Since the time of Aristotle, it was recognized that all biological processes, traits and behaviors of human individuals in a population exhibit varying degrees of individuality and do not confirm to a fixed standard values. Yet, there was hardly any appreciation for the prevalence of genetic individuality in the human population. This was about to change after the publication of the first draft of the human genome sequence.
A reference standard with no matching items
In 2003, the complete draft of the human genome was made available on the internet which became the gold standard or technically the "reference genome" for human species, thanks to the multi-million dollar human genome project. However, the "reference" sequence is actually not identical to any individual's genome.
A species with unparalleled heterogeneity
Now, a growing number of personal genome sequences from both asymptomatic healthy individuals and symptomatic individuals with various diseases are generating large amounts of individual genome sequences, revealing the extent of genetic individuality in the general population (Lander E, 2011). The numbers of individual genomes is increasing consistently, with more and more research and clinical labs affording to the latest DNA sequencing technologies. As the genome sequences of multiple individuals were compared, countless very rare variants, many of which probably exist in only a single or a few individuals were being discovered. The extent of polymorphic genome variation among different individuals and different populations worldwide is simply inescapable. Calculations based on these polymorphism data lead to the inevitable conclusion that virtually every individual will be found to have his or her own unique constitution of gene products. To put it simple, every personal genome sequencing will frequently lead to the
discovery of many novel genetic variants that was never found before. However, the incidence of such novel genetic variants discovery will decrease as more and more genomes from more and more populations are sequenced. Therefore, in our efforts to the exploration of molecular basis of rare and common human disorders, we must NOT ignore or fail to apply the concept of genetic individuality. To this end, and rightly so, many personal genome sequencing datasets and resources are made available online, providing broad access to scientists and clinicians worldwide to help them come up with their strategies to apply this knowledge in their working hypotheses.
Genetic and molecular basis of biological individuality
With a near complete understanding of the role of common as well as rare variation in dictating the individual-specific aspects of human biological traits, we are more likely to be able to exploit the impact of that variation in human health, and deliver on the promise of individualized medicine.
Chemical & biological individuality
Although the idea that individuals of a species do not conform to an absolutely rigid standard when it comes to biological traits was not popular or widely preached in life science research, it was not new to the research community. In his 1902 Lancet publication, Sir Archibald E. Garrod interpreted the wide range of physiological values of various metabolites among closely related individuals as indicative of metabolic individuality (Garrod AE, 1902). He supported the view that there is no rigid uniformity of chemical processes in the individual members of a species. He argued that different individuals will differ slightly in their chemistry and structure of metabolites, therefore should exhibit conspicuous deviations from the expected species-specific type of metabolism. This means, already about a 100 years ago, the chemistry-driven knowledge of metabolic individuality among human individuals was established. One could demonstrate the chemical individuality of humans using urine samples in a test tube. And then 50 years later, GR Burgio once again followed on this idea of molecular individuality by drawing parallels between biological
individuality and the immunological uniqueness of individuals. He published
many papers elaborating on the concept of individuality of immune
response (also first suggested by Garrod AE), lucidly illustrating how the ability of different individuals
to respond differently to the same antigen is encoded in their genome,
via the polymorphic genetic variation in the histocompatibility genes
(Burgio GR, 1987).
Signalling individuality
And about 3 decade later, in 2015, I provided the first evidence for individuality of phosphotyrosine signalling - I argued that different individuals differ and exhibit differences at the propensity of STAT3 phosphorylation levels, depending on the presence or absence of polymorphic transmembrane protein variants that acquire the ability to recruit STAT3 to inner membranes (Ulaganathan VK, 2020).
Molecular basis of biological individuality
Since metabolites are products of enzymatic pathways mediated by proteinous enzymes which are products of genes, it is very likely that metabolic individuality has a genetic basis. The synthesis of gene products is often regulated by the environment via transmembrane signalling pathways which often ends up modifying pre-existing DNA-binding proteins in the cytoplasm, using chemicals such as phosphates, methyl, sumoyl, acetyl groups, ubiquitin chains and many other metabolite-mediated protein modifications. In other words, metabolites are critical component of gene regulation mechanisms. Therefore, metabolic individuality and genetic individuality are inseparable concepts. It is beyond doubt that studying subtle individual-specific differences in metabolic and signalling pathways will provide a more holistic and better integrated picture of biological individuality of human species and is much likely to help us better understand the "missing heritability" problem of complex diseases.
Figure Legend. Human population is composed of genetically heterogeneous out-bred individuals. A combination of genetic, metabolic and signalling differences give rise to gene regulation events unique to an individual thereby generating the truly biological individuality for every humans.
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