Gene and Chromosomal Mutations

A mutation is a permanent change in the DNA sequence of a cell; gene mutations alter one or a few bases within a gene, while chromosomal mutations change the structure or number of whole chromosomes. In brief: the main gene mutations are substitutions (one base replaced), insertions and deletions (bases added or removed). Insertions or deletions that are not multiples of three bases cause a frameshift, which usually has a severe effect. Many mutations have no effect, some are harmful, and a few are beneficial.

Mutations are the original source of all new alleles and therefore of the variation on which evolution depends. They are also the cause of genetic diseases and many cancers. This guide classifies mutations, explains their effects on proteins with the genetic code, describes causes and repair, works through examples including sickle-cell anemia and corrects common mistakes.

What is a mutation?

A mutation is a change in the nucleotide sequence of DNA. Mutations in body (somatic) cells may cause cancer, but they are not passed on to children. Mutations in the gametes or the cells that form them (germline mutations) can be inherited. Each person is estimated to have about 30 to 70 new mutations compared with their parents, nearly all in non-coding DNA with no effect.

What are gene mutations?

Gene (point) mutations affect one or a few nucleotides in a gene.

Substitution

One base is replaced by another. The effect depends on the new codon.

• Silent mutation: the new codon codes for the same amino acid, because of the degeneracy of the code. For example, GAA to GAG, both coding for glutamic acid. There is no change in the protein.
• Missense mutation: the new codon codes for a different amino acid. The protein may be changed, as in sickle-cell anemia.
• Nonsense mutation: the new codon is a stop codon, such as UAU to UAA. The protein is cut short and is usually non-functional.

Insertion and deletion

One or more bases are added (insertion) or removed (deletion). If the number of bases is a multiple of three, amino acids are added or removed, but the rest of the sequence stays in frame. Otherwise, a frameshift occurs.

What are frameshift mutations?

Because the code is read in groups of three, adding or deleting one or two bases shifts the reading frame for all the codons after the mutation. All the amino acids that follow are usually different, and a stop codon often appears soon, so the protein is usually non-functional. Frameshifts therefore usually have more severe effects than substitutions. Examples of diseases caused by insertions or deletions include cystic fibrosis (often a deletion of three bases that removes a single amino acid, ΔF508) and Tay-Sachs disease (an insertion of four bases in the gene for an enzyme).

What are chromosomal mutations?

Chromosomal mutations affect large regions of DNA, or the number of chromosomes.

• Deletion: a segment of a chromosome is lost. In cri-du-chat syndrome, part of chromosome 5 is missing.
• Duplication: a segment is repeated, which gives extra copies of genes. Duplications are an important source of new genes in evolution.
• Inversion: a segment is reversed within the chromosome.
• Translocation: a segment moves to a different chromosome. A translocation between chromosomes 9 and 22 produces the “Philadelphia chromosome”, which is found in most cases of chronic myeloid leukemia.
• Changes in chromosome number (aneuploidy and polyploidy): caused by nondisjunction in meiosis, such as trisomy 21 (Down syndrome). Polyploidy, with extra complete sets of chromosomes, is common in plants and less common in animals.

What are the effects of mutations?

• Neutral: most mutations, for example those in non-coding DNA or silent mutations, have no effect on fitness.
• Harmful: they may cause genetic disease or cancer. Examples are cystic fibrosis, sickle-cell anemia and Huntington’s disease.
• Beneficial: rare, but important in evolution. For example, a mutation in the CCR5 gene gives some people resistance to HIV. The mutation that allows adults to digest lactose (lactase persistence) spread in populations that kept dairy animals.

A mutation may be harmful in one environment and beneficial in another. The sickle-cell allele is harmful in homozygotes, who develop sickle-cell disease, but heterozygous carriers are more resistant to malaria, so the allele is common in regions where malaria is common.

Mutation types compared

Worked example: effects of mutations on a protein

Start with this section of an mRNA, which is read in the frame from AUG: 5′-AUG GAA GUU CAG UAA-3′. It codes for Met–Glu–Val–Gln, then stop.

1. Silent substitution: change GAA to GAG. GAG also codes for Glu. The protein is unchanged: Met–Glu–Val–Gln.
2. Missense substitution: change GAA to GUA. GUA codes for Val. The protein is Met–Val–Val–Gln. This is the type of change that causes sickle-cell anemia: in the beta-globin gene, GAG (Glu) changes to GUG (Val) at position 6, and hemoglobin molecules stick together at low oxygen.
3. Nonsense substitution: change GAA to UAA. The protein is only Met, since UAA is a stop codon.
4. Deletion of one base: delete the first A of GAA. The sequence AUG GAA GUU CAG UAA becomes AUG GAG UUC AGU AA… Read in threes: AUG | GAG | UUC | AGU | AA. The amino acids are Met–Glu–Phe–Ser, and the final two bases AA are an incomplete codon. The stop codon is lost, and the rest of the protein is different.
5. Insertion of three bases: insert GGG after AUG. AUG GGG GAA GUU CAG UAA codes for Met–Gly–Glu–Val–Gln. One amino acid is added, and the others are unchanged.

The comparison shows the typical ranking of severity, from least to most severe: silent, then missense, then nonsense and frameshift. The effects of a missense mutation also depend on where the changed amino acid is. A change at the active site of an enzyme can inactivate it, but a change in a less important part may have no effect.

What causes mutations?

• Spontaneous errors in DNA replication that escape proofreading and repair.
• Mutagens: factors that increase the mutation rate. They include ionizing radiation (X-rays, gamma rays), ultraviolet light (which causes thymine dimers and skin cancer), and chemicals such as those in tobacco smoke, asbestos and some food contaminants.
• Viruses and transposable elements that insert themselves into genes.

Cells have DNA repair systems that correct most damage. People with inherited defects in repair, such as xeroderma pigmentosum, are extremely sensitive to ultraviolet light and have a high risk of skin cancer.

How were mutations discovered?

Hugo de Vries used the term mutation for sudden inherited changes in evening primrose plants around 1900. Hermann Muller showed in 1927 that X-rays cause mutations in fruit flies, and he received the Nobel Prize in Physiology or Medicine in 1946. Vernon Ingram showed in 1956 that sickle-cell hemoglobin differs from normal hemoglobin by one amino acid. Bruce Ames developed a test using bacteria in the 1970s to find out whether chemicals cause mutations.

Which mistakes are common?

Mistake 1: Saying that all mutations are harmful

Most are neutral, and some are beneficial. Harm depends on where the mutation is and on the environment.

Mistake 2: Assuming a mutation always changes the protein

Silent mutations and mutations in non-coding DNA do not change the amino acid sequence.

Mistake 3: Mixing up frameshift and substitution effects

A substitution changes one codon. A frameshift changes every codon after the mutation.

Mistake 4: Thinking that every mutation is inherited

Only mutations in germline cells can be passed to offspring. Somatic mutations are not.