Tropical Diseases: From Molecule to Bedside (Advances in Experimental Medicine and Biology)
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Sequencing the genomes or exomes a protein-coding portion of the genome of individual patients or populations, is becoming a collective approach for finding the causative genetic variants especially in complex diseases like cancers [ 24 ]. Characterizing the genetic profile of each tumor type will be helpful in devising the effective line of treatment for each type of tumor. Nearly 50 FDA Food and Drug Administration approved drugs have labels containing information about pharmacogenomics details [ 19 ].
Bioinformaticians have also lately been able to build the datasets that can systematically characterize the wide array of genomic variations among different sets of tumor models [ 21 ]. NGS platforms have the formidable ability to screen wide variety of genomic aberrations, such as single nucleotide variants SNVs , copy number variations CNVs , multiple nucleotide variants MNVs , and small and large insertions and deletions of various genes [ 27 ]. Currently discoveries in clinical diagnostics outpace the development of targeted therapies [ 28 ] and is supposed to expand greatly as more targets become known.
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Similarly, WES Whole Exome Sequencing has been found to be instrumental in identifying single nucleotide variants in circulating tumor cells especially in prostate cancer patients, hence, helping to devise therapies, as well as monitoring future relapses of cancer. The genome and genome analysis reveal the decreasing cost of sequencing genomes and exponential growth of sequenced genomes, as well as the share of genomic data analysis in next few years [ 32 ]. More than a decade after the completion of the human genome project, many in the scientific fraternity might be forgiven for thinking that genome-based medical tests would be at the forefront in medical diagnosis and treatment.
However, rapid progress in next-generation sequencing technologies has started to bring genomic medicine out of dormancy and, as a result, genomic methodologies have started getting inculcated into advanced medical specialties at a rapid pace. DNA sequencing technologies are making large-scale personal genome sequencing PGS a rapidly-approaching reality [ 33 ] and, thus, giving rise to the field of personalized genomic medicine. Personalized genome sequencing PGS is opening up new possibilities for patients through the individualized preventive healthcare iPH system.
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Complete human genome sequencing is now becoming available at an increasing scale and decreasing cost, thanks to fast-developing massively-parallel genome processing based on micro- and nanoarrays [ 33 ]. The dramatic price decrease, along with the upsurge in its applications, especially in the molecular diagnostic field, is going to herald a new phase in personal genome sequence PGS.
The data generated by NGS and other omics tools are enabling, and will further enable, clinicians to make improved diagnostic and treatment decisions in future clinics, e. The identification of variants in genes like BRCA1 , BRCA2 , and TP53 using the Illumina HiSeq platform is higher sensitivity than traditional diagnostic methods, hence demonstrating the effectiveness of NGS tools in cancer diagnostics and also deciphering the sophisticated mechanisms of gene-gene interactions [ 23 ].
The advent of novel sequencing technologies such as Nanopore technology is emerging as a frontline method for parallel genome sequencing methods and is contributing in establishing NGS as a relevant tool for clinical sequencing technology for future.
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By removing most of the throughput and resource limitations seen with customary methods, next generation genomic applications have provided scientists with the required ability to analyze the large array of genes or genomes in a single run. Although large-scale genome sequencing is an exhilarating scheme, the real challenge lies in converting the resulting data into an actionable clinical outcomes Figure 2.
Genome sequencing has already started making its presence felt in the global healthcare area [ 37 ] and is rapidly making inroads into the field of molecular diagnostics. The launching of ClinVar database at NCBI is a right step in studying, sharing the clinically-relevant variants among research groups involved in research and development of treatment for genetic diseases GDs. The schematic representation of next generation biotechnologies especially genome-based discoveries and their applications for patient and population-based studies for improving individualized, as well as the public, healthcare system.
Obtaining complete genetic and epigenetic information coupled with routine transcriptome profiling and numerous other functional genomic tests will inevitably lead to the comprehensive understanding of the molecular edifice of various chronic diseases [ 33 ]. To analyze and interpret the increasing amount of sequencing data a number of statistical methods and bioinformatics pipelines have to be developed for read alignment, variant detection point mutation, copy number variation, etc.
Due to the multifactorial nature of some diseases, pinpointing the cause or causes will be a daunting task [ 24 ]. Personalized genome sequencing will facilitate the identification of diverse molecular signatures both at genetic and epigenetic levels and the role environment plays in disease development and progression [ 12 ]. In the last ten years, the advancements in next-generation sequencing NGS technologies and target enrichment methods have resulted in the identification of genes responsible for more than 40 rare disorders [ 38 ].
Although there are certain risks associated with the PGS, the most serious being an over-interpretation of results based on limited understanding of the contextual information [ 33 ]. Therefore, utmost care needs to be taken to devise clinical strategies before employing genome-based applications for disease treatment. The environment has been known to play a significant role in disease development and progression, and nutrition has been particularly found to modulate gene activities at different levels with either activation or repression of key regulatory factors [ 39 ].
