Introduction:
Genetic variations can mediate normal and abnormal functions, and this has been a major issue in medicine. Functional genetics involves the genes and part of DNA (deoxyribonucleic acid) which is located between the genes contributing to different phenotypes (physical characteristics). Researchers use genome-wide scale studies (a study that consists of the entire set of DNA of many people, which helps in identifying variations) to narrow down the gene regions for easy analysis. Functional genetics aims to determine how the genes all together produce particular phenotypes.
What Is Functional Genetics?
Functional genetics is the study of the functions and properties of a single gene and variations in these genes. This involves the study of entire genes and their products which are present in the cells and fluids. Functional genetics can explain gene-gene interaction at different loci (a specific part of the gene) and gene-environment interactions. Several approaches involve duplication, maintenance, and repair of DNA (deoxyribonucleic acid); transcription and maturation of RNA (ribonucleic acid); and translation, post-translation, and functions of proteins and metabolites. The study of the combination of nucleic acid and protein helps in understanding chromatin and epigenetics, which is the study of the effects of behavior and environment on gene expression. A major challenge in studying functional genetics is the study of exon (part of DNA which is present in messenger RNA) and intron (non-coding sequences which separate the exons) variations.
What Are the Approaches Used in Studying Functional Genetics?
The different approaches that are used are collectively known as omics, which include:
1. Genomics: A cell that contains a complete set of DNA is called genomics. There are about twenty-five thousand genes in the human genome. Genomics is the study of genomes present in an organism. This study uses DNA sequencing methods, recombinant DNA, and bio information to assemble, sequence, and analyze the function and structure of genomes. This study focuses on interactions such as pleiotropy (a phenomenon where a single gene expresses multiple traits), epistasis (a phenomenon where another gene or genes inhibit the expression of one gene), and heterosis (a phenomenon in which the offspring has superior phenotypes than the parents); and interaction between allele and loci within the genome.
2. Epigenomics: Epigenomes are chemical compounds that affect the genome. Environmental factors include exposure to drugs, chemicals, tobacco, smoking, infectious disease, metals like cadmium, infectious diseases like Epstein-Barr virus, and dietary exposure to chemicals. These epigenomes can bind to the DNA and affect their functions, such as activating or inactivating genes and controlling protein production. These epigenomic changes do not affect the sequence of DNA but change the DNA’s instructions. Some epigenomic changes are DNA methylation and histone modification. The study of these epigenomes is called epigenomics.
3. Transcriptomics: Human genome contains DNA, which carries the instructions. These instructions are transcribed into RNA. Therefore, transcription is a process where RNA copy is made from a piece of DNA. The RNA strand which is formed when a gene is transcribed is called an RNA transcript, and the transcriptome is the collection of all the gene transcripts. Collecting the RNA sequences and analyzing them helps in understanding the gene function and their expression related to a disease condition. The study of these RNA molecules is called transcriptomics.
4. Proteomics: It is the study of the function, structure, interactions, and compositions of proteins. This can provide better function and structure of functional genetics and is superior to genomics. There are about a million human proteins, and some are modified. Analysis of proteins is done using two-dimensional gel electrophoresis and the latest multidimensional protein identification technology (MudPIT).
5. Metabolomics: It is the study of small molecules called metabolites, and their interaction with the biological system is called the metabolome. Metabolite levels are associated with cellular phenotype, therefore helping in understanding the functional state of a cell. The tools which are used in this approach are liquid chromatography (a method that is used to separate proteins and small substances from a mixture) and nuclear magnetic resonance (NMR) spectroscopy (a method to study the nucleus of molecules when placed under a strong magnetic field). This study helps in understanding new metabolic pathways and complex cellular metabolism and can help in identifying new targets for therapeutic management. This represents the molecular phenotype.
6. Interactomics: It is the study of interactions between various proteins and molecules and their consequences within the cells. This helps understand the effects on traits that are varied or preserved with these interactions. Protein-protein interaction is studied using a two-hybrid system, in which a protein of interest is fused with the DNA binding domain, and another protein is fused to the activation domain. Both proteins are expressed in cells; the transcriptionally activated protein is associated with the phenotype and is read out. This has the limitation of using only two proteins at a time.
How Is Functional Genetics Involved in Cardiovascular Diseases?
Variations in genetics can also help in determining the response to a drug, its efficacy, and its toxicity. Splicing mechanisms (separation from the sequence of DNA to extract a particular part) can also be used for therapeutic purposes. The use of functional genetics helps in understanding biological mechanisms underlying cardiovascular diseases. According to the studies:
- Pharmacological studies show genetic variations and also help in determining the response to a drug, its efficacy, and its toxicity. In the case of intermediate phenotypes (a mixture of phenotypes of parents), there are genetic variations in drug metabolite levels and platelet function. For example, oral P2Y12 inhibitor Clopidogrel response varies among many people, and people who have an intermediate type that is high residual on-Clopidogrel platelet reactivity have an increased risk for myocardial infarction.
- Gene polymorphisms of protein that involve in metabolism and absorption of Clopidogrel cause 15 to 20 percent of variations and are often associated with poor prognosis.
- The vascular smooth muscle cells (VSMCs) play an important role in the atherothrombotic (formation of plaque and blood clots in the blood vessels) process by proliferation, migration, remodeling, and matrix synthesis. The transcriptome approach by using RNA expression profiling showed that there were differences in mRNA levels in VSMCs of pre-atheromatous and atheromatous conditions. This approach suggested that genes are involved in the biological pathways of atherothrombosis.
- Studying mRNA splicing helps in understanding gene expressions. An increased level of intron 7 of the coagulation F7 gene is associated with cardiovascular disease. This region has repeats of 37 bp. Therefore this approach helps in understanding the functional role of sequence variations.
- Dominant mechanisms also help in understanding diseases. For example, a high level of von Willebrand factor (VWF, a factor that is involved in hemostasis and platelet adhesion) is associated with a high risk of cardiovascular disease.
Conclusion:
Finding among the gene variations which are involved in functional roles associated with cardiovascular disease is a challenging task. Understanding the mechanisms of normal and pathological conditions can open new ways in diagnosis, prophylactic and therapeutic management.
