Lecture 5- Mutations

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What are mutations?

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Mutations are changes in the DNA sequence. They can occur by a change in a base(s) , the loss of a base(s) or the addition of a base(s). The normal or unaffected allele of a gene is often called the "wild-type" allele. It designates the common allele in the population.

-Mutations can occur spontaneously or can be induced by various agents (mutagens--usually chemical). In either case, the only way that a mutation can be passed onto the next generation is if the mutation is produced in a germ cell.

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What is a somatic mutation?

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- genetic alteration acquired by a somatic cell that can be passed to the progeny of the mutated cell in the course of cell division. These mutations are not passed down to the next organismal generation, they are not inherited.

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What is a germline mutation?

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- Germline mutations affect very every cell in a organism and are passed on to offspring, they are heritable mutations.

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Point Mutations

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Point Mutations

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What is a missense mutation?

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- A single base change in a codon that results in a change of amino acid at that spot. Examples of disease that result form a missense point mutation: some forms of cystic fibrosis and sickle cell anemia

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What is a nonsense mutation?

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A change in a codon that results in a stop codon and premature terminations of the protein (Stop codons are UAA, UAG, and UGA). Nonsense mutations are designated with that name because they result in a truncated, or non-functional protein. Importantly nonsense mutations do not shorten the mRNA, they only shorten the protein. Disease example: the blood disorder Thalassemia can be caused by a nonsense mutation in the beta globin gene.

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What is a silent mutation?

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-A single base change that does not change the identity of the amino acid. This has no consequence for the protein.

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What happens in a frameshift mutation?

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-If the insertion or deletion is 1 or 2 bases, this will result in a frameshift mutation. A frameshift results in the rest of the protein not making "sense", since each codon starting with the position of the insertion or deletion will different from what it was before. Disease example: Tay-sachs is often caused by an insertion of 4 nucleotides.

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What happens when the insertion or deletion of exactly three bases?

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-An insertion or deletion of exactly three bases in frame would not result in a frame shift because the three added or deleted bases would code for a single amino acid and would not throw off the "reading frame". However an insertion of three bases in the middle of a codon would also cause a frameshift. Disease example: the most common cause of cystic fibrosis is the deletion of one amino acid.

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What happens in expanding repeats?

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-This is an unusual form of mutation in which a sequence actually lengthens form generation to generation. The symptoms associated with such mutations often worsen as the particular region expands in length. This phenomenon is called "anticipations" Triplet repeats are sometimes within genes, and other times, are in introns or other regions between genes. While rare, this type of mutation causes several important disease including Fragile X Syndrome and Huntington Disease.

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What happens during myotonic dystrophy?

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Myotonic dystrophy, which is an autosomal dominant trait, becomes more severe with each generation. It becomes worse worse in each generation because the gene expands. In the gene is the trinucleotide CTG, which is normally present in 5- 37 copies ( a variable number, even in unaffected individuals). Mildly affected individuals have 50-100 copies. Moderate limb weakness is associated with 100-700 copies. Severely affected individuals have greater than 1000 copies. The mutations occur in a NON-CODING region of the dystrophin gene. Even though the repeats are in an intron, they still affect the function of the protein. It is hypothesized that the mRNA gets so big that it cannot be transported out of the nucleus to the cytoplasm.

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Note 1

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A mutation in the DNA such as those described above will be transcribed into the RNA as well. Mutations DO NOT STOP transcription (unless they occur in the promoter region, then they can alter the amount of mRNA transcribed). An insertion or a deletion can change the length of an mRNA because it changes the length of the DNA. But single changes in DNA sequences will be faithfully copied into mRNA. Thus, nonsense and missense mutations do not change the length of the mRNA, but rather effect translation

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Note 2

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Only mutations in DNA will be copied or carried on (inherited) from cell to cell or person to person. Remember that you inherit DNA form your parents, not mRNA and not protein. Thus, even if a mutation does occur in an mRNA, only that mRNA will have the mutation. Any other mRNAs made from a DNA sequence will be normal... unless the DNA sequence itself is changed.

-Heritabel mutations occur in DNA, not mRNA or protein.

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How can the location of a DNA change can alter its effect?

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- The particular position of a mutation is important for considering what treatments may be possible, since a mutation may not affect a protein, or could affect protein structure, or could even affect the production of protein.

1.) A mutation can occur in the DNA that encodes a protein.

2.) It can occur in the splice site between an exon and an intron. This might alter the splicing pattern, causing the omission of an exon or leaving allowing an intron to remain in the processed mRNA for instance.

3.) It can occur in an intron, or in DNA that's between genes. This may also have implications for mRNA processing for Myotonic dystrophy above.

4.) It can occur in the promoter region. A mutation here would affect the amount of transcription of mRNA from that DNA, and hence could affect the level of translation and thus the levels of that protein in the body.

