Student Reader


A mutation is any change in the nucleotide sequence or arrangement of DNA; mutations are one of only four evolutionary agents.

There are three categories of mutations: genome mutations, which arise from chromosome missegregation and change how many intact chromosomes are in a cell, leading to aneuploidy; chromosome mutations, which arise from chromosome rearrangement and restructure an individual chromosome; and gene mutations, which are base pair mutations affecting an individual gene.

An inherited mutation is a mutation passed on from ancestors; a de novo mutation is a new and non-inherited mutation. Disease mutations interfere with protein synthesis at one of the steps in the list to the bottom right.

  1. Transcription
  2. Translation
  3. 2° & 3° Interaction
  4. Protein Processing
  5. 4° Interaction
  6. Localization
  7. Cofactor Interaction
  8. Actual Activity

Somatic mutations are not passed on to progeny and only affect some cells of the body; a tumor is a common example of a somatic mutation. Germline mutation affect germ cells (cells which differentiate into eggs or sperm) and are passed onto progeny. Many germline mutations occur either in the fertilized egg (the zygote), leading to both germ and somatic cells containing the mutation. Dynamic mutations worsen during gametogenesis, leading to a worsened phenotype in each generation. Examples of dynamic mutations include Huntington Disease and Fragile X Syndrome, which involve repeat sequences extending during gametogenesis.

Some mutations are more likely to be maternal and other mutations are more likely to be paternal. Primary oocytes develop fetally and ovulate years and decades later; the older an oocyte is, the more likely it is to undergo nondisjunction. This nondisjunction leads to trisomy (which can be viable) and monosomy (which is almost never viable). For this reason, aneuploidy is maternal in at least 80% of all cases and occurs more often with maternal age. On the other hand, spermatogenesis occurs throughout a man's entire life. With mutations accumulating during each round of replication, point mutations are almost always paternal and increase with paternal age.

Point mutations

Point mutations are substitutions of one base pair for another. A transition is when one pyrimidine is swapped for another -- such as C for T, or T for C -- or one purine is swapped for another -- such as A for G, or G for A. A transversion is when a pyrimidine and a purine swap. Transitions are more frequent because when cytosines methylate to form 5-methylcytosine, they can spontaneously deaminate to thymidine.

Missense MutationA missense mutation is the changing of a single base-pair. Within a coding region, this usually leads to a change of a single amino acid in the protein product. However, if this mutation is in the 5' or 3' untranslated region then a missense can lead to underexpression of the protein product.
Nonsense MutationA nonsense mutation (aka chain termination mutation) is the replacement of a codon encoding an amino acid with a stop codon. This stop codon ends transcription of that gene prematurely, with an incomplete and unstable mRNA formed. Most of these mRNAs just fall apart; however, the few that are translated result in truncated proteins that quickly disintegrate.
RNA Processing MutationAn RNA processing mutation interferes with splicing of mRNA. If the point mutation alters a splice donor or splice acceptor site, then RNA splicing is interfered with or abolished at that location. If the point mutation creates a new splice donor or splice acceptor site, then this new site competes with normal splicing and the processed mRNA might still contain introns.

Deletions, insertions, inversions and translocations

There are deletions (removal of DNA), insertions (addition of DNA), inversions (reversal of the orientation of a DNA segment), translocations (moving of a DNA segment) and combinations thereof. Some deletions and insertions are small changes which are detectable only via PCR or genome sequencing; these usually shift the reading frame (a frameshift mutation) and lead to truncation of the mRNA by an early stop codon in the new reading frame. Some larger mutations can be detected via Southern blotting. For a mutation to be detectable by chromosome banding, it must involve at least 2 million base pairs.

Deletions, insertions, inversions and translocations often arise via faulty recombination. For example, unequal crossing over is crossing over without proper exchange of genetic information, leading to insertions in one chromosomes and deletions in another. Another form of faulty recombination is when mispaired chromosomes or sister chromatids exchange genetic information.

