Review articles
 

By Mr. Robby Kumar
Corresponding Author Mr. Robby Kumar
SSR Medical College, Mauritius, - Mauritius
Submitting Author Dr. Robby Kumar
BIOTECHNOLOGY

Genomics, Epigenomics, Toxicogenomics, Proteomics, MicroRNomics, Pharmacogenomics

Kumar R. Genomics in Medical Science: An Overview. WebmedCentral BIOTECHNOLOGY 2011;2(12):WMC002580
doi: 10.9754/journal.wmc.2011.002580
No
Submitted on: 04 Dec 2011 08:33:21 PM GMT
Published on: 05 Dec 2011 08:44:24 AM GMT

Abstract


Genomics is the study of an organism's genome and the use of the genes. It deals with the systematic use of genome information, associated with other data, to provide answers in biology, medicine, and industry.
Genomics has the potential of offering new therapeutic methods for the treatment of some diseases, as well as new diagnostic methods. Other applications are in the food and agriculture sectors. The major tools and methods related to genomics are bioinformatics, genetic analysis, measurement of gene expression, and determination of gene function.

Introduction


Human genomics, the study of structure, function, and interactions of all genes in the human genome, promises to improve the diagnosis, treatment, and prevention of disease. This is due to the result of the completion of the Human Genome Project. It is anticipated that genomics will bring to physicians a powerful means to discover hereditary elements that interact with environmental factors leading to disease (1). The ‘‘Genomic Revolution’’ has transformed our vision and understanding of how living organisms and systems interact with each other and with the environment (2). Increasingly, the science of genomics serves as the foundation for translational research for advancing the management of many important diseases (3).

Genomics and Infectious disease: Current status


Infectious disease management is also transforming thanks to molecular technologies as seen in HIV (4,5), tuberculosis, malaria , and other neglected tropical diseases . Discovering novel pathogens and elucidating the implications of genetic variation among existing pathogens is critical for rapidly mitigating pandemic threats, as demonstrated recently with severe acute respiratory syndrome (SARS) and avian (H5N1) and pandemic H1N1 2009 influenza(3).
H1N1 2009 Influenza: Genomics.
Genomics can be readily applied to follow outbreaks of infectious diseases. This is clearly illustrated during the severe acute respiratory syndrome (SARS) outbreak in 2002–2003 and the emergence and worldwide spread of the pandemic H1N1 2009 influenza virus this year. In both cases, genomics played a key role in the immediate response to the outbreak. Initially, very little was known about the virus responsible for the SARS outbreak. Pangenomic virus microarrays identified it as a coronavirus (6); however, it was only through detailed sequencing that the specific genotype of this virus could be determined (7). Comparative sequence analysis identified the SARS virus as distinct from other coronaviruses in terms of its encoded proteins responsible for antigen presentation. This finding ultimately lead to development of diagnostics (8) and potential therapeutics (9). This example of a sequencing approach as a rapid response to a virus outbreak demonstrates that genomics can be a useful and important, if not essential, epidemiological tool. In the ongoing H1N1 influenza outbreak, the National Center for Biotechnology Information (NCBI) established the Influenza Virus Resource, containing 462 complete viral genome sequences from worldwide viral samples. Some of the genomic data was completed, compared, and released to the public within two weeks of isolation of the DNA. The rapid generation of genome sequence data is providing a paradigm shift in the analysis of infectious disease outbreaks, from more classical methods of isolation to the rapid molecular examination of the pathogen in question.(9)
The fundamental idea that responses to environmental factors or treatments is to be found in our individual differences, the underlying concept of “genomic medicine”, is rooted in antiquity and based on millennia of simple observation. The objective of genomic medicine is to determine the genetic bases of those differences in response to environmental agents, including medications, and differences that may predispose to the development of common and potentially personally devastating and societally expensive disorders, and to use them in populations to thwart adverse response, increase the frequency of beneficial response, and intervene to prevent or delay onset of disease.(10) Approximately 1100 different genes have been shown to have at least one mutation in them that causes a disease. Total number of disease genes = approx. 1500 (11)

