There’s not enough bandwidth in these blog discussions to address genetics in depth. But a quick review of basic genetics might be valuable here because more than ¾ of our immune system’s functions and regulation is influenced by the 20,000 to 25,000 genes found on the DNA (deoxyribonucleic acid) double helix, packaged into chromosomes in the cell nucleus (Figure 3.1 and 3.2).
These chromosomes are identified in a form called a karyotype (Figure 3.3). Immunogenetics is the branch of science that explores the relationship between the immune system and genetics. Back in Blog #5, we described T and B lymphocytes and their surface receptors. All of these protein receptors are genetically produced and encoded (programmed) from the Major Histocompatibility Complex (MHC Class 1 and 2) genes. The MHC genes are referred to as “the key to self-recognition” and are believed to have evolved over 600 million years (see Blog #6).
The chemical modifications to DNA and the chemical interactions involving the manufacture of proteins represent, a second level of human genetics termed epigenetics or epigenomics. Epigenetics refers to the study of inheritable changes in gene expression that occur without a change in DNA sequence. Types include DNA methylation which adds a chemical group to DNA; histone modification; and non-coding RNA attaching to coding RNA. Research has shown that epigenetic mechanisms provide an additional layer of transcriptional control that regulates how genes are expressed. Epigenetic abnormalities are associated with genetic disorders, cancer, autoimmune diseases, aging, and pediatric syndromes, among others.
A genome is an organism’s complete set of DNA, the chemical compounds that control the genetic interactions of the genes between each other and the environment to develop and direct the activities of every organism. The science of immunogenomics deals with the immense volume of clinical material in the human genome and the human immune system through cellular and molecular biology.
Protein synthesis and the cellular process of DNA transcription and RNA translation (Figure 3.5), collectively known as “the central dogma of molecular biology” or the science of “transcriptomics” (Figures 3.4 and 3.6) is the singularly most important function of the genome and immunome (the total genes and proteins that make up the immune system). Mutations in these genes are directly or indirectly responsible for all human diseases. Among the approximate 3 billion chromosomes within the nuclei of the cells, with four base compound sequences within the DNA (deoxyribonucleic acid) helixes constituting the 20,000 to 25,000 genes, the number of possible combinations within these base compound sequences (“genetic codes”) is astronomical.
And yet, it is among these prodigious numbers of gene sequences that congenital (hereditary) and acquired mutations occur. Fortunately, only an infinitesimal amount of them (less than 60 per gene) override “apoptosis” (a normal cell’s ability to self-destruct when something goes wrong) to produce genetic disorders or diseases.
Determining the order of DNA proteins (nucleotides) in an individual’s genetic code, called DNA sequencing, has advanced genetics both for research and clinically. The original sequencing technology (the Sanger method) took months and even years to sequence viral genomes and all of a person’s DNA. The development of next-generation sequencing (NGS, also called high-throughput or massively parallel sequencing) using artificial intelligence (AI) big data analytics has sped up the process, taking only days to weeks to sequence a human genome while dramatically reducing the cost. This is the method now being used to determine the whole genome sequence (WGS) or an even faster method, exome (coding portion of genes) sequencing. The clinical value of these NGS methods demonstrated their value in their use for rapidly identifying coronavirus variants. The original Sanger method used to sequence the complete human genome (the Human Genome Project to be discussed in the next blog #11) took 20 years to accomplish at a cost of $3 billion. Using NGS, sequencing the complete human genome can be accomplished in 24 hours for under $500. Now that’s progress!
Discussion Questions:
Inheritable epigenetic changes are responsible for abnormalities are associated with genetic disorders and diseases. What are some examples of the 3 types of epigenetic changes?
Sequencing the DNA nucleotides in an individual’s genetic code has proven to be of existential value to humankind. Can you name some of the most prominent applications of DNA sequencing?
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