Medical Genetics Wk 8 Flashcards
Gene Mutations Are Classified in Various Ways
A mutation can be defined as an alteration in the nucleotide sequence of an organism’s genome. Any base- pair change in any part of a DNA molecule can be considered a mutation. Mutations are a source of genetic variation and provide the raw material for natural selection. They are also the source of genetic damage that contributes to cell death, genetic diseases, and cancer. Gene mutations occur primarily in the base-pair sequence of DNA within and surrounding individual genes. Because of the wide range of types and effects of mutations, geneticists classify mutations according to several different schemes.
Classification Based on Type of Molecular Change
Classification Based on Effect on Function
Classification Based on Location of Mutation
Classification Based on Type of Molecular Change
Geneticists often classify gene mutations in terms of the nucleotide changes that constitute the mutation. A change of one base pair to another in a DNA molecule is known as a point mutation, or base substitution.
Missense mutation - A change of one nucleotide of a triplet within a proteincoding portion of a gene may result in the creation of a new triplet that codes for a different amino acid in the protein product
Nonsense mutation - The triplet will be changed into a stop codon, resulting in the termination of translation of the protein.
Silent mutation - The point mutation alters a codon but does not result in a change in the amino acid at that position in the protein (due to degeneracy of the genetic code).
Neutral mutations – Mutations that occur in noncoding regions.
Most silent mutations, which do not change the amino acid sequence of the encoded protein, can also be considered neutral mutations. However, some silent mutations may alter a DNA sequence that codes for regulatory function, such as an RNA splicing signal, resulting in an altered protein and a discernible phenotype.
Classification Based on Type of Molecular Change /cont./
Two other terms used to describe base substitutions are transition and transversion. If a pyrimidine replaces a pyrimidine or a purine replaces a purine, a transition has occurred. If a purine replaces a pyrimidine, or vice versa, a transversion has occurred.
Classification Based on Type of Molecular Change /cont./
The loss or addition of a single nucleotide causes all of the subsequent three-letter codons to be changed. These are called frameshift mutations because the frame of triplet reading during translation is altered. A frameshift mutation will occur when any number of bases are added or deleted, except multiples of three, which would reestablish the initial frame of reading. It is possible that one of the many altered triplets will be UAA, UAG, or UGA, the translation termination codons. When one of these triplets is encountered during translation, polypeptide synthesis is terminated at that point. Obviously, the results of frameshift mutations can be very severe, such as producing a truncated protein or defective enzymes, especially if they occur early in the coding sequence.
Classification Based on Type of Molecular Change /cont./
Experimental evidence supporting the triplet nature of the code was subsequently derived from research by Francis Crick and his colleagues. Using phage T4, they studied frameshift mutations, which result from the addition or deletion of one or more nucleotides within a gene and subsequently the mRNA transcribed from it. The gain or loss of letters shifts the reading frame during translation. Crick and his colleagues found that the gain or loss of one or two nucleotides caused a frameshift mutation, but when three nucleotides were involved, the frame of reading was reestablished (Figure). This would not occur if the code was anything other than a triplet.
The effect of frameshift mutations on a DNA sequence with the repeating triplet sequence GAG. (a) The insertion of a single nucleotide shifts all subsequent triplet reading frames. (b) The insertion of three nucleotides changes only two triplets, but the frame of reading is then reestablished to the original sequence.
Classification Based on Type of Molecular Change /cont./
Analogy showing the effects of substitution, deletion, and insertion of one letter in
a sentence composed of three-letter words to demonstrate point and frameshift mutations.
Classification Based on Effect on Function
A new phenotype results from a change in functional activity of the cellular product specified by that gene. Often, the mutation causes the diminution or the loss of the specific wild-type function. For example, if a gene is responsible for the synthesis of a specific enzyme, a mutation in that gene may ultimately change the conformation of this enzyme and reduce or eliminate its affinity for the substrate. Such a mutation is designated as a loss-of-function mutation. If the loss is complete, the mutation has resulted in what is called a null allele. Other mutations may enhance the function of the wild-type product. Most often when this occurs, it is the result of increasing the quantity of the gene product. For example, the mutation may be affecting the regulation of transcription of the gene under consideration. Such mutations, designated gain-of-function mutations, most often result in dominant alleles, since one copy of the mutation in a diploid organism is sufficient to alter the normal phenotype.
Gain-of- function mutations
Loss-of- function mutations
Classification Based on Effect on Function
Loss-of-function mutation is one that reduces or eliminates the function of the gene product. Most loss-of-function mutations are recessive.
Mutations that result in complete loss of function are known as null mutations. A recessive mutation results in a wild-type phenotype when present in a diploid organism and the other allele is wild type.