Functional Genomics


Understanding the function of genes and other parts of the genome is known as functional genomics. Functional genomics is a field of molecular biology that is attempting to make use of the vast wealth of data produced by genome sequencing projects to describe genome function. Functional genomics uses sensitive techniques like DNA microarrays, proteomics, metabolomics and mutation analysis to describe the function and interactions of genes.(12)
The development and application of global (genome- wide or system- wide) experimental approaches to assess gene function by making use of the information and reagents provided by structural genomics [in the original more limited sense of construction of high- resolution genetic, physical and transcript maps of an organism. It is characterized by high throughput or large- scale experimental methodologies combined with statistical and computational analysis of the results. The fundamental strategy is to expand the scope of biological investigation from studying single genes or proteins to studying all genes or proteins at once in a systematic fashion.(13)
Human Genome Project
The Human Genome Project, which was led at the National Institutes of Health (NIH) by the National Human Genome Research Institute, produced a very high-quality version of the human genome sequence that is freely available in public databases. That international project was successfully completed in April 2003, under budget and more than two years ahead of schedule. The sequence is not that of one person, but is a composite derived from several individuals. Therefore, it is a "representative" or generic sequence. To ensure anonymity of the DNA donors, more blood samples (nearly 100) were collected from volunteers than were used, and no names were attached to the samples that were analyzed. Thus, not even the donors knew whether their samples were actually used. The Human Genome Project was designed to generate a resource that could be used for a broad range of biomedical studies.(14,15) The major impact of the completion of the human genome sequence is the understanding of disease etiology with deduced therapy. The catalog of monogenic diseases should be easily completed through in silico cloning. The major challenge today is to decipher the polygenic and multifactorial etiology of common diseases, such as cancer, cardiovascular, nutritional, allergic, auto-immune, degenerative disorders. In fact every gene, when mutated, is a potential disease gene, and we end up with the new concept of 'reverse medicine', by which we will derive new morbid entities and pathogenic pathways from the knowledge of the structure and function of every gene.(16) Identifying all of the human genes is but one step in understandingdisease pathogenesis. These new proteinsfunction (and malfunction) in novel and complex metabolic pathways should be seen.While the human genome sequence gives us a road map, much workremains in understanding where the road leads and what detoursmay exist. There is a complex,multigenic disorders that are responsible for some of the most commonmaladies in society such as atherosclerosis, hypertension, diabetes,psychiatric disorders, and stroke. (17,18)
Toxicogenomics
Current goals of toxicogenomics, which would also be relevant to immunotoxicology, include hazard identification by comparing microarray results with analyses of structure activity relationships or animal bioassays, risk characterization by coupling genomic data with population exposure assessment or cross-species comparisons provide a template that immunotoxicologists may apply to reach these same goals.(21) One of the most likely immune mediated adverse effects of chemical exposure is hypersensitivity, researchers have shown the development of an in vitro approach to detect potential contact allergens by following gene expression in cells exposed to a known strong sensitizer or irritant. Changes in gene expression by dinitrosulphobenzene-activated dendritic cells generated from CD14+ adherent human mononuclear cells identified 29 candidate target genes important in the response to sensitizing agents (22) Genomics has been used successfully to study mechanisms of action (specific pathways associated with immunotoxicity of a specific chemical).(21)
MicroRNomics
RNomics is studysncRNAs on the genomic scale (23). The standard pathway of informationflow in a cell from DNA to message RNA (mRNA) to protein hasbeen the dominant theme in molecular biology. However, recentanalyses of the human and animal genomes have demonstrated thatthe majority of RNA transcripts are not protein coding RNAs(mRNAs), but noncoding RNAs (ncRNAs) (24) Indeed,large-scale complementary DNA sequencing and genome tiling arraystudies have shown that 50% of genomic DNA in humans is transcribedinto RNA transcripts, of which 2% is translated into proteinsand the remaining 98% is ncRNAs (24).  In general,the sizes of the majority of ncRNA species vary from 18 nt to500 nt, well below the size of the majority of mRNA species,and are therefore termed small ncRNAs (sncRNAs). The term ncRNAis commonly employed for RNA that does not encode a protein,but this does not mean that such RNAs do not contain informationor have function (24). For example, ribosomalRNAs and transfer RNAs, which make up a large proportion ofRNA based on amount, are two known sncRNAs that provide helpfor protein expression. Quite recently, two novel classes ofsncRNAs were discovered: microRNAs (miRNAs) and small interferingRNAs (siRNAs). miRNAs and siRNAs have similar sizes (18–23 nt) and sharethe similar mechanisms of gene expression regulation. However,their biogenesis and origins are different. siRNAsare produced from long, double-stranded (bimolecular) RNAs,or long hairpins, often of exogenous origin, and usually targetsequences at the same locus or elsewhere in the genome for destruction(gene silencing). In contrast, miRNAs are endogenous. They areencoded within the genome and come from endogenous short hairpinprecursors and usually target sequences at other loci. Therefore,miRNAs may be more important because they are endogenous regulatorsof gene expression. Microarray analysis of miRNAs on the genome scale is the mostpowerful method in microRNomics to determine the expressionsignature of cells, tissues, and organs within an organism underdifferent conditions. Expression profiles have recently been generated and diagnosed by microarrayanalysis in chronic lymphocyticleukemia (CLL), breast, colon, lung, pancreatic endocrine, pancreatic adenocarcinoma, prostate, stomach, and glioblastomas, cardiovascular diseases and many more leathal conditions.These microRNomic approaches reveal that a large number of miRNAsare aberrantly expressed in diverse cancers. The majority ofthese dysregulated miRNAs are targeted at either oncogenes ortumor-suppressing genes. As tissue and cell-specific expressionis an important feature for miRNAs, these bioinformatic measurementsof expression profiles are useful to identify and diagnose humancancers. It is well known that some miRNAs are critical regulatorsfor cell differentiation, and identification of these key miRNAs'expression signatures could be an alternative way to evaluatecancer progression and prognosis.(25)

