Genetics 19
HC 10-14
19.1
DNA contains our genetic material and in theory does not change over time; however,
mutations can appear which refer to a heritable, permanent structural change in the genetic
material. These mutations can exert phenotypic effects, either detrimental or beneficial; in
both ways, they preserve the continuity of life, they give the variation needed to adapt and
are the foundation for evolutionary change. Nevertheless, mutations also bring about
negative effects and many diseases. Because mutations can be harmful, organisms derived
ways to repair damaged DNA, though these mechanisms are most often the underlying
cause of mistakes. But how in general do mutations affect phenotypes? There are three
levels of mutations:
1. Chromosome mutations: changes in chromosome structure; deletion, duplication,
inversion, transition, etc.
2. Genome mutations: changes in chromosome number; euploidy, aneuploidy.
3. Small mutations: 1 up to a few base changes within a particular gene or promoter.
The latter is more extensively discussed in the following. A gene mutation occurs when the
sequence of DNA is altered in a permanent way:
- Point mutation change in single base pair.
o Base substitution: one base is substituted by another,
Transition: when a purine gets substituted by another purine (A-G), or
pyrimidine-pyrimidine (T-C). These are more common, because they
have minimal change regarding the structure of the base.
Transversion: when a purine gets substituted by a pyrimidine. This
sets forth a major change, so has more drastic effects.
o Deletion or addition
A mutation in the coding sequence affects the amino acid sequence and therefore also the
protein, which carries along phenotypic effects. There are various effects of point mutations:
- Silent mutation: do not alter amino acid sequence, because of the degeneracy of the
genetic code (the wobble base) the same amino acid can be built in for a different
code. However, it does not always have to be silent, because some codons have
more tRNAs associated, so there’s a higher transcription rate; if due to a silent
mutation the codon is associated with another tRNA that appears in much less
amount, the transcription rate is lowered, causing lower protein expression.
- Missense mutation: base mutations whereby a codon that coded for one amino acid
is changed in such a way, that it codes for another amino acid.
- Nonsense mutation: a normal amino acid coding codon mutates into a stop codon,
arresting/shortening the polypeptide dramatically and unexpectedly.
- Frameshift: concerns deletions and additions, which delete or incorporate a base.
Normally, the code is read in multiples of three, but if one base is taken out or
added, the multiple is influenced and different codons of three amino acids are read;
the reading frame shifts. This gives rise to a completely different amino acid.
The last two have the most dramatic, mainly inhibitory, effects on phenotype and protein
expression. Missense mutations usually involve one amino acid, whereas a protein has
hundreds, so the effect is less detectable; gives a neutral mutation.
, It must be noticed, that mutations in the coding region do not merely affect the phenotype,
also mutations in non-coding regions can have certain effects, since it can influence gene
expression. Mutations in the (core) promoter region can either increase expression (up
promoter mutation) or decrease affinity and so expression (down promoter mutation).
Moreover, mutations in the 5’ UTR may affect translation (by influencing Kozak’s rule) and
those in splice recognition sites affect splicing, like proteins that cannot recognise intron-
exon boundaries due to mutations and thus splice the exon out. Also microRNA can affect
translation, because normally it would bind to the mRNA and inhibit translation, but due
mutations this cannot happen and there is no inhibition of protein synthesis and it might be
overexpressed.
Gene mutations can affect the wild-type – the most prevalent genotype in a population, like
the consensus – and can even change the DNA sequence so that the mutation is rare in the
population, giving a mutant allele; a forward mutation gave a new variation that differs from
the wild-type; a mutant/variant. Reversion changes the mutant allele back to the wild-type
allele. Mutations also can affect phenotype, there are variants then:
- Deleterious mutations: decreases chance of survival and reproduction
o Lethal mutations: death of an organism
- Beneficial mutations: enhances survival and/or reproductive success. A mutation
new allele selection evolutionary change/success.
- Conditional mutants: phenotype merely affected under certain conditions.
A second mutations sometimes affects the first mutation, who are then termed suppressor
mutations; suppresses phenotypic effects of another mutation. It differs from reversion,
because it happens at another site in the DNA. The site can be within the same gene;
intragenic suppressor change in protein structure that compensates first mutations. The
site can also be in a different gene; intergenic suppressor involve a change in the
expression of one gene that compensates for the loss-of-function of another, like another
protein with a similar structure that takes over its job.
In the bigger picture, a chromosomal rearrangement might cause a chromosomal break
point (two pieces break and re-join with other chromosome pieces) in the middle of a gene,
affecting its function. A gene could also be left intact but still lose its function when moved
to a new location; position effect. Inversions and translocations might cause genes to move
next to an enhancer/silencer, influencing its expression, or position genes in euchromatic or
heterochromatic regions, where they are not supposed to be.
The timing of a mutation in multicellular species proves critical for the severity of the effect
and whether or not the mutation is passed on to offspring. Along these lines, germ line
mutations happen directly in germ cells – give rise to gametes – like sperm or precursors
thereof, which may pass the mutation to the offspring. Though, the mutation is apparent in
the whole body, it is only expressed in cells that create the protein associated with it.
Somatic mutations happen in somatic cells – all bodily cells except germ line – at any time
during the development but are not heritable like germ-line mutations. An example is
cancer. If it happens early in embryonic development, the adult organism will carry the
mutations in a large patch of cells, but not in the gametes. Such a region that differs
genotypically from the rest gives genetic mosaic.
19.2
Skip this paragraph.
