Mutations are heritable sequence variations in the nucleotide sequence of genomic or mitochondrial DNA resulting in disease. Alternative variants of genetic information at a particular locus are called alleles. For many genes there is a single version, or normal allele, present in the majority of individuals. Other versions of the gene may be mutant alleles, which differ from the normal allele by mutation. When at least two normal alleles are present in a population, the locus is defined as polymorphic, for example, the common blood group ABO.
Since a change in the coding sequence of a gene can affect all copies of the resulting polypeptide, mutations can be particularly damaging to a cell or organism. Many human diseases, often devastating in their effects, are due to mutations in a single gene. Examples of single gene disorders include phenylketonuria, cystic fibrosis and Huntington disease.
Mutations can occur through exposure to mutagenic agents, but most arise spontaneously through errors in DNA replication and repair. Both small and large DNA alterations can occur spontaneously. Mutations are continuously corrected by DNA repair enzymes, but if a mutation occurs and is not corrected (a de novo or sporadic mutation), and arises in a gamete, it can be transmitted to the subsequent generation. Furthermore some tissues within an individual may have two populations of cells, which differ genetically, a phenomenon known as mosaicism. Where two genetically different populations of cells are within the germline (gonadal tissues), this is known as germline mosaicism, and has implications regarding carrier testing using peripheral blood samples or other tissues in these individuals. When this occurs in somatic tissues this is known as somatic mosaicism, and has been implicated in a number of conditions, for instance most cancers.
At the DNA level, a change in the genetic code may represent a substitution (the replacement of a single nucleotide by another), a deletion (the loss of one or more nucleotides), or an insertion (the addition of one of more nucleotides into the gene). A mutation of even a single base pair may result in a missense mutation (where one amino acid is substituted for another), a nonsense mutation (where a stop codon replaces an amino acid), or a frameshift mutation (which causes a change in reading frame, and the introduction of spurious amino acids unrelated to the polypeptide function generally followed by a premature stop codon).
Not all sequence variations have an effect on the polypeptide sequence of the encoded protein. This depends on the nature of the change and its location in the gene. For example, sequence variations in non-coding DNA are generally not expected to result in a phenotype, unless they occur in regulatory sequences controlling the expression of the gene or splicing of the message (removal of the introns). Even sequence variations in coding DNA may not alter the protein product due to redundancy in the genetic code. If the mutation does not alter the polypeptide product, it is known as a silent mutation or polymorphism.
Mutations are expressed through Mendelian patterns of Inheritance
Mutations exert their phenotypic effect through either a loss- or gain-of-function. Loss-of-function mutations result in loss of a gene product or reduced activity, and gain-of-function mutations result in either increased levels of gene expression or the development of a new function of the gene product.
Recessive mutations (where the phenotype is expressed in homozygotes) inactivate the gene and lead to a loss-of-function; for example, the Δ F508 mutation in the CFTR gene (in cystic fibrosis). Dominant mutations (where the phenotype is expressed in heterozygotes) often lead to a gain-of-function; however, they may also be associated with a loss-of-function. In some cases, both copies of a gene are required for normal function, so that removing a single copy leads to a mutant phenotype.
Such situations are referred to as haplo-insufficient. In other cases, mutations in one allele may lead to a structural change in the protein that interferes with the function of the wild-type protein encoded by the other allele. These are referred to as dominant negative mutations.
Interestingly, different mutations in the same gene can produce two or more dominant conditions; for example, the COL1A1 or COL1A2 genes that encode type I collagen. Mutations in these genes usually produce osteogenesis imperfecta (OI; brittle bone disease) - the OI types with milder symptoms occur due to haplo-insufficiency, and more severe forms through dominant negative effects of missense mutations.
Although more than 99% of human DNA sequences are identical across the population, as stated above, not all changes in DNA sequence observed between individuals represent mutations. Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide in the genome sequence is altered.
SNPs make up about 90% of all human genetic variation and can occur in both coding and non-coding regions of the genome.
For example, a SNP might change the DNA sequence A A CGTTAA to A T CGTTAA.
For a variation to be considered a SNP, it must occur in at least 1% of the population (a mutation is defined as being present at <1% in the population). Whilst many SNPs have no effect on cell function, it is thought that others could predispose individuals to disease or influence their response to a drug. Thus SNPs and other types of genetic variation are useful in genetic linkage studies and more generally are of great value in biomedical research.
A nomenclature proposed for human sequence variations is now widely used in laboratory reports and the scientific literature.(See Dunnen and Antoniarakis 2001).
J. T. den Dunnen, E. Antonarakis. Nomenclature for the description of human sequence variations. Hum Genet (2001) 109(1) :121-124
Strachan T, Read AP. 2003. Human Molecular Genetics 3. NewYork: Garland Press
opac.library.usyd.edu.au/record=b2677891~S4 - General text on Human Molecular Genetics
Gelehrter .TD, Collins FS and Ginsburg D. 1998. Principles of Medical Genetics. Baltimore: Williams & Wilkins.