Structural Genomics


Structural genomics aims to delineate the total repertoire of protein folds, thereby providing three-dimensional portraits for all proteins in a living organism and to infer molecular functions of the proteins. The goal of obtaining protein structures on a genomic scale has motivated the development of high-throughput technologies for macromolecular structure determination, which have begun to produce structures at a greater rate than previously possible. These new structures have revealed many unexpected functional and evolution relationships that were hidden at the sequence level.(26) Structural genomics, by design, is a hypothesis-generating instead of a hypothesis-driven endeavor. It shares this aspect with many new high-throughput genomics projects in the evolving molecular biology discipline although— unlike other genomics projects—structural genomics continues to generate very high resolution, detailed molecular data.(27)
The ultimate goal of structural genomics is to obtain the structure of each protein coded by each gene within a genome to determine gene function. Because of cost and time limitations, it remains impractical to solve the structure for every gene product experimentally. Up to a point, reasonably accurate three-dimensional structures can be deduced for proteins with homologous sequences by using comparative modeling. Beyond this, fold recognition or threading methods can be used for proteins showing little homology to any known fold, although this is relatively time-consuming and limited by the library of template folds currently available.(28)
Eukaryotic proteins (particularly those from humans and higher vertebrates) are difficult targets for structural genomics because of a number of factors. (a) The gene models for eukaryotic proteins are poorly developed. (b) Eukaryotic proteins contain a large number of introns and are subject to alternative splicing patterns. (c) Eukaryotic proteins frequently require chaperones for proper folding. (d) Eukaryotic proteins contain considerably more regions of intrinsic disorder, and a large fraction of them (~60%) are fully natively disordered. (e) Because of difficulties in producing and solubilizing them, few structures of recombinant eukaryotic membrane proteins have been determined.(29)

