A genetic mutation is a change in the sequence of deoxyribonucleic acid (DNA), the instruction manual found in nearly every cell. These alterations can range from a single misplaced molecular building block to the insertion or deletion of large segments of genetic material. The frequency of these changes depends entirely on the cell type being examined. We must distinguish between mutations passed down from parent to child (germline) and those acquired in body tissues throughout a person’s life (somatic).
Measuring the Germline Mutation Rate
The germline mutation rate tracks new, inherited changes that arise in reproductive cells but are absent in both parents. Scientists estimate this rate using trio sequencing—sequencing the entire genomes of parents and their children—to identify de novo mutations. This analysis shows that the human germline is remarkably stable.
The rate of single nucleotide variants (SNVs), the most common type of change, is estimated at approximately \(1.1\) to \(1.5 \times 10^{-8}\) mutations per base pair per generation. Given the size of the human genome, this translates to about 60 to 80 new point mutations introduced into each new generation.
A notable factor influencing this rate is the age of the father. Since male reproductive stem cells continuously divide to produce sperm, the number of cell divisions increases with age, raising the chance of replication errors. Consequently, the majority of de novo mutations—approximately 76%—originate in the paternal germline.
Sources of DNA Damage and Mutagenesis
Mutations result from DNA damage, categorized as either endogenous (internal) or exogenous (external) in origin.
Endogenous Sources
The most common source of internal mutations are errors occurring during DNA replication. Although cellular machinery is highly accurate, incorporating the wrong nucleotide occasionally happens, and if this error escapes repair, it becomes a permanent mutation. Other internal sources include spontaneous chemical alterations, such as the deamination of bases, and reactive oxygen species (ROS) produced during normal cellular metabolism.
Exogenous Sources
The environment contributes through external factors that directly damage the DNA structure. Ultraviolet (UV) radiation from the sun causes adjacent pyrimidine bases to form chemical cross-links, known as dimers. Chemical exposures, such as polycyclic aromatic hydrocarbons found in smoke, can form bulky chemical attachments called DNA adducts. Ionizing radiation, like X-rays, is particularly damaging because it generates free radicals that cause single- and double-strand breaks in the DNA helix. Although cells possess robust repair mechanisms, damage that overwhelms these systems results in a fixed mutation.
Somatic Mutations and Tissue-Specific Frequency
Somatic mutations are acquired in non-reproductive body cells and are not passed on to offspring. These mutations accumulate throughout an individual’s lifespan, and their frequency is measured per cell division. The rate of somatic mutation varies significantly across different tissues, reflecting their unique rates of cell turnover and exposure to damage.
Rapidly dividing tissues, such as the epithelial lining of the gut, show mutation rates ranging from approximately \(3.5 \times 10^{-9}\) to \(1.6 \times 10^{-7}\) per base pair per cell division. Stem cells in these tissues may acquire around 40 new mutations annually. This accumulation is the primary driver of age-related health concerns, particularly cancer, which arises when changes affect genes that control cell growth.
The accumulation of these changes creates a genetic patchwork, known as mosaicism, where different cells in the same person have distinct genetic codes. Even cells that rarely or never divide, like neurons, accumulate mutations at a steady rate, roughly 15 to 17 per year. In these non-dividing cells, mutations are a consequence of ongoing damage and the imperfect repair of that damage over time.
The Spectrum of Mutational Outcomes
The biological consequence of a mutation ranges from no effect to a complete loss of function. Most changes are neutral or silent, meaning they do not alter the function of the protein the gene codes for. These silent changes may occur in non-coding regions of the DNA or result in a change to a protein-coding sequence that does not affect the final amino acid.
A smaller fraction of mutations are pathogenic, leading to impaired cellular function or genetic disorders. The accumulation of specific harmful somatic mutations underlies the development of diseases like cancer. Conversely, a very small number of mutations are beneficial, providing a selective advantage that is acted upon by natural selection and drives evolutionary adaptation.