An inversion changes more than one nucleotide in a gene by replacing the original sequence with the same sequence in reverse order. A reading frame consists of groups of three nucleotides that each code for one amino acid.
A frameshift variant occurs when there is an addition or loss of nucleotides that shifts the grouping and changes the code for all downstream amino acids. The resulting protein is usually nonfunctional.
Insertions, deletions, and duplications can all be frameshift variants. Some regions of DNA contain short sequences of nucleotides that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of sequences of three nucleotides, and a tetranucleotide repeat is made up of sequences of four nucleotides. A repeat expansion is a variant that increases the number of times that the short DNA sequence is repeated.
This type of variant can cause the resulting protein to function improperly. Other chapters in Help Me Understand Genetics. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice.
Contact a health care provider if you have questions about your health. What kinds of gene variants are possible? From Genetics Home Reference. Variant types include the following: Substitution This type of variant replaces one DNA building block nucleotide with another. Missense : A missense variant is a type of substitution in which the nucleotide change results in the replacement of one protein building block amino acid with another in the protein made from the gene. The amino acid change may alter the function of the protein.
UV light can also cause covalent bonds to form between adjacent pyrimidine bases on a DNA strand, which results in the formation of pyrimidine dimers. Repair machinery exists to cope with these mutations, but it is somewhat prone to error, which means that some dimers go unrepaired.
Furthermore, some people have an inherited genetic disorder called xeroderma pigmentosum XP , which involves mutations in the genes that code for the proteins involved in repairing UV-light damage.
In people with XP, exposure to UV light triggers a high frequency of mutations in skin cells, which in turn results in a high occurrence of skin cancer. As a result, such individuals are unable to go outdoors during daylight hours. In addition to ultraviolet light, organisms are exposed to more energetic ionizing radiation in the form of cosmic rays, gamma rays, and X-rays. Ionizing radiation induces double-stranded breaks in DNA, and the resulting repair can likewise introduce mutations if carried out imperfectly.
Unlike UV light, however, these forms of radiation penetrate tissue well, so they can cause mutations anywhere in the body. Deamination , or the removal of an amine group from a base, may also occur. Deamination of cytosine converts it to uracil , which will pair with adenine instead of guanine at the next replication, resulting in a base substitution.
Repair enzymes can recognize uracil as not belonging in DNA, and they will normally repair such a lesion. However, if the cytosine residue in question is methylated a common modification involved in gene regulation , deamination will instead result in conversion to thymine. Because thymine is a normal component of DNA, this change will go unrecognized by repair enzymes Figure 6. Figure 6: Deamination is a spontaneous mutation that occurs when an amine group is removed from a nitrogenous base.
The nitrogenous base cytosine is converted to uracil after the loss of an amine group. Because uracil forms base-pairs with adenine, while cytosine forms base-pairs with guanine, the conversion of cytosine to uracil causes base substitutions in DNA.
Genetics: A Conceptual Approach , 2nd ed. Errors that occur during DNA replication play an important role in some mutations, especially trinucleotide repeat TNR expansions.
It is thought that the ability of repeat sequences to form secondary structures, such as intrastrand hairpins, during replication might contribute to slippage of DNA polymerase, causing this enzyme to slide back and repeat replication of the previous segment Figure 7. Supporting this hypothesis, lagging-strand synthesis has been shown to be particularly sensitive to repeat expansion. As previously mentioned, repeats also occur in nonmitotic tissue, and CAG repeats have further been shown to accumulate in mice defective for individual DNA repair pathways, suggesting that multiple repair mechanisms must be operative in repeat expansion in nonproliferating cells Pearson et al.
In agreement with this hypothesis, studies have revealed increased repeat instability following induction of double-stranded breaks and UV-induced lesions, which are corrected by nucleotide excision repair.
To date, all diseases associated with TNRs involve repeat instability upon transmission from parent to offspring, often in a sex-specific manner. For example, the CAG repeats that characterize Huntington's disease typically exhibit greater expansion when inherited paternally. This expansion has been shown to occur prior to meiosis, when germ cells are proliferating. Thus, mutations are not always a result of mutagens encountered in the environment.
There is a natural—albeit low—error rate that occurs during DNA replication. In most cases, the extensive network of DNA repair machinery that exists in the cell halts cell division before an incorrectly placed nucleotide is set in place and a mismatch is made in the complementary strand. However, if the repair machinery does not catch the mistake before the complementary strand is formed, the mutation is established in the cell. This mutation can then be inherited in daughter cells or in embryos if the mutation has occurred in the germ line.
Together, these different classes of mutations and their causes serve to place organisms at risk for disease and to provide the raw material for evolution. Thus, mutations are often detrimental to individuals, but they serve to diversify the overall population. Denissenko, M. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P Science , — Greenblatt, M.
Mutations in the P53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Research 54 , — International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome.
Nature , — link to article. Kimchi-Sarfaty, C. Mulligan, L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nells, E. Nature 15 , 13—14 link to article. Pearson, C. Repeat instability: Mechanisms of dynamic mutations. Nature Reviews Genetics 6 , — link to article. Seidl, H. Ultraviolet exposure as the main initiator of P53 mutations in basal cell carcinomas from psoralen and ultraviolet A-treated patients with psoriasis. Journal of Investigative Dermatology , — Twyman, R.
Mutation or polymorphism? Viguera, E. Replication slippage involves DNA polymerase pausing and dissociation. EMBO Journal 20 , — Restriction Enzymes. Genetic Mutation. Functions and Utility of Alu Jumping Genes. Transposons: The Jumping Genes. DNA Transcription. What is a Gene? Colinearity and Transcription Units. Copy Number Variation. Copy Number Variation and Genetic Disease. Copy Number Variation and Human Disease.
Tandem Repeats and Morphological Variation. Chemical Structure of RNA. Eukaryotic Genome Complexity. RNA Functions. Citation: Clancy, S. Nature Education 1 1 A single base change can create a devastating genetic disorder or a beneficial adaptation, or it might have no effect.
How do mutations happen, and how do they influence the future of a species? Aa Aa Aa. The Relationship Between Mutations and Polymorphisms. Point mutations that occur in DNA sequences encoding proteins are either silent, missense or nonsense. Silent : If abase substitution occurs in the third position of the codon there is a good chance that a synonymous codon will be generated. Thus the amino acid sequence encoded by the gene is not changed and the mutation is said to be silent.
Missence : When base substitution results in the generation of a codon that specifies a different amino acid and hence leads to a different polypeptide sequence. Depending on the type of amino acid substitution the missense mutation is either conservative or nonconservative.
Nonsense : When a base substitution results in a stop codon ultimately truncating translation and most likely leading to a nonfunctional protein. A deletion, resulting in a frameshift, results when one or more base pairs are lost from the DNA see Figure above. If one or two bases are deleted the translational frame is altered resulting in a garbled message and nonfunctional product. A deletion of three or more bases leave the reading frame intact. A deletion of one or more codons results in a protein missing one or more amino acids.
This may be deleterious or not. The insertion of additional base pairs may lead to frameshifts depending on whether or not multiples of three base pairs are inserted. Combinations of insertions and deletions leading to a variety of outcomes are also possible. On very, very rare occasions DNA polymerase will incorporate a noncomplementary base into the daughter strand.
During the next round of replication the missincorporated base would lead to a mutation. This, however, is very rare as the exonuclease functions as a proofreading mechanism recognizing mismatched base pairs and excising them.
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