Comparative Genomics


Comparative genomics is the analysis and comparison of genomes from different species. The purpose is to gain a better understanding of how species have evolved and to determine the function of genes and noncoding regions of the genome. Researchers have learned a great deal about the function of human genes by examining their counterparts in simpler model organisms such as the mouse. Genome researchers look at many different features when comparing genomes: sequence similarity, gene location, the length and number of coding regions (called exons) within genes, the amount of noncoding DNA in each genome, and highly conserved regions maintained in organisms as simple as bacteria and as complex as humans.(30) For genetics and development, for immunology and pharmacology, for cancer and heart disease, even for behaviour, learning and memory and psychiatric disorders (31,32) the laboratory mouse has become an indispensable tool. From Sequence of the human genome it appears to have far fewer protein-coding genes(less than 30,000) than accepted 80,000–100,000. Analysis of the mouse genome backs up this finding. The sequencing consortium estimates that it contains 27,000–30,500 protein-coding genes. Ninety-nine per cent of these genes have a sequence match in the human genome and 96% of these lie within 'syntenic' regions of mouse and human chromosomes.(33) Based on pairwise alignments of nearly 13,000 (out of about 28,000) orthologous gene pairs, the consortium found that the encoded proteins had a median amino-acid sequence identity of 78.5%. In comparison, orthologous mouse and rat proteins are, on average, 97% identical(34), and a sample of human and Caenorhabditis elegans (nematode) proteins had an average of 49% of their amino acids in common (35)
Knockout mice are transgenic mice whose genetic code has been altered by the insertion of foreign genetic material into their DNA. Using this technology, researchers target specific genes --causing them to be expressed or inactivated. These mice are then bred --creating a population of offspring with the trait.  When researchers isolate human genes with unknown functions, they can create knockout mice with these genes and observe the results. Instead of creating merely the mouse equivalent of the human gene, researchers are able to reproduce and express actual human genes and their corresponding proteins in mice. Subsequent offspring will inherit not only the instructions coded by their original mouse genome, but also the traits coded for by the inserted human DNA. This helps researchers understand health and disease by observing how genes work in cells.  Knockout mice have many benefits. They not only allow researchers to determine gene function and understand diseases at the molecular level, but they also aid scientists in testing new drugs and devising novel therapies. (30,33)

Epigenomics


Epigenetics is an emerging frontier of science that involves the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence. For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome.(38)
Epigenetic mechanisms are affected by several factors and processes including development in utero and in childhood, environmental chemicals, drugs and pharmaceuticals, aging, and diet. DNA methylation is what occurs when methyl groups, an epigenetic factor found in some dietary sources, can tag DNA and activate or repress genes.  Histones are proteins around which DNA can wind for compaction and gene regulation. Histone modification occurs when the binding of epigenetic factors to histone “tails” alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated. All of these factors and processes can have an effect on people’s health and influence their health possibly resulting in cancer, autoimmune disease, mental disorders, or diabetes among other illnesses. epigenetic modifications to chromatin,  include 5' methylation of the cytosine residue in CpG dinucleotides of Dna, covalent modifications (including methylation, acetylation, phosphorylation and ubiquitination) of histones, the proteins that package Dna into chromatin, and the gene-regulating and ch romatinorganizing activities of noncoding rnas. these epigenetic modifications change the binding of transcription activators and repressors to specific gene promoters, and/or alter the large-scale conformation and function of chromatin itself, which modulates gene expression, the best- studied examples of developmental epigenetic processes in mammals include X-chromosome inactivation in females and parent- specific expression of imprinted genes.(39,40) in general, Dna methylation seems to be involved in long-term silencing of gene expression, Whereas histone modifications have a short-term and flexible effect, but substantial crosstalk exists between these different mechanisms.(41,42) The epigenomics can predict the high rik diseases such as cardiovascular diseases, cancer and diabetes mellitus by seening epigenomic markers, such as methylation patterns in specific gene promoters, may enable the identification of individuals who will have increased susceptibility to chronic disease in adulthood because of adverse factors in their early environment. After identification of such individuals may allow the prevention of disease, either by lifestyle modification or by active nutritional or pharmacological intervention.(42,43,44,45)