One of the promises of the human genome project was that it could revolutionize the understanding of the underlying causes of most of the genetic diseases by delineating the sequential arrangement of base pairs of DNA molecules [ 40 ]. Therefore, delineating the environmental factors for disease predisposition have become a prerogative for contemporary research and NGS applications are playing a pivotal role in solving this intricate relationship.
In some diseases, environmental factors can alter chromatin structure not by making changes in DNA sequences but rather by modification of chromatin or DNA, and these changes have commonly been termed as epigenetic modifications [ 42 ]. The occurrence of epigenetic markers modifications and other molecular signatures on the chromatin have long been identified to influence the gene expression and other associated genome regulatory mechanisms [ 43 ].
These epigenetic modifications are structural adjustments in the DNA molecules resulting from post-translational modifications PTMs of histone proteins such as acetylation, methylation, phosphorylation, alterations of DNA methylation levels, etc. Best known epigenetic modification has been DNA methylation, as it is known to widely regulate gene expression in various cellular systems and have commonly been targeted by scientists for understanding many chronic illnesses like cancers.
Epigenetic modifications has been found to be a major contributor to the germline and somatic cell mutations and has been proven by many studies. Early-life stress have been identified as one of the important factor for causing epigenetic markings e. Several drugs targeting epigenetic sites are also undergoing clinical trials to assess the post-epigenetic drug treatment effects in order to assess the effect of epigenetic targeting molecules. The discovery of biomarkers, especially epigenetic regulators, have become a matter of urgency as the latest discoveries are going to boost our current understanding of disease progression, drug risk assessment, and varied responses to drug treatments in different patients [ 45 ].
Nowadays, genomic tools are also enabling scientists to identify diet-induced changes at molecular genetic level. This new branch of genomics involving the study of the relationship between nutrition and genomics has been termed as nutrigenomics [ 19 ]. Today, we know that some of the non-infectious diseases like asthma, allergies, cancer, obesity, etc. Therefore, the possibility that these exposures can induce the onset of transgenerationally-transmitted diseases which, in turn, can have the profound effect on human health. Transgenerational epigenetic inheritance has gained increased attention due to the possibility that exposure to environmental contaminants induces diseases that propagate through generations by inducing epigenetic alterations even during gamete formation [ 46 ].
These transgenerational epigenetic changes increase the abnormal reproductive or metabolic phenotypes causing the incidence of obesity, polycystic ovary syndrome PCOS , germ cell apoptosis, etc. Our current understanding of the epigenome has trailed well behind our knowledge of the genomes, since it has been very difficult to study [ 48 ]. The application of next-generation sequencing platforms from RNA libraries RNA-Seq , chromatin immunopreciptate CHiP-Seq , bisulfite-treated DNA sequencing, and other omic-based technologies are making it feasible to study epigenomes in a high-throughput fashion [ 49 ].
The launching of the Human Epigenome Project HEP by the international consortium is a positive step in that direction in order to comprehend the effect of epigenetic modifications on normal and altered human genomes [ 48 ]. To date around experimental results have been released for use by the scientific community [ 48 ]. Of particular interest to researchers are projects which are mapping exposed and accessible parts of chromatin, long-distance chromatin interactions, DNA methylation sites, and other important chromatin proteins.
Systematic mapping of transcription factors and its binding sites, other DNA-protein interaction sites, histone markers, 3D chromatin structure, DNA regulatory-factor occupancy patterns as well as other epigenetic signatures are providing scientists with the wealth of information about various functional aspects of genomes [ 51 ]. The ENCODE program still continues to create the comprehensive catalog of functional gene elements present both in human and mouse genomes by identifying histone modifications sites, transcriptions factors, RNA-binding proteins as well as measuring the levels of DNA methylation and hypersensitivity sites [ 48 ].
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The integration of overall ENCODE data will help scientists to explore the role of various candidate functional elements in disease etiologies as well as in understanding their functioning in biological systems. High-throughput genomic technologies such as latest microarrays, next-generation sequencing NGS , epigenomics studies and ENCODE results are introducing new paradigms in genomic medicine as well as deciphering the effect of environmental factors on disease development and progression through a new emerging field in omics technology known as Exposomics study of the environmental exposure on genomes [ 53 , 54 ].
With the euphoria surrounding the accomplishment of the Human Genome Project HGP in , genome-based discoveries could not get implemented into clinical applications for disease treatment. However, in recent times, genomic findings have begun to get introduced into medical facilities, especially in the areas of oncology, infection biology, and other rare and undiagnosed diseases and credit goes to various NGS-based platforms. The triumph of genome sequencing has also brought many technical challenges, like analytical and interpretative calculations, ranging from validations of a large number of genetic changes in patients, and their feasibility, to managing and analyzing the terabytes of data, will be challenging tasks for the scientific community [ 58 ].
The bottlenecks in omics approaches, especially large-scale genomics, is data management, integration, analysis, as well as interpretation by genomicists and adaptation by clinicians [ 58 ]. Genome-Wide Association Studies GWAS have previously created fine and detailed genotypic information at high-resolution level [ 59 ] hand helping in identifying common genetic determinants in diseases [ 3 ] and that, together with omics-based applications, will create a new paradigms in contemporary medicine. As genomics is propelled by rapid advances in technology and computational proficiencies, genomic procedures are going to become a part of every medical specialty and will primarily involve applications to detect genetic variations that are associated with high-risk disease factors, as well as abnormal responses to drug treatments [ 60 ].
