Physiologic noise obscures genotype–phenotype correlations

Attempting to draw precise genotype–phenotype correlations has been one of the primary goals in medical genetics since the completion of the Human Genome Project. In light of the great public attention to genetic achievements—frequently exaggerated or misinterpreted by the media—patients and families often expect at least definite diagnosis and prognosis if not a cure upon entering a medical genetics clinic. However, it is becoming clear that even if an accurate, genetically confirmed diagnosis can be made of a monogenic disease, our ability to provide precise prognosis for an individual is significantly limited. This is usually a surprise even to people working in the field of medicine or biology. This ‘‘surprise’’ may originate from the rather static (now out-of-date) interpretation of the Mendelian one gene–one phenotype principle. More and more observations are published regarding the significantly variable phenotypic expression not only from a defective single gene, but also from a specific mutation within the same gene [Kellermayer, 2006; Teszas et al., 2006; Young et al., 2006]. Disconcordancy can be observed even among identical twins affected by the same genetic defect [Baser et al., 1996; Mekus et al., 2000; Kamath et al., 2002]. Therefore, the expression of a gene into a phenotype appears to be a much more complex, dynamic and variable process than could be perceived from the initial ingenious observations of Georg Mendel. For example, epistatic effects resulting from complimentary genes/mutations or random variations of other interacting genes may affect gene transcription. Furthermore, physiologic noise due to stochastic components is bound to be present not only during the transcription and translation of a specific gene, but in protein–protein, cell–cell (i.e. tissue), tissue– tissue (i.e. organism), and organism–environment interactions originating from the specific gene product as well. The manifestation of human disease resulting from a genetic defect may depend more upon alterations in physiology at the tissue, or organism level in several disorders, rather than upon cellular defects [Szigeti and Kellermayer, 2006]. While physiologic noise may appear as an obstacle formedical genetics,wehave come to realize that the noisy or stochastic nature of biological processes is likely of fundamental essence to life. Such random fluctuations within the living material may be constructive, elemental forces in the life cycle of the organism [Bahar et al., 2006; Samoilov et al., 2006] and in the dynamic associations between organic and inorganic material that build up the living cell [Jaeken, 2006]. This diverse stochasticity is likely the origin of individuality in human disease. Consequently, when dealing with a patient one cannot speakof a disease in general, but only of the illness or altered physiologic state of the individual person. In such instances we are left with mere speculations about prognosis derived from statistical and anecdotal medical information. Thus, it is humbling, yet intriguing at the same time to be practicing medicine in the beginning of the 21st century. In my opinion, the Human Genome Project not only provided an immense amount of information, but also opened a new window through which one can only marvel