Pharmacogenomics


The term pharmacogenomics describes a polygenic or genome-wide approach to identifying genetic determinants of drug response, utilizing both information from the human genome project and technologies such as high throughput sequencing, DNA and protein microarrays, and bioinformatics. Improving therapeutic efficacy and reducing drug toxicity are two of the most important goals of genomics and genetics in clinical practice.(46)
Benefits of pharmacogenomics include:
a) Powerful and improved Drugs/Medicines: Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. This will facilitate drug discovery and allow drug makers to produce a therapy more targeted to specific diseases. This accuracy not only will maximize therapeutic effects but also decrease damage to nearby healthy cells.
b)Determining Appropriate Drug Dosages: Current methods of basing dosages on weight and age will be replaced with dosages based on a person's genetics --how well the body processes the medicine and the time it takes to metabolize it. This will maximize the therapy's value and decrease the likelihood of overdose.
c)Screening for Disease: Knowing one's genetic code will allow a person to make adequate lifestyle and environmental changes at an early age so as to avoid or lessen the severity of a genetic disease. Likewise, advance knowledge of a particular disease susceptibility will allow careful monitoring, and treatments can be introduced at the most appropriate stage to maximize their therapy.
d)Better Vaccines: Vaccines made of genetic material, either DNA or RNA, promise all the benefits of existing vaccines without all the risks. They will activate the immune system but will be unable to cause infections. They will be inexpensive, stable, easy to store, and capable of being engineered to carry several strains of a pathogen at once. (30,47)

Conclusion


The field of biodefense has thoroughly embraced genomics and made it a keystone for developing better identification technologies, diagnostic tools, and vaccines and improving our understanding of pathogen virulence and evolution. Enabling technologies and bioinformatics tools have shifted genomics from a separate research discipline to a tool so powerful that it can provide novel insights that were not imaginable a few years ago, including for example redefining the notion of strains or cultures in the context of biopreparedness or microbial forensics. Challenges remain, though, mostly in the form of large amounts of data that are being generated, and will continue to be generated in the future, and are becoming difficult to manage. The need for better bioinformatic algorithms, access to faster computing capabilities, larger or novel and more efficient data storage devices, and better training in genomics are all in critical demand, and will be required to fully embrace the genomic revolution.(9) There are several areas of new knowledge that will have to be developed to create a reality of genomic medicine. These include the characterization of genomic variation among individuals in the target populations (and each separate population will probably have to be studied anew), the identification of the clinically significant variants in each group, the assessment of the extent to which intervention could change predicted outcome–taking into account other changes in environmental exposure and behaviors, and the development of an understanding of the costs of these processes for the society and weighing them against other societal needs.(10) Selecting strategies for monitoring the DNA variations associated with human disease requires careful consideration and new innovative methodologies. First, the cost of detecting DNA variations is still too high to enable screening for tens of thousands of SNPs in massive epidemiological study samples. Second, the annotation and cataloging of variations and their frequencies in various populations is not systematically organized. Third, the selection of relevant variants for epidemiological and functional studies is still a guessing game. We know amazingly little about the relative importance of variations in the regulatory and intronic sequences of human genes and how they differ between populations. Fourth, quantitative analyses of the effects of thousands of DNA variations and the "genome-wide" variant profiles that predispose individuals to complex diseases are still in their infancy. All of these issues require methodological developments, coordinated efforts, and better solutions than those currently available to genetic epidemiologists.(11) We are rapidly advancing upon the postgenomic era in which genetic information will have to be examined in multiple health care situations throughout the lives of individuals. Currently, newborn babies can be screened for treatable genetic diseases such as phenylketonuria. Perhaps in the not-so-distant future, children at high risk for coronary artery disease will be identified and treated to prevent changes in their vascular walls during adulthood. Parents will have the option to be told their carrier status for many recessive diseases before they decide to start a family. For middle-aged and older populations, we will be able to determine risk profiles for numerous late-onset diseases, preferably before the appearance of symptoms, which at least could be partly prevented through dietary or pharmaceutical interventions.

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