HC 10-14
19.1
DNA contains our genetic material and in theory does not change over time; however,
mutations can appear which refer to a heritable, permanent structural change in the genetic
material. These mutations can exert phenotypic effects, either detrimental or beneficial; in
both ways, they preserve the continuity of life, they give the variation needed to adapt and
are the foundation for evolutionary change. Nevertheless, mutations also bring about
negative effects and many diseases. Because mutations can be harmful, organisms derived
ways to repair damaged DNA, though these mechanisms are most often the underlying
cause of mistakes. But how in general do mutations affect phenotypes? There are three
levels of mutations:
1. Chromosome mutations: changes in chromosome structure; deletion, duplication,
inversion, transition, etc.
2. Genome mutations: changes in chromosome number; euploidy, aneuploidy.
3. Small mutations: 1 up to a few base changes within a particular gene or promoter.
The latter is more extensively discussed in the following. A gene mutation occurs when the
sequence of DNA is altered in a permanent way:
- Point mutation change in single base pair.
o Base substitution: one base is substituted by another,
Transition: when a purine gets substituted by another purine (A-G), or
pyrimidine-pyrimidine (T-C). These are more common, because they
have minimal change regarding the structure of the base.
Transversion: when a purine gets substituted by a pyrimidine. This
sets forth a major change, so has more drastic effects.
o Deletion or addition
A mutation in the coding sequence affects the amino acid sequence and therefore also the
protein, which carries along phenotypic effects. There are various effects of point mutations:
- Silent mutation: do not alter amino acid sequence, because of the degeneracy of the
genetic code (the wobble base) the same amino acid can be built in for a different
code. However, it does not always have to be silent, because some codons have
more tRNAs associated, so there’s a higher transcription rate; if due to a silent
mutation the codon is associated with another tRNA that appears in much less
amount, the transcription rate is lowered, causing lower protein expression.
- Missense mutation: base mutations whereby a codon that coded for one amino acid
is changed in such a way, that it codes for another amino acid.
- Nonsense mutation: a normal amino acid coding codon mutates into a stop codon,
arresting/shortening the polypeptide dramatically and unexpectedly.
- Frameshift: concerns deletions and additions, which delete or incorporate a base.
Normally, the code is read in multiples of three, but if one base is taken out or
added, the multiple is influenced and different codons of three amino acids are read;
the reading frame shifts. This gives rise to a completely different amino acid.
The last two have the most dramatic, mainly inhibitory, effects on phenotype and protein
expression. Missense mutations usually involve one amino acid, whereas a protein has
hundreds, so the effect is less detectable; gives a neutral mutation.
, It must be noticed, that mutations in the coding region do not merely affect the phenotype,
also mutations in non-coding regions can have certain effects, since it can influence gene
expression. Mutations in the (core) promoter region can either increase expression (up
promoter mutation) or decrease affinity and so expression (down promoter mutation).
Moreover, mutations in the 5’ UTR may affect translation (by influencing Kozak’s rule) and
those in splice recognition sites affect splicing, like proteins that cannot recognise intron-
exon boundaries due to mutations and thus splice the exon out. Also microRNA can affect
translation, because normally it would bind to the mRNA and inhibit translation, but due
mutations this cannot happen and there is no inhibition of protein synthesis and it might be
overexpressed.
Gene mutations can affect the wild-type – the most prevalent genotype in a population, like
the consensus – and can even change the DNA sequence so that the mutation is rare in the
population, giving a mutant allele; a forward mutation gave a new variation that differs from
the wild-type; a mutant/variant. Reversion changes the mutant allele back to the wild-type
allele. Mutations also can affect phenotype, there are variants then:
- Deleterious mutations: decreases chance of survival and reproduction
o Lethal mutations: death of an organism
- Beneficial mutations: enhances survival and/or reproductive success. A mutation
new allele selection evolutionary change/success.
- Conditional mutants: phenotype merely affected under certain conditions.
A second mutations sometimes affects the first mutation, who are then termed suppressor
mutations; suppresses phenotypic effects of another mutation. It differs from reversion,
because it happens at another site in the DNA. The site can be within the same gene;
intragenic suppressor change in protein structure that compensates first mutations. The
site can also be in a different gene; intergenic suppressor involve a change in the
expression of one gene that compensates for the loss-of-function of another, like another
protein with a similar structure that takes over its job.
In the bigger picture, a chromosomal rearrangement might cause a chromosomal break
point (two pieces break and re-join with other chromosome pieces) in the middle of a gene,
affecting its function. A gene could also be left intact but still lose its function when moved
to a new location; position effect. Inversions and translocations might cause genes to move
next to an enhancer/silencer, influencing its expression, or position genes in euchromatic or
heterochromatic regions, where they are not supposed to be.
The timing of a mutation in multicellular species proves critical for the severity of the effect
and whether or not the mutation is passed on to offspring. Along these lines, germ line
mutations happen directly in germ cells – give rise to gametes – like sperm or precursors
thereof, which may pass the mutation to the offspring. Though, the mutation is apparent in
the whole body, it is only expressed in cells that create the protein associated with it.
Somatic mutations happen in somatic cells – all bodily cells except germ line – at any time
during the development but are not heritable like germ-line mutations. An example is
cancer. If it happens early in embryonic development, the adult organism will carry the
mutations in a large patch of cells, but not in the gametes. Such a region that differs
genotypically from the rest gives genetic mosaic.
19.2
Skip this paragraph.
