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  1. The word genetic is used in several ways. Two ways pertain to genes as physiologic mechanisms, and to variation in inherited units. These are the predominant connotations in biomedical genetics.

  2. Most cases of complex human diseases arise sporadically. However, a common situation is that a disease manifests a significant level of familial aggregation of risk, for which mapping has only been able to identify a responsible gene in a few Mendelian cases. There is usually considerable phenotypic variation among affected families and even among individuals in the same family. This is not easy to explain because similar phenotypes are found in the sporadic cases.

  3. This common situation shows that the disease can be causally genetic, yet even intensified mapping effort has so far been unable to identify genes that account for more than a small fraction of the overall familial risk. How environmental and genetic factors can produce the same phenotype is usually unclear, but the general explanation is that variation at many loci may be involved, with different genotypes involved in each instance. Unfortunately, with this kind of inheritance the individual "polygenes" are hard to find by current methods, making prediction of phenotypes from genotypes very problematic.

  4. One reason for these problems may relate to a third meaning of genetic. DNA sequence variation is transmitted not only across the germ lines; variation also arises by somatic mutation (SM) during the lifetime of each individual. SM explains the kind of epidemiologic features described above as seen in cancer, and may play a comparable role in many other diseases. Most known types of mutation also occur mitotically.

  5. SM can be better understood by analogies and homologies between evolutionary molding of variation inherited by individuals from generation to generation, and variation inherited by generations of cells within individuals. Depending on when SM occurs in an individual’s life, the result can be patchy among cells or can produce regionally or functionally nested affected tissues. The net occurrence of SM depends on mutation and mutation-repair rates, mitotic rates, gene expression patterns, environmental exposure to mutagens, and other factors whose details are largely unknown at present.

  6. For SM to have a detectable impact on health, its effects must be amplified beyond the cell in which it first occurs. Amplification can occur in many ways, the best known being cellular proliferation (as in cancer), or somatic mosaicism in development. But there are other amplification mechanisms as well.

  7. The main characteristic for SM to be a plausible etiologic factor is that the disease can be viewed biologically as a disorder of cell behavior closely related to gene function. Epilepsy may be a good exemplar of these principles. As with other disorders having the features described above, most epilepsies have defied mapping analysis, yet their underlying pathology, undamped neuronal signaling, is closely connected to gene function (i.e., involves neurotransmitters and ion channels). This plausibility case is laid out here in some detail.

  8. SM will be challenging to document and understand. But if a disease is due to aberrant cell behavior, studies of SM will have the ancillary benefit of contributing to our understanding of basic cell biology. Many new technologies are being developed that can be applied to detect and characterize SM.

  9. SM is an omnipresent phenomenon whose potential etiologic importance should be carefully considered as one of several ways that a given disease might be genetic. But until it becomes the direct object of study SM will remain a cryptic etiologic force responsible for many cases of diseases that are essentially genetic but that cannot be mapped in families.

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