of the DBT’s ambitions. “The strategy seems overwhelming, overburdened, and implementation would be a Herculean task,” says Nalini Vemuri, vice-president for research and development at the Gurgaon-based company Lifecare Innovations. The strategy spans four major areas — health care, food and nutrition, energy and education. But although these represent an “impressive vision”, says Vemuri, a more narrowly focused goal, for example to improve the country’s research in malaria and tuberculosis, would have a better chance of success.

Chinnaswamy S.,National Institute of Biomedical Genomics
Journal of Interferon and Cytokine Research | Year: 2014

Human genetic variation plays a critical role in both spontaneous clearance of and response to interferon (IFN)-based therapies against hepatitis C virus (HCV) as shown by the success of recent genome-wide association studies (GWAS). Several GWAS and later validation studies have shown that single nucleotide polymorphisms (SNPs) at the IFNL3 (formerly IL28B) locus on chromosome 19 are involved in eliminating HCV in human patients. No doubt that this information is helping clinicians worldwide in making better clinical decisions in anti-HCV therapy, but the biological mechanisms involving the SNPs leading to differential responses to therapy and spontaneous clearance of HCV remain elusive. Recent reports including the discovery of a novel IFN (IFN-λ4) gene at the IFNL3 locus and in vitro functional studies implicating 2 SNPs as causal variants lead to novel conclusions and perhaps to new directions in research. An attempt is made in this review to summarize the major findings of the GWAS, the efforts involved in the discovery of causal SNPs; and to explain the biological basis for spontaneous clearance and response to treatment in HCV infections. © 2014 Mary Ann Liebert, Inc.

Srivastava P.K.,Indian Institute of Science | Srivastava P.K.,Imperial College London | Moturu T.R.,Indian Institute of Science | Pandey P.,National Institute of Biomedical Genomics | And 2 more authors.
BMC Genomics | Year: 2014

Background: Deep-sequencing has enabled the identification of large numbers of miRNAs and siRNAs, making the high-throughput target identification a main limiting factor in defining their function. In plants, several tools have been developed to predict targets, majority of them being trained on Arabidopsis datasets. An extensive and systematic evaluation has not been made for their suitability for predicting targets in species other than Arabidopsis. Nor, these have not been evaluated for their suitability for high-throughput target prediction at genome level. Results: We evaluated the performance of 11 computational tools in identifying genome-wide targets in Arabidopsis and other plants with procedures that optimized score-cutoffs for estimating targets. Targetfinder was most efficient [89% 'precision' (accuracy of prediction), 97% 'recall' (sensitivity)] in predicting 'true-positive' targets in Arabidopsis miRNA-mRNA interactions. In contrast, only 46% of true positive interactions from non-Arabidopsis species were detected, indicating low 'recall' values. Score optimizations increased the 'recall' to only 70% (corresponding 'precision': 65%) for datasets of true miRNA-mRNA interactions in species other than Arabidopsis. Combining the results of Targetfinder and psRNATarget delivers high true positive coverage, whereas the intersection of psRNATarget and Tapirhybrid outputs deliver highly 'precise' predictions. The large number of 'false negative' predictions delivered from non-Arabidopsis datasets by all the available tools indicate the diversity in miRNAs-mRNA interaction features between Arabidopsis and other species. A subset of miRNA-mRNA interactions differed significantly for features in seed regions as well as the total number of matches/mismatches.Conclusion: Although, many plant miRNA target prediction tools may be optimized to predict targets with high specificity in Arabidopsis, such optimized thresholds may not be suitable for many targets in non-Arabidopsis species. More importantly, non-conventional features of miRNA-mRNA interaction may exist in plants indicating alternate mode of miRNA target recognition. Incorporation of these divergent features would enable next-generation of algorithms to better identify target interactions. © 2014 Srivastava et al.; licensee BioMed Central Ltd.

Majumder P.P.,National Institute of Biomedical Genomics
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

Considerable variation in antibody response (AR) was observed among recipients of an injectable typhoid vaccine and an oral cholera vaccine. We sought to find whether polymorphisms in genes of the immune system, both innate and adaptive, were associated with the observed variation in response. For both vaccines, we were able to discover and validate several polymorphisms that were significantly associated with immune response. For the typhoid vaccines, these polymorphisms were on genes that belonged to pathways of polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signalling and eventual production of antimicrobial peptides. For the cholera vaccine, the pathways included epithelial barrier integrity, intestinal homeostasis and leucocyte recruitment. Even though traditional wisdom indicates that both vaccines should act as T-cell-independent antigens, our findings reveal that the vaccines induce AR using different pathways. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Majumder P.P.,National Institute of Biomedical Genomics | Basu A.,National Institute of Biomedical Genomics
Cold Spring Harbor Perspectives in Biology | Year: 2015

Recent advances in molecular and statistical genetics have enabled the reconstruction of human history by studying living humans. The ability to sequence and study DNA by calibrating the rate of accumulation of changes with evolutionary time has enabled robust inferences about how humans have evolved. These data indicate that modern humans evolved in Africa about 150,000 years ago and, consistent with paleontological evidence, migrated out of Africa. And through a series of settlements, demographic expansions, and further migrations, they populated the entire world. One of the first waves of migration from Africa was into India. Subsequent, more recent, waves of migration from other parts of the world have resulted in India being a genetic melting pot. Contemporary India has a rich tapestry of cultures and ecologies. There are about 400 tribal groups and more than 4000 groups of castes and subcastes, speaking dialects of 22 recognized languages belonging to four major language families. The contemporary social structure of Indian populations is characterized by endogamy with different degrees of porosity. The social structure, possibly coupled with large ecological heterogeneity, has resulted in considerable genetic diversity and local genetic differences within India. In this essay, we provide genetic evidence of how India may have been peopled, the nature and extent of its genetic diversity, and genetic structure among the extant populations of India. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

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