Fundamentals of Bioinformatics - Ogurtsov, A.N. 2013

Foundations of Bioinformatics
Genomes and Proteomes
Bioinformatics in Medicine

Decoding The Human Genome, as well as the genomes of other organisms, can help improve human health. Despite some vocal opposition—typically coming from those who are either uninformed or have a vested interest in halting such research—several key medical Applications have emerged.

Disease Diagnosis and Risk Assessment. DNA Sequencing and analysis can reveal missing genes or Mutations. Identifying specific sequences of disease-associated genes enables rapid and reliable diagnosis in the following scenarios:

a) when a patient presents with symptoms;

b) for prenatal screening of potential disorders, such as cystic fibrosis;

c) for Genetic Counseling of couples planning to have children;

d) for presymptomatic testing of late-onset inherited conditions, such as Huntington's disease.

Huntington's disease is an inherited neurodegenerative disorder affecting approximately 30,000 people in the United States alone. Its symptoms are severe, including uncontrollable dance-like movements, psychiatric disturbances, personality changes, and cognitive decline. Death typically ensues within 10 to 15 years after symptom onset. The defective Gene was introduced to New England during the colonial period in the 17th century, and Huntington's disease may even have been the underlying cause of certain witchcraft accusations. The gene has persisted in the population because the disease typically manifests between the ages of 30 and 50—well past the onset of the reproductive years.

In the past, young people from families affected by Huntington's disease lived in fear of having children, unaware of whether they had inherited the condition. The 1993 Discovery of the gene whose mutation causes Huntington's disease made it possible to accurately identify carriers. The gene contains multiple trinucleotide CAG repeats, which encode polyglutamine (poly-Q) stretches in the corresponding protein. Huntington's disease is one of several familial neurodegenerative disorders characterized by trinucleotide repeats.

The longer the CAG repeat tract, the earlier the onset of the disease and the more severe the symptoms. A normal gene contains 11–28 CAG repeats. Individuals with 29–34 repeats almost never develop the disease, whereas those with 35–41 repeats may exhibit only relatively mild symptoms. People with more than 41 trinucleotide repeats almost invariably suffer from full-blown Huntington's disease.

Inheritance of this condition exhibits a phenomenon known as anticipation: the repeats tend to lengthen in successive generations, progressively increasing disease severity and lowering the age of onset. For reasons that remain unclear, this effect is more pronounced when transmitted through paternal genes rather than maternal ones. Consequently, individuals in the borderline group carrying a gene with 29–41 repeats must carefully consider the potential risk to their offspring.

In many cases, our genes do not seal our fate irrevocably; rather, they present predispositions that we can manage. A prime example of a genetically detectable risk factor is a₁-antitrypsin, a protein whose normal function is to inhibit Elastase in lung alveoli. Individuals homozygous for the Z mutant of a₁-antitrypsin (342Glu→Lys) produce only a non-functional protein. They are at high risk for developing emphysema due to lung tissue Damage caused by uninhibited elastase activity, as well as Liver disease resulting from the accumulation of polymerized a₁-antitrypsin in hepatocytes. For such individuals, cigarette smoking almost inevitably triggers emphysema. In these instances, disease expression arises from a combination of genetic predisposition and environmental factors.

Often, the relationship between genotype and disease risk is even more complex. Conditions such as asthma depend on the interplay of numerous genes alongside various environmental influences.

In other instances, a gene may be present and structurally normal, yet a mutation elsewhere—such as in a regulatory region—can alter its expression level or tissue distribution. Such abnormalities can be detected by measuring protein activity. Therefore, analyzing protein expression is a vital pathway toward discovering new therapeutic strategies.

Pharmacogenetics and Personalized Medicine. Because individuals metabolize the same pharmaceutical drug differently, varying dosages may be required for different patients under identical conditions. Analyzing a patient's genome sequence allows for the Selection of drugs and dosages tailored specifically to their individual profile.

This rapidly expanding field is known as pharmacogenomics (see also Section 15.1). Physicians will increasingly be able to avoid the risks associated with prescribing therapies that carry severe, often fatal, side effects—and which are costly in any case. Today, healthcare systems spend billions of dollars treating patients for adverse reactions to prescribed medications (adverse drug reactions).

For example, the drug 6-mercaptopurine is highly toxic, yet it is essential for treating childhood leukemia. A small subset of patients with a high risk of fatal toxicity due to a deficiency in the enzyme thiopurine methyltransferase requires supplemental medication during therapy. Enzyme testing allows such high-risk patients to be identified in advance.

Conversely, it is now becoming possible to utilize pharmaceutical drugs that are safe and effective for patients who were previously excluded, even though those drugs were shelved during or before clinical trials due to slow efficacy or severe side effects in a subset of individuals.

Drug Target Identification. A drug target is typically a protein whose function can be modulated by a pharmaceutical agent to alleviate symptoms or counteract the underlying causes of a disease (see Section 15.3).

Precise target identification allows for a more rational approach to drug design. Among currently used medications, about half act on receptors, roughly a quarter on Enzymes, and about a quarter on Hormones. Only around 7% interact with unknown targets.

The rising prevalence of antibiotic-resistant Bacteria has triggered a crisis in the Prevention of infectious diseases. Future generations will likely look back on the latter half of the 20th century as a brief window in history when bacterial infections were successfully controlled—a feat achieved neither before nor since.

By leveraging genomic analysis, researchers can modify existing drugs and lessen the urgent need to discover entirely new ones.

Genome Analysis can also aid in the search for novel drug targets. Differential Genomics and the comparison of protein expression profiles between drug-sensitive and drug-resistant strains of pathogenic pathogens can pinpoint the specific Proteins responsible for microbial resistance.

Studying genomic variations between tumor Cells and normal cells is expected to help identify differentially expressed regions, thereby revealing proteins that can serve as potential targets for anticancer therapeutics.

Gene Therapy. If a gene is missing or defective, the ideal solution would be to replace it with a normal functional copy or at least boost its expression level to increase the concentration of its protein product. Conversely, if a gene is hyperactive, the goal would be to turn it off.

Simple protein replacement therapies are already successful for many conditions, the most prominent Examples being Insulin administration for Diabetes Mellitus and factor VIII (antihemophilic globulin) replacement for classic hemophilia.

Gene transfer has been successfully performed in animal experiments, with human proteins being produced in the milk of cows and sheep. In patients suffering from cystic fibrosis, gene replacement therapy using an adenovirus has yielded promising results.

The method of gene silencing is known as antisense therapy. The concept involves introducing DNA or RНК that binds in a specific manner to a targeted region of a gene. Binding to endogenous DNA can prevent METABOLISM/31.html">Transcription, whereas binding to mRНК can inhibit Translation. Antisense therapy has achieved certain successes in treating conditions such as cytomegalovirus colitis and Crohn's disease.

Antisense therapy is also highly attractive because it can exert a direct effect on target synthesis and allows for the rapid progression through drug development stages.

Review Questions and Assignments

1. In which cases is the sequencing of Biological Sequences performed?

2. What do structural, functional, and comparative genomics deal with?

3. What is The Essence of the shotgun sequencing method?

4. What four types of DNA markers are used in mapping the human genome?

5. What are the focuses of Structural and functional Proteomics?

6. What are the three MAIN STAGES OF proteome research?

7. What is The quaternary Structure of a protein and what are its Functions?

8. What information is obtained through Homology protein modeling?

9. What are gene, replacement, and antisense therapies?