Types of Genetic Mutations: How DNA Changes Affect Organisms

Point Mutations: Single Base Changes

Point mutations involve the substitution of one nucleotide for another at a single position in the DNA sequence. They are classified by their effect on the encoded protein. Silent (synonymous) mutations change a codon without changing the amino acid it specifies, thanks to the redundancy of the genetic code. For example, both GCU and GCC code for the amino acid alanine, so a U-to-C change at the third position has no effect on the protein.

Missense mutations change one amino acid to another. The severity depends on the chemical similarity between the original and replacement amino acids and the location within the protein. A conservative substitution (replacing one hydrophobic amino acid with another) at a non-critical position may have no functional effect. A radical substitution at the active site of an enzyme can completely abolish function. Sickle cell disease results from a single missense mutation changing glutamic acid to valine in beta-globin.

Nonsense mutations convert an amino acid codon into a premature stop codon, truncating the protein. The earlier in the gene the nonsense mutation occurs, the shorter and more likely nonfunctional the resulting protein fragment. Cells have a quality control mechanism called nonsense-mediated decay that detects and destroys mRNAs containing premature stop codons, often preventing truncated proteins from being produced at all.

Insertions and Deletions

Insertions add one or more nucleotides to the DNA sequence, while deletions remove them. When the number of inserted or deleted bases is not a multiple of three, the result is a frameshift mutation that changes the reading frame of all subsequent codons. Because every codon downstream of the frameshift is read differently, the entire protein sequence after the mutation point is altered, usually producing a nonfunctional protein followed by a premature stop codon.

In-frame insertions or deletions (adding or removing exactly 3, 6, 9, etc. nucleotides) do not shift the reading frame but add or remove amino acids from the protein. The most common mutation causing cystic fibrosis is a three-nucleotide deletion (delta-F508) that removes a single phenylalanine from the CFTR protein, causing it to misfold and be degraded before reaching the cell membrane.

Chromosomal Mutations

Large-scale mutations affect substantial portions of chromosomes. Deletions remove segments of DNA ranging from thousands to millions of base pairs, potentially eliminating multiple genes. Duplications create extra copies of chromosomal segments. Inversions flip a segment of DNA within a chromosome, reversing its orientation. Translocations move segments between non-homologous chromosomes.

Aneuploidy, the gain or loss of entire chromosomes, results from errors in chromosome segregation during cell division. Trisomy (three copies of a chromosome) causes Down syndrome (chromosome 21), Edwards syndrome (chromosome 18), and Patau syndrome (chromosome 13). Monosomy (one copy) is usually lethal for autosomes but viable for sex chromosomes, as in Turner syndrome (45,X). Polyploidy (complete extra sets of chromosomes) is lethal in humans but common and sometimes beneficial in plants.

Causes of Mutations

Spontaneous mutations arise from errors in normal cellular processes. DNA polymerase occasionally incorporates wrong nucleotides that escape proofreading. Depurination (spontaneous loss of purine bases) occurs thousands of times per cell per day. Deamination converts cytosine to uracil, which if not repaired before replication causes a C-to-T transition. Replication slippage at repetitive sequences can cause small insertions or deletions.

Induced mutations result from exposure to mutagens, agents that increase mutation rates above background levels. Chemical mutagens include alkylating agents (which add chemical groups to bases, causing mispairing), base analogs (which incorporate into DNA and pair incorrectly), and intercalating agents (which insert between base pairs, causing frameshift mutations during replication). Physical mutagens include ultraviolet radiation (which causes thymine dimers) and ionizing radiation (which breaks DNA strands directly).

Somatic vs. Germline Mutations

Somatic mutations occur in body cells and affect only the individual in which they arise. They cannot be passed to offspring but can cause disease within the individual, most notably cancer. All cancers begin with somatic mutations in genes controlling cell growth, division, and death (oncogenes and tumor suppressor genes). Somatic mutations accumulate throughout life, which partly explains why cancer risk increases with age.

Germline mutations occur in reproductive cells (eggs and sperm) or their precursors and can be transmitted to the next generation. Every individual carries approximately 60 to 80 new germline mutations not present in either parent, most of which are neutral. Occasionally, a new germline mutation causes a genetic disorder in a child born to unaffected parents, which is called a de novo mutation.

Mutations and Evolution

Mutations are the ultimate source of all genetic variation. Without mutations, there would be no new alleles, no raw material for natural selection, and no evolution. The vast majority of mutations are neutral (having no effect on fitness) or deleterious (reducing fitness), but a small fraction are beneficial in particular environmental contexts.

The mutation rate in humans is approximately 1 to 2 point mutations per 100 million base pairs per generation, or about 60 to 80 new mutations per individual per generation. This rate represents a balance: too low a rate would limit adaptive potential, while too high a rate would cause an unsustainable burden of harmful mutations. DNA repair mechanisms maintain this rate by correcting the vast majority of DNA damage before it becomes a permanent mutation.