Some loss-of-function mutations can be dominant. A dominant mutation results in a mutant phenotype in a diploid organism, even when the wild-type allele is also present. Dominant mutations in diploid organisms can have several different types of effects.
A dominant negative mutation in one allele may encode a gene product that is inactive and directly interferes with the function of the product of the wild-type allele.
Haploinsufficiency, which occurs when one allele is inactivated by mutation, leaving the individual with only one functional copy of a gene.
In humans, Marfan syndrome is an example of a disorder caused by haploinsufficiency—in this case as a result of a loss-of-function mutation in one copy of the fibrillin-1 (FBN1) gene.
Classification Based on Effect on Function /cont./
Gain-of-function mutation codes for a gene product with enhanced, negative, or new functions.
This may be due to a change in the amino acid sequence of the protein that confers a new activity, or it may result from a mutation in a regulatory region of the gene, leading to expression of the gene at higher levels or at abnormal times or places. Typically, gain-of-function mutations are dominant.
Examples of gain-of-function mutations include the genetic conversion of proto-oncogenes, which regulate the cell cycle, to oncogenes, where regulation is overridden by excess gene product. The result is the creation of a cancerous cell.
Classification Based on Effect on Function /cont./
A suppressor mutation is a mutation that either reverts or relieves the effects of a previous mutation. A suppressor mutation may be two types:
Intragenic suppressor mutation - A suppressor mutation can occur within the same gene that suffered the first mutation.
Example of an intragenic suppressor mutation is one that creates a codon specifying a correct (or similar) amino acid, so as to restore function to a mutated gene product. For instance, if the first mutation changed the sequence 5’-TTA-3’ (which codes for leucine) to 5’-GTA-3’ (which codes for valine), then a second mutation occurring in the valine codon, changing it to 5’-CTA-3’, would restore the codon to one that codes for leucine.
Intergenic suppressor mutation - A suppressor mutation can
occur elsewhere in the genome
An example of a mutation that would act as an intergenic suppressor mutation would be as follows. A mutated gene may encode a protein whose structure has been altered so that it will not interact with another protein with which it would normally interact. If the gene encoding the second protein acquires a mutation that alters the structure of its gene product in such a way that it can now interact with the first mutant protein, the second mutation would be considered an intergenic suppressor mutation.
Classification Based on Effect on Function /cont./
Depending on their type and location, mutations can have a wide range of phenotypic effects, from none to severe. Some examples of mutation types based on their phenotypic outcomes are listed in Table.- look at GOODNOTES
Classification Based on Location of Mutation
Mutations may be classified according to the cell type or chromosomal locations in which they occur.
Somatic mutations are those occurring in any cell in the body except germ cells.
Germ-line mutations occur only in germ cells.
Hereditary (germline mutations) mutations are inherited from a parent and are present throughout a person’s life in virtually every cell in the body.
Acquired (or somatic) mutations occur at some time during a person’s life and are present only in certain cells, not in every cell in the body. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Mutations arising in somatic cells are not transmitted to future generations
Classification Based on Location of Mutation /cont./
Autosomal mutations are mutations within genes located on the autosomes.
X-linked and Y-linked mutations are those within genes located on the
X or Y chromosome, respectively.
Inherited dominant autosomal mutations will be expressed phenotypically in the first generation. X-linked recessive mutations arising in the gametes of a female (the homogametic sex; having two X chromosomes) may be expressed in male offspring, who are by definition hemizygous for the gene mutation because they have one X and one Y chromosome. This will occur provided that the male offspring receives the affected X chromosome. Because of heterozygosity, the occurrence of an autosomal recessive mutation in the gametes of either males or females (even one resulting in a lethal allele) may go unnoticed for many generations, until the resultant allele has become widespread in the population. Usually, the new allele will become evident only when a chance mating brings two copies of it together into the homozygous condition.
SICKLE CELL DISEASE (β-Globin Glu6Val Mutation)
MAJOR PHENOTYPIC FEATURES
• Age at onset: Childhood • Anemia
• Infarction
• Asplenia
Sickle cell disease is an autosomal recessive disorder of hemoglobin in which the β subunit genes have a
missense mutation that substitutes valine for glutamic acid at amino acid 6. Hemoglobin is composed of four subunits, two α subunits encoded by HBA on chromosome 16 and two β subunits encoded by the HBB gene on chromosome 11. The Glu6Val mutation in β-globin decreases the solubility of deoxygenated hemoglobin and causes it to form a gelatinous network of stiff fibrous polymers that distort the red blood cell, giving it a sickle shape (see Fig.). These sickled erythrocytes occlude capillaries and cause infarctions.
Sickle cell disease - symptoms
Swollen hands and feet
Visual problems
Fever
Delayed growth
Pale skin
Late puberty
