Clinical significance and strategies to analyze genetic polymorphisms

A DNA polymorphism can be defined as a difference in the primary sequence of DNA, and the frequency of the rarer allele among the general population exceeds 1%. Several types of polymorphisms, including minisatellite and microsatellite markers, deletion or insertion of short nucleotide sequences, and single nucleotide polymorphisms(SNPs), are present in human genome, with different frequencies and different distribution patterns. SNPs are very common and clinically important, because they often appear within genes, particularly within coding sequences. The biological significance of a polymorphism differs significantly depending upon its location within the genome. For example, polymorphisms located outside genes usually do not have biological consequences, and will be used merely as markers for genetic linkage. On the other hand, those located within a gene may cause subtle changes in transcription, mRNA stability, or protein conformation if amino acid substitution occurs. These subtle changes in biologically important factors then alter susceptibility to certain disorders. Environmental factors often interact with genes. Relationships between genetic polymorphisms and disease susceptibility have been reported on many kinds of human diseases, including neurological and psychiatric disorders, infectious diseases, endocrine and metabolic disorders, malignancy, as well as cardiovascular diseases. Recent years have seen the progress in novel strategies for rapid genotyping of a large numbers of polymorphisms, and also, for searching unknown SNPs.