Allelic variations, normal

Maynard Smith What do you mean by normal allelic variations ... 

Rutter By normal I mean that they occur commonly in the general population without being associated with the disease. In a sense all allelic variations are mutations, but in medical genetics one would tend to make a distinction between a gene for phenylketonuria which is obviously causing pathology, as opposed to ApoE4 which is a normal variation but nevertheless carries with it an increased statistical risk for Alzheimer s. 

The importance of VDR in bone metabolism arises from studies of polymorphisms of the VDR gene. These show that normal allelic variations in the VDR gene may account for inherited variability in bone mass and density. Specific alleles of the VDR gene predict the density of femoral and vertebral bone in prepubertal American girls of Mexican descent. In the development of osteoporosis, a disorder determined by multiple genetic and environmental factors, variants of the VDR gene and its products may play a significant role. One of the important functions of the VDR protein is calcium absorption. 

Fig. 6.41. Dose/Genotype Relationship A schematic representation of the potential benefit of adjusting drug dose to patient genotype. The theoretical normal drug concentration/time curve is depicted by the dashed line in the concentration/time curves of Patients A-D at the top of the figure while the theoretical genetic drug concentration/time curve for each patient is expressed by the solid line. The allele status for each patient is shown below the theoretical plots. The oval containing the X indicates the presence of the detrimental allelic variation. The extra oval in Patient D indicates duplication of one of the normal alleles. The bar graph at the bottom of the figure indicates the normal doses (shaded) compared to the dose adjustments that should be made based on the patient s allele status (180).

Single Nucleotide Polymorphisms (SNPs) are single base pair positions in genomic DNA at which normal individuals in a given population show different sequence alternatives (alleles) with the least frequent allele having an abundance of 1% or greater. SNPs occur once every 100-300 bases and are hence the most common genetic variations. 

The authors demonstrated that these polymorphisms alter mRNA stability and therefore enzyme activity. They showed that whereas phosphorylated USF-1 bound the normal consensus sequence, the G-to-C substitution abolished the binding (42,59). In vitro transcription analysis showed that the TSER 3RC allele caused a lower transcription rate than the TSER 3RG variant, which was comparable to the TSER 2R genotype. Interestingly, the frequency of the 3RC allele among all 3R alleles showed a variation of 56%, 47%, 28%, and 37% for Whites, Hispanics, Alfican-Americans, and Singapore... 

An effective and elegantly uncomplicated method for directly assessing allele-specific transcript abundance within a normal chromosomal context has been used by several groups (22,23,25) to examine allele-specific expression in human samples. Cowles et al. (26) have used this method to examine such variation between mouse strains. These groups use SNPs in the transcribed regions of genes as tools to measure allele-specific expression levels of genes... 

Kunst CB, Warren ST. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 1994 77 853-61. 

---