TNBGGA: The No Bullshit Guide to Genetic Analysis

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chapter_08 [2024/08/31 17:33] – [Types of mutations based on DNA alteration] mikechapter_08 [2025/03/09 12:05] (current) – [Types of mutations based on DNA alteration] mike
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 +<-chapter_07|Chapter 07^table_of_contents|Table of Contents^chapter_09|Chapter 09->
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 +<typo fs:x-large>Chapter 08. %%Mutations and suppressors%%</typo>
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 A major goal of genetic analysis is to discover new genes and to understand their function. Geneticists use mutations to perturb gene function as a general strategy to study genes. In many ways it's the same conceptual approach that toddlers use to figure how things work in the world - you break things one at a time and see what happens.  A major goal of genetic analysis is to discover new genes and to understand their function. Geneticists use mutations to perturb gene function as a general strategy to study genes. In many ways it's the same conceptual approach that toddlers use to figure how things work in the world - you break things one at a time and see what happens. 
  
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 ^  Mutation type  ^  Description  ^ ^  Mutation type  ^  Description  ^
-|  Missense  |A base change that converts one nucleotide base into another. Many missense mutations are silent because the encoded amino acid remains the same or the amino acid substitution is sufficiently subtle so as not to compromise activity of the enzyme. Missense mutations that have a marked effect often affect the active site of an enzyme or grossly disrupt protein folding.  |+|  Silent   |A base change that converts one nucleotide base into another, but does not result in any change in amino acid incorporated into the protein encoded by the gene. Except in extremely rare cases involving something called RNA editing (not discussed in this book), these kinds of mutations almost never have an effect on the phenotype.  | 
 +|  Missense  |A base change that converts one nucleotide base into another, leading to a change in the amino acid that is incorporated into the protein encoded by the gene. Not all missense mutations have obvious mutant phenotypes; in some cases the amino acid substitution is sufficiently subtle so as not to compromise activity of a protein. Missense mutations that have a marked effect often affect the active site of an enzyme or grossly disrupt protein folding.  |
 |  Nonsense  |A base change that converts a codon within the coding sequence into a stop codon. Note that there is only a limited set of sense codons that can be converted to a stop codon by a single base change. Nonsense mutations lead to a truncated (shortened) protein product. Nonsense mutations that occur early in the gene sequence will completely inactivate the gene. Sometimes nonsense mutations that occur late in the gene sequence will not disrupt gene function.  | |  Nonsense  |A base change that converts a codon within the coding sequence into a stop codon. Note that there is only a limited set of sense codons that can be converted to a stop codon by a single base change. Nonsense mutations lead to a truncated (shortened) protein product. Nonsense mutations that occur early in the gene sequence will completely inactivate the gene. Sometimes nonsense mutations that occur late in the gene sequence will not disrupt gene function.  |
-|  Indel  |"Indel" is a portmanteau of "insertion and/or deletion"; an indel is the addition or deletion of a base or bases. If the number of bases added or deleted is not a multiple of three, this causes the coding sequence to be shifted out of register; this is called a frameshift mutation. Addition or deletion of a multiple of three bases does not cause a frameshift, and such an indel may or may not affect gene function. After a frameshift mutation is encountered during translation, missense codons will be read up to the first stop codon. Like nonsense mutations, frameshift mutations usually lead to complete inactivation of the gene.  |+|  Indel  |"Indel" is a portmanteau of "insertion and/or deletion"; an indel is the addition or deletion of a base or bases. If the number of bases added or deleted is not a multiple of three, this causes the coding sequence to be shifted out of register; this is called a frameshift mutation. Addition or deletion of a multiple of three bases does not cause a frameshift, and such an indel may or may not affect gene function. After a frameshift mutation is encountered during translation, missense codons will be read up to the first stop codon. Like nonsense mutations, frameshift mutations usually lead to complete inactivation of the gene. Indels created by most chemical mutagens such as proflavine or acridine orange are usually just insertions or deletions of single bases.  |
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 ^  Mutation type  ^  Description  ^ ^  Mutation type  ^  Description  ^
-|  Amorphic  |  a mutant allele that has 0% activity. Also called a null mutation.  | +|  Amorphic  |a mutant allele that has 0% activity. Also called a null mutation or a complete loss of function mutation.  | 
-|  Hypomorphic  |  a mutant allele that produces less than 100% of activity.  | +|  Hypomorphic  |a mutant allele that produces less than 100% of activity. Also called a partial loss of function mutation.  | 
-|  Hypermorphic  |  a mutant allele that produces greater than 100% of activity  | +|  Hypermorphic  |a mutant allele that produces greater than 100% of activity. Also called a gain of function mutation.  | 
-|  Antimorphic  |  a mutant allele, that when combined with $lacZ^+$ as a merodiploid (more about this Chap. 9) produces less than 100% activity.  | +|  Antimorphic  |a mutant allele, that when combined with $lacZ^+$ as a merodiploid (more about this [[chapter_09|Chap. 09]]) produces less than 100% activity. Also called a dominant negative mutation.  | 
-|  Neomorphic  |  a mutant allele that has a different function as $lacZ$. For instance, it might have a new enzymatic function that acts on glucose and glucose analogs instead of galactose.  |+|  Neomorphic  |a mutant allele that has a different function as $lacZ$. For instance, it might have a new enzymatic function that acts on glucose and glucose analogs instead of galactose.  Can also be called a gain of function mutation.  |
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-Mutations occur spontaneously in nature; this is the driving force behind evolution. Naturally occurring mutations can occur due to the inherent error rate of DNA polymerase or naturally occurring mutagens from environmental sources such as natural sources of radiation or certain kinds of foods. However, natural mutation rates are very low. As an interesting historical note, the Drosophila $white$ mutation we learned about in [[chapter-04|Chapter 04]] was a spontaneous mutation that Morgan found by sheer luck (although he was smart enough to recognize its value). But Morgan quickly realized that if he wanted more mutants to study, he would have to increase the mutation rate experimentally. +Mutations occur spontaneously in nature; this is the driving force behind evolution. Naturally occurring mutations can occur due to the inherent error rate of DNA polymerase or naturally occurring mutagens from environmental sources such as natural sources of radiation or certain kinds of foods. However, natural mutation rates are very low. As an interesting historical note, the Drosophila $white$ mutation we learned about in [[chapter_04|Chapter 04]] was a spontaneous mutation that Morgan found by sheer luck (although he was smart enough to recognize its value). But Morgan quickly realized that if he wanted more mutants to study, he would have to increase the mutation rate experimentally. 
  
