(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
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. Through a number of previous blog discussions we have mentioned T and B lymphocytes and their surface receptors. All of these cells and receptors are genetically produced and programmed from very powerful genes called the Major Histocompatibility Complex or MHC genes. These MHC genes are referred to as “the key to self-recognition” and they are believed to have evolved over 600 million years (see Blog #6). The chemistry of our DNA and its interactions involved in the making of proteins that make up all the tissue and cells in our bodies is an exquisite process. It is a process that occurs without changing the chemical structure of the DNA through an interaction with our RNA. This extraordinary genetic process is effectively what builds and rebuilds our bodies throughout our lifetime. It also is responsible for how bodies and immune system function, but it is responsible as well for genetic diseases and mutations that produce things like autoimmune disease, cancers, pediatric syndromes and ultimately, the aging process itself. Included in our understanding of our genetic functions, we must also understand the concept, indeed its foundation, our genome. This is our complete set of DNA, our genes and their interactions between each other, between our environment, and the direct activities of our immune system and every organ system in our body. Specifically, the science of immunogenomics deals with the immense volume of the human genome and its relationship with the human immune system and all its cellular, chemical and biological functions.
Protein synthesis, the process that produces all of our cells and tissues uses an extraordinarily complex, step-by-step molecular interaction between DNA and RNA which is known as “the central dogma of molecular biology.” It is without a doubt the singularly most important function of our genome and also responsible for the total genes and proteins that make up our immune system. This collection of immune cells, chemicals and functions is referred to as our “immunome.” Mutations in the genes of the genome and immunome are directly or indirectly responsible for all human diseases. Among the approximate 3 billion chromosomes within the nuclei of the cells and their DNA are our 20,000 to 25,000 genes. The number of possible combinations within the chemicals of these genes, or the “genetic codes,” is astronomical. It is among these prodigious numbers of gene combinations that congenital or hereditary, and acquired aberrations or mutations occur. Fortunately, only an infinitesimal amount of them, less than 60 per gene, override a normal cell’s ability to self-destruct (apoptosis) when something goes wrong to produce genetic disorders or diseases. Determining the order of DNA proteins, or their “sequence,” a person’s genetic code is called DNA sequencing and has advanced genetics both for research and clinically. The original sequencing technology took months and even years to record the complete sequence of a person’s DNA. The development of next-generation sequencing (NGS, also called high-throughput or massively parallel sequencing) uses artificial intelligence (AI) and big data analytics. This has sped up the process, now 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 (the coding portion of genes) sequencing. The clinical value of these NGS methods have dramatically demonstrated their value in their use for rapidly identifying coronavirus variants. The original method used to sequence the complete human genome, called 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 now be accomplished in 24 hours for under $500. Now that’s progress!
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