Mutations Versus Polymorphisms
Mutations are changes in DNA that can lead to disease, whereas polymorphisms are variations in DNA that were previously thought to rarely cause disease. The difference is not always easy to determine. In general, mutations change amino acid sequence or, more dramatically, lead to a shortening or nonproduction of the protein encoded by the gene. Polymorphisms tend not to cause a change in the amino acid sequence (because of the built-in redundancy in the DNA code) or a change from one amino acid to a similar amino acid. However, some synonymous changes, though not changes in amino acid sequence, could affect splicing. Many of the disease-associated single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) are found in the noncoding regions of the genome.
Mutations can involve a change in a single base pair; simple deletion or insertion of DNA material; or more complex rearrangements such as inversions, duplications, or translocations. Deletion, insertion, or duplication of any number of base pairs in other than groups of 3 creates a frameshift in the entire DNA sequence downstream, resulting in the eventual formation of a stop codon and truncation of the message.
Mutations that result in no active gene product being produced are called null mutations. Null mutations include missense or nonsense mutations that (1) produce either a stop codon directly or a frameshift with creation of a premature stop codon downstream or (2) cause an alteration at the acceptor splice junction site, resulting in the loss of exons or inappropriate incorporation of introns into the spliced mRNA.
Mutations can also lead to a gain of function that may be beneficial (leading to evolution) or detrimental (leading to disease). An example of a beneficial gain in function is the emergence, among bacteria, of antibiotic resistance. An example of a detrimental gain of function is a receptor protein that binds too tightly with its target protein, creating loss of normal physiologic function. Most autosomal dominant disorders are of this type.
Single base-pair mutations may code for the same amino acid or a tolerable change in the amino acid sequence, leading to harmless polymorphisms or DNA variations that are in turn inherited. These are called conserved base-pair mutations.
A polymorphism is any variation in DNA sequence that occurs, by convention, at a frequency of greater than 1% in the normal population. Key polymorphisms associated with disease include those in the region of the CFH gene in age-related macular degeneration and the LOXL1 gene in pseudoexfoliation syndrome. Many polymorphisms are silent and simply linked to the disease mutation, but some may influence disease.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.