 ==== Chemical mutagens ==== ==== Chemical mutagens ====
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   * Base analogs are chemicals that resemble deoxyribonucleotides and can be incorporated into DNA by DNA polymerase. However, they mis-pair with regular dNTPs, so after a round of DNA replication the wrong dNTP is incorporated into the newly synthesized ssDNA strand.    * Base analogs are chemicals that resemble deoxyribonucleotides and can be incorporated into DNA by DNA polymerase. However, they mis-pair with regular dNTPs, so after a round of DNA replication the wrong dNTP is incorporated into the newly synthesized ssDNA strand. 
   * Base modifying agents are chemicals that react with the G, A, T, or C bases and alter their structure such that they mis-pair regular dNTPs. For instance, ethyl methanesulfonate (EMS) is an alkylating agent that reacts with the guanine (G) bases in DNA, converting them to O<sup>6</sup>-ethylguanine). This modified base pairs with a T, whereas G normally pairs with C. This means that after a round of DNA replication, a G/C pair will change into an A/T pair. EMS is very commonly used in genetics research to generate mutants.    * Base modifying agents are chemicals that react with the G, A, T, or C bases and alter their structure such that they mis-pair regular dNTPs. For instance, ethyl methanesulfonate (EMS) is an alkylating agent that reacts with the guanine (G) bases in DNA, converting them to O<sup>6</sup>-ethylguanine). This modified base pairs with a T, whereas G normally pairs with C. This means that after a round of DNA replication, a G/C pair will change into an A/T pair. EMS is very commonly used in genetics research to generate mutants. 
-  * Intercalating agents do not chemically modify DNA. Instead, they cause DNA polymerase to slip or stutter so that it randomly adds or deletes bases while replicating DNA. Proflavin was famously used by Francis Crick in ridiculously complicated bacteriophage genetic experiments to demonstrate that the genetic code is a continuous triplet code. +  * Intercalating agents do not chemically modify DNA. Instead, they cause DNA polymerase to slip or stutter so that it randomly adds or deletes bases while replicating DNA. Proflavin was famously used by [[wp>francis_crick|Francis Crick]] in ridiculously complicated bacteriophage genetic experiments to demonstrate that the genetic code is a continuous triplet code. 
  
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chapter_08.1725150792.txt.gz · Last modified: 2024/08/31 17:33 by mike