Genetic polymorphisms are common variations in DNA that account for many inter-individual differences, including blood type, nutrient utilization and drug responses. These “genetic typos” have served beneficial purposes throughout evolution, allowing populations to adapt to changing environments. However, unfavorable physiological effects are also well-documented for a small number of polymorphisms, including those affecting drug or nutrient metabolism.
Mutations vs. Polymorphisms
The terms genetic polymorphism and mutation are sometimes used interchangeably, but there are several important distinctions.
Mutations are rare, affecting less than 1% of the population. They are highly penetrant, meaning that they can independently cause a predictable, heritable phenotype that is largely unaltered by the environment. Examples include sickle cell anemia and color blindness.
Polymorphisms affect a large percentage of the population. In contrast to mutations, they impart mild and variable phenotypes, and in many cases, there is no phenotype at all. However, a growing number of polymorphisms are clearly associated with a clinical trait. Examples include CYP1A2 rs762551 and PEMT rs12325817, which alter caffeine and choline metabolism, respectively. The traits are often modified by environmental factors and by other genes. Therefore, they do not cause a fully heritable or predictable phenotype.
Important Terms and Definitions
Gene: A sequence of DNA that contains instructions for a cell to make a specific protein that the body needs.
Genome: The sum of all of your genes. Humans carry an estimated 20,000-25,000 protein-coding genes. Polymorphisms within those genes make one person different from the next.
Phenotype: The physiological characteristic(s) imparted by a genetic variation.
Genotype: The version of a gene that a person carries, i.e. whether a polymorphism affects its sequence. Genotype is the output of a genetic test.
Polymorphism: A DNA sequence variation that alters the gene in some way. Often, it is a simple substitution of one letter (nucleotide) for another (e.g. A –> C). Less commonly, the gene can be duplicated or deleted, or contain an inserted or deleted piece of DNA. Polymorphisms do not independently cause disease, but they can be risk factors. They can also have health benefits.
Single Nucleotide Polymorphism (SNP): A DNA sequence variation in which one nucleotide is substituted for another. Sometimes this affects the encoded protein, but most of the time, it has no effect. SNPs of medical significance cause a substitution in the regulatory or coding regions that affects the expression or function of the protein (Figure 1).
Mutation: A rare DNA sequence variation that creates a different version of a gene. Like SNPs, mutations can involve one nucleotide (point mutations). Alternatively, they can involve deletions of large sections of DNA or entire chromosomes. In contrast to polymorphisms, mutations have potentially serious phenotypes that are more difficult to modify through diet, lifestyle and environment.
Penetrance: The proportion of carriers with a genetic variation that express the associated trait (phenotype). Polymorphisms have low penetrance, while mutations have high penetrance.
Figure 1. Most SNPs fall outside of the coding region and therefore have no effect on the gene function. This describes the majority of the 10 million SNPs cataloged in the human genome. SNPs that affect regulatory or coding regions can be clinically significant, but only if they influence the structure or amount of the expressed protein.
New to Genetics?
To familiarize yourself with basic concepts, I recommend Help Me Understand Genetics, an illustrated introduction provided by the U.S. National Libraries of Medicine: https://ghr.nlm.nih.gov/primer.