1 This allowed our ancestral predecessors to fight hypermutability with hypermutability. One of the numerous ideas is the evolutionary “big bang” which occurred over a relatively short period 500 million years ago. Thus, the obvious question is how humans can protect themselves. Our genomes are highly stable, and have extremely predictable protein–RNA integration networks (simple cell functions). By contrast, humans “divide” approximately every two decades. These pathogens are not only capable of exponential growth but also contain machinery that can produce trillions of themselves every day, resulting in incredible evolutionary speed. Likewise, pathogenic bacteria and parasites can divide within minutes and reach copies of 1 × 10 8 mL –1 of blood. Pathogenic viruses can multiply rapidly and reach 1 × 10 7 copies mL –1 of blood. Finally, we discuss how TCR NGS can add to immunodiagnostics and integrate with other omics platforms for both a deeper understanding of TCR biology and its use in the clinical setting. We next catalogue new signatures and phenomenon discovered by TCR next generation sequencing (NGS) in health and disease and work that remain to be done in this space. The standardization of TCR sequencing data is discussed in preparation for big data bioinformatics and predictive analysis. This review describes the genetics and architecture of the human TCR and highlights surprising new discoveries over the past years that have disproved very old dogmas. The TCR evolved hypervariability to fight the hypervariability of pathogens and cancers that look to consume our resources. The TCR system is arguably the most complex known to science. Over countless generations, our antecedents tuned the function of the T-cell receptor (TCR). The adaptive immune system arose 600 million years ago in a cold-blooded fish.
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