Mutation nomenclature

MissensePhe15TyrA missense mutation is described by the wild-type amino acid, its residue and the resulting mutant amino acid. The example shows a mutation where a phenylalanine is converted to tyrosene at residue 15 of a gene.
NonsenseSer25XA nonsense mutation is described by the wild-type amino acid, its residue and then an X to represent the mutant stop codon. The example shows a mutation where serine is replaced with a stop codon at residue 25 of a gene.
Nucleotide Changeg.3000G>A
If the full genomic sequence is known, a nucleotide change is denoted by a prefix (g for genomic and c for cDNA), followed by the number of that nucleotide, the original nucleotide, a '>' symbol, and finally the mutant nucleotide. Mutations identified in genomic DNA are denoted with capitalized nucleotides; mutations identified in non-genomic DNA are denoted with lower-case nucleotides. The first example shows a genomic mutation at position 3,000 where a G transitions to an A; and the second example shows the same mutation at position 1,000 on cDNA.
If the full genomic sequence is not known, then nucleotides are counted either: up from the 5' splice donor site, with +1 being the invariant G of the GT at the 5' splice donor site; or down from the 3' splice acceptor site, with -1 being the invariant G of the AG at the 3' splice acceptor site. The first example shows a transversion at the T of the 5' splice donor site; the second example shows a transversion at the A of the 3' splice acceptor site.
Deletionsc.1000_10003delGCATSmall deletions begin with a prefix (g or c for genomic or cDNA), followed by the locations of the deleted nucleotides, then a del for deletion, and finally the nucleotides deleted. The example shows a four-nucleotide deletion of a G,C, A and T at respective locations 1000, 1001, 1002 and 1003.
Insertionsc.1000_10001insATGCSmall insertions begin with a prefix (g or c for genomic or cDNA), followed by the nucleotides flanking the insertion, then an ins for insertion, and finally the nucleotides inserted. The example shows an insertion of A,T,G and C between nucleotides 1000 and 1001.
Nomenclature table derived from Nussbaum, McInnes & Willard: Genetics in Medicine, 7th ed. Philadelphia, Saunders, 2007. (pg 181)

Effect on Protein Function

Loss of functionα-thalassemia
Turner Syndrome
Loss of function mutations leads to a lower gene dosage. Examples of loss of function diseases are the α-thalassemias (where the entire α-globin gene is deleted), β-thalassemias (premature stop codon or coding missense), Turner Syndrome (a monosomy where a chromosome is lost) and retinoblastoma (where a somatic mutation lead to loss of function of tumor-suppressor genes). Many loss-of-functional diseases are less severe in heterozygotes; oftentimes, a single functional allele is enough for a healthy or mild-diseases phenotype.
Gain of functionTrisomy 21
Charcot-Marie-Tooth 1A
Hemoglobin Kempsey
Gain of function mutations lead to increased activity of a certain protein in tissues which normally express it (as opposed to heterocrhonic or ectopic expression). This increased activity can be due to a higher gene dosage, as in Down Syndrome (a third copy of part or all of Chromosome 21) or Charcot-Marie Tooth Type 1A (duplication of a particular gene) or even progression of certain cancers. Alternatively, one function of a protein might be detrimentally hyperactive. Examples include: hemoglobin Kempsey, a mutant hemoglobin with such high oxygen affinity that it does not release oxygen to tissues; and achondroplasia, where an over-strong signal (from exceptional binding of a growth factor receptor) leads to growth retardation.
Novel propertySickle CellNovel property mutations give encoded proteins new properties. For example, the hemoglobin chains of sickle cells aggregate into long fibers which deform the cell and impair its function. Some novel property mutations are also loss of function mutations; mutants with novel glycosylation sites are rendered inactive by glycosylation.
Heterochronic and
ectopic expression
Some CancersCertain mutations are simply due to gene expression at the wrong time (heterochronic) or in the wrong tissue (ectopic). For example, constitutive expression of proliferation genes (known as oncogenes) can lead to tumor formation.