The scale and proficiency of sequencing that can now be achieved have reached unparalleled levels and are helping varied research areas ranging from medicine, [ 61 ] agriculture, forensic sciences, etc. Next generation sequencing technologies have tremendous capacity to analyze multiple genes at a time and have begun to replace Sanger sequencing, pyrosequencing, and real-time PCR-like methodologies are widely being employed in various laboratories [ 62 ].
The interaction of multiple factors including genes, non-coding RNAs, as well as proteins in cellular systems, are known to form complex networks of biomolecules known as interactome which, along with a systems biology approach, will widely be explored while devising distinctive contours for future therapeutic interventions. Future doctors and health care providers will rely more on a kind of internet-of-DNA in which medical professionals will search for better drugs and effective lines of treatment through dedicated online web networks like Amazon, Google, etc.
The modern medicine has made tremendous contributions to the public healthcare and well-being, e. However, to what extent it has helped to reduce morbidity and mortality patterns, as well as what impact it has made to wellbeing and life expectancy, is still a debatable question [ 43 ]. Scientists have now begun to understand the interconnections between genetics and diseases more accurately and extensively than before. Technological advancements like NGS has made rapid inroads in our understanding of the genetics, environment and occupational diseases [ 64 ].
The genomic research discoveries, like pharmacogenomics, etc. To put it into perspective, the human genome is known to contain about 20 thousand genes [ 65 ], but it is been suggested that the current level of medications target approximately genes, i. The other genetic-based tests are also being explored to find a link between genome perturbations and their linkage with environmental, as well as biological, risk factors like nutrition, aging, chemical agents, etc.
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The system-level annotation, especially macromolecular interaction networks, will greatly help in inducting high-throughput omics data and, hence, provide new possibilities for unrealized therapies and diagnosis through human interactomics. The test for NGS-based approaches will be to improve the standardization of procedures, as well as storage, analysis, and interpretation of data, besides other ethical aspects, which will be debated in coming years [ 29 ]. One of the most daunting difficulties faced by NGS tools is the inability of physicians and patients in understanding the ways of using genomic information for healthcare benefits.
The establishment of a central repository of data collection for all genome sequencing projects for data-sharing [ 30 ] and its usage for diagnostic and therapeutic purposes will be a great step in implementing genomic information for modern clinical care. The cycle of translational genomics medicine indicating applications of personalized medicine for patient and population-based genomic studies, especially in pharmacogenomics. The big data generated by Next Generation Sequencing platforms are also known to be highly and poorly predictive, validated, and non-validated, and more or less probabilistic [ 66 ], therefore clinicians and other medical staff must take the utmost caution when applying genome-based applications especially in medical diagnosis and prognosis.
Clinicians and other medical staff should also abreast themselves with the latest developments, as well as risk factors associated with misinterpretation of data [ 12 ]. Traditional medical geneticists are undoubtedly going to play a vital role in advancing genome-based approaches and, therefore, there is a persuasive need for various medical fraternities to embrace the latest cutting-edge genomic knowledge. Critical to the implementation of public precision medicine approach will be to educate doctors, medical professional, nurses, and other associated medical staff about the uses and benefits of genomic tools for disease prevention and therapeutics for healthy societies Figure 2.
Initiation of a number of genomic projects like H3Africa Initiative Human Hereditary and Health in Africa , Qatar Genome Project, Mexico National Institute of Genomic Medicine being started in low and middle-income countries is hopefully going to bring a paradigm shift in the healthcare approach in developing countries [ 40 , 66 ]. Therefore, implementation of large population-based genome programs in other developing countries should also be encouraged by sharing technical know-how and generous funding by different international granting agencies.
The expansion and implementation of population based genomic projects in developing countries with a vast population base will be a windfall for worldwide precision public healthcare. Scientists should, thus, concentrate on how comprehensive or focused the elucidation of genome sequencing outcomes should be. Therefore, there is a need to fill the void between high-throughput sequencing and the capacity to manage, interpret, and analyze the omics data and implement it in clinical care.
The major logistical difficulty will be the delivery of genome sequencing data to clinicians and how they can use and implement the same for treatment and patient care, as well as how family members will be able to understand the pros and cons of genomic medicine [ 67 ]. Other critical and ethical issues would be whether to disclose the prediction-based genomic information to parents especially for conditions that do not have immediate consequences for the health of the child in the immediate future, like adult-onset diseases, etc.
I am also thankful to him for providing me an opportunity to work as a senior research fellow in his laboratory. I am also thankful to Arnab Mukhophadyay, staff scientist at Molecular Aging Laboratory, National Institute of Immunology, New Delhi, India, for providing me junior research fellowship for project on Next Generation Sequencing and Aging as well as valuable suggestions and advice during the writing of the manuscript.
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