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How can we relate changes in DNA to phenotype?

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-Changes in DNA can alter protein function or the amount of a protein that is produced. This can create an observable change in an organism (for instance a person) that we call a phenotype.

-When a person is heterozygous for a particular gene (when they have two different alleles, or DNA sequences, of that gene) they will have two different mRNA and protein sequences as well. When an allele is recessive it is because having o the amount of health protein is sufficient for a normal phenotype.

-Sometimes having 50% protein from the disease allele and 50% protein from the health allele will cause an in between phenotype. T his because 50% of the healthy protein is not enough to maintain normal function of the cell. In this case we observe "incomplete dominance"

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Why might the point mutations in the cystic fibrosis lead to a less severe variant of the disease than the deletion mutation?

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1

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Compare two kinds of mutations and the effects they have on mRNA and protein.

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2

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What is a mutation?

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- A mutation is a change in a genes's nucleotide base sequence that is rare in a population and can cause a mutant phenotype. A polymorphism is a more common and typically less harmful genetic change.

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What is the difference between the germline mutation and a somatic mutation?

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- A germline mutation originates in meiosis, affects all cells of an individual, and can be transmitted to the next generation in gametes. A somatic mutation originates in mitosis and affects a subset of cells.

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What effects does a mutation have?

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- A mutation disrupts the function or abundance of a protein or introduces a new function. Most loss-of-function mutations are recessive, and most gain-of-function mutations are dominant.

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Where can mutations cause a variety of disorder?

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- Mutations in the beta globin and collagen genes cause a variety of disorders.

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Why is nomenclature inconsistent?

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-Whether different mutations in a gene cause the same or distinct illness varies; nomenclature is inconsistent.

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What are allelic disorders?

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- Allelic disorder have different phenotypes but result from mutations in the same gene.

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What are spontaneous mutation?

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- A spontaneous mutation arise due to chemical phenomena or to an error in DNA replication. Spontaneous mutation rate is characteristic of a gene and is more likely in repeats. In gonadal mosaicism, only some gametes a spontaneous mutation.

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What are mutagens?

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-Mutagens are chemicals or radiation that delete, substitute, or add bases. An organism may be exposed to a mutagen intentionally, accidentally, or naturally.

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What is the difference between a transition and a trnasversion? Missense and Nonsense?

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- A point mutation alters a single DNA base. It may be a transition (urine to purine or pyrimidine to pyrimidine) or a transversion ( purine to pyrimidine or vice versa). A missense mutation substitutes one amino acid for another, while a nonsense mutation substitutes a "stop" codon for a codon that specifies an amino acid, shortening the protein product. Splice-site mutation add or delete amino acids.

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What is a deletion mutation, insertion mutation, frameshift mutation, and tandem duplication?

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-A deletion removes genetic material and an insertion mutation adds it. A frameshift mutation alters the sequence of amino acids (reading frame). A tandem duplication is a copy of a gene next to the original.

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How does a pseudogene occur?

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- A pseudogene results when a duplicate of a gene mutates. It may disrupt chromosome pairing, causing mutation.

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Transposons

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-Transposons may disrupt the functions of genes they jump into.

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What are expanding repeat mutations?

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-Expanding repeat mutations add stretches of the same amino acid to a protein. they expand because they attract each other, which affects replication

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What are copy number variants?

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- Copy number variants are DNA sequences that are repeated a different number of times among individuals. They may have no effect on phenotype or may directly or indirectly cause disease.

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What effects can mutations have in globin genes?

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-Mutations in the globin genes may affect the ability of the blood to transport oxygen, or they may have no effect.

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What are the effects of synonymous codons?

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- Synonymous codons limit the effects of mutation. Changes in the second codon position may substitute a similarly shaped amino acid

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What are conditional mutations?

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- Conditional mutations are expressed only in response to certain environmental triggers.

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How can there be protection against mutation?

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Sending the most recently replicated DNA into cells headed for differentiation, while sending older strands into stem cells, protects against mutation.

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What is the function of DNA polymerase?

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-DNA polymerase proofreads DNA, but repair enzymes correct error in other ways

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Photoreactivation repair

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Photoreactivation repair uses light energy to split pyrimidine dimers.

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What is excision repair, nucleotide excision repair, and base excision repair?

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- In excision repair, pyrimidine dimers are removed and the area filled in correctly. Nucleotide excision repair replaces up to 30 nucleotides from various sources of mutation. Base excision repair fixes up to five bases that paired incorrectly due to oxidative damage.

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What is a mismatch repair?

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-Mismatch repair proofreads newly replicated DNA for loops that indicate noncomplementary base pairing.

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DNA repair

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- DNA repair fixes the sugar-phosphate backbone. Damage tolerance enables replication to continue beyond a mismatch

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DNA repair

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-Mutations in repair genes break chromosomes and increase cancer risk.