Pathogenic mutations and non-pathogenic DNA polymorphisms in the most common neurodegenerative disorders

Introduction
It is worth noting that genetic polymorphisms were defined by evolutionists in the pre-genomic era, in the early sixties. Given that advantageous or neutral variability of the organisms should be preferred by the basic process of natural evolution, i.e. natural selection, their frequency within a given population is expected to be high. In contrast, negative features should be gradually eliminated throughout the generations, so their frequency should be low. Although quite arbitrarily, variability occurring in the population with a minimal frequency of 1% was classified as DNA polymorphism. Similarly, rare variants with a frequency of <1% should be considered pathogenic due to their low frequency [13].
In fact, 54% of DNA variants dispersed in the human genome occur with a frequency below 1%, but they are not deleterious mutations. Only 23% of neutral DNA variants occur with a frequency higher than 10% [29]. The probability of finding a neutral variant in a patient which does not occur in 50 healthy controls (100 chromosomes) is about 15%. Thus, the probability of a false assumption that a harmless DNA variant is a pathogenic mutation reaches 15% [29].
In the pre-genomic era, any DNA variant not resulting in an amino acid change was considered a harmless polymorphism. Nowadays, however, numerous DNA variants that are not associated with an amino acid change have been shown to have deleterious effects [5].
A DNA variant localized in the conserved protein domain with a significant biochemical function (regulatory domains, ATP-binding domains) is thought to have a deleterious effect.
A deletion of a non-conserved hydrophilic loop domain VI (HLVI) of presenilin (Cys263-Leu381) does not alter Aß42 production; thus mutations in the presenilin 1 and 2 genes located within the HL domain may be expected to have no deleterious effect. Indeed, the Glu318Gly and Thr354Ile substitutions have been shown to be non-pathogenic mutations [20,24,42].
Finally, a question whether a certain mutation segregates with a phenotype is important in the assessment of its pathogenic effect. In fact, over 97% of cases observed by clinical geneticists are sporadic ones, and thus there is no possibility to determine segregation with the phenotype [27]. Even in large pedigrees the lack of segregation of the mutation with the phenotype may be caused by a low penetrance.

Pathogenic mutations in Parkinson’s disease...


View full text...