Mutations
- What is meant by ‘mutation’?
- When/how do they happen?
- What sort of impact might they have?
8.7 in text
- Mutations
Some definitions
gene: a segment of nucleic acid that controls a specific trait.
Most familiarly structural genes (coding for a protein),
but also including rRNA, tRNA, and regulator sequences.
allele: one of several possible versions of a gene,
found at the same chromosomal site (gene locus)
as other alleles of the same gene.
chromosome: in eukaryotes a complete linear (double) strand of DNA
with accompanying proteins.
In prokaryotes the chromosome is circular, and there is only one.
genome: an organism’s entire complement of genetic material…
May be applied to mean only one set of chromosomes
(diploids would be said to have 2 genomes in somatic cells).
May or may not be used to include mitochondrial/chloroplast DNA.
Gene mutation (point mutation) : base pair substitution
“Wild Type”
DNA
...GCTATGACCATGATTACGGATTCACTG...
...CGATACTGGTACTAATGCCTAAGTGAC...
mRNA
↓ transcription
...GCU AUG ACC AUG AUU ACG GAU UCA CUG
Protein
↓ translation (without anticodons)
Met-Thr - Met - Ile- Thr - Asp-Ser- Leu...
Missense mutation
DNA
base swapped ↓
...GCTATGACCATGATTAGGGATTCACTG...
...CGATACTGGTACTAATCCCTAAGTGAC...
mRNA
↓ transcription
...GCU AUG ACC AUG AUU AGG GAU UCA CUG...
Protein
↓ translation
Met-Thr - Met - Ile -Arg -Asp-Ser-Leu...
In sickle-cell anemia, a point mutation, leading to a one amino acid change,
makes a significant change in the resulting hemoglobin.
Hb β → ATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACT..
Hb s → ATG GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACT..
MVHLTPEEKSAVT.. (E is the single letter abbreviation for glutamic acid)
MVHLTPVEKSAVT.. (V is the single letter abbreviation for valine)
This is the coding sequence for the entire normal β protein of hemoglobin
(there are two α and two β proteins per hemoglobin).
Here is the substituted nucleotide.
↓
ATGGTGCACCTGACTCCTGAGGAGAAGTCTGCGGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAG
TTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGG
GGATCTGTCCACTCCTGATGCAGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGT
GCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACT
GTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCA
TCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAAT
GCCCTGGCCCACAAGTATCACTAAGCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCC
CTAAGTCCAACTACTAAACTGGGGGATATTATGAAGGGCCTTGAGCATCTGGATTCTGCCTAATAAAAAA
CATTTATTTTCATTGC
Unaffected hemoglobin molecule
site of hydrophilic glutamic acids that get swapped
↓
←β chains
← heme group
←α chains
Substituting hydrophobic valine
for the glutamic
acids at that one locus
causes the hemoglobins to
clump together,
causing a series of symptoms…
http://genomics.energy.gov/
www.bio.davidson.edu/.../2005/Eppolito/intro.htm
Should fetuses be screened?
Sickle-cell trait is the inheritance
of only one copy of the gene:
This is generally asymptomatic,
and confers resistance to malaria.
so, S-C anemia is a classic illustration of
natural selection.
There are similar hemoglobin variations
in other sub-tropical
areas of the globe.
Gene mutation: substitution (cont.)
“Wild Type”
DNA
...GCTATGACCATGATTACGGATTCACTG...
...CGATACTGGTACTAATGCCTAAGTGAC...
mRNA
↓ transcription
...GCU AUG ACC AUG AUU ACG GAU UCA CUG
Protein
↓ translation (without anticodons)
Met-Thr- Met- Ile - Thr - Asp- Ser- Leu...
Nonsense Mutation
DNA
base swapped ↓
...GCTATGACCATGATTACGGATTGACTG...
...CGATACTGGTACTAATGCCTAACTGAC...
mRNA
↓ transcription
...GCU AUG ACC AUG AUU ACG GAU UGA CUG...
Protein
↓ translation
Met -Thr- Met- Ile - Thr- Asp (UGA = stop)
Gene mutations: insertion/deletion
“Wild Type”
DNA
...GCTATGACCATGATTACGGATTCACTG...
...CGATACTGGTACTAATGCCTAAGTGAC...
mRNA
↓ transcription
...GCU AUG ACC AUG AUU ACG GAU UCA CUG
Protein
↓ translation (without anticodons)
Met-Thr- Met- Ile - Thr - Asp- Ser- Leu...
Frameshift Mutation
DNA
↓ added base
...GCTATGACCCATGATTACGGATTCACTG...
...CGATACTGGGTACTAATGCCTAAGTGAC...
mRNA
↓ transcription
...GCU AUG ACC CAU GAU UAC GGA UUC ACU G...
Protein
↓ translation
Met -Thr- His -Asp-Tyr-Gly- Phe-Thr-
Example of a problem caused by a frame shift mutation:
“People with thalassemia make less hemoglobin [because the mRNA degrades faster]
and have fewer circulating red blood cells than normal, which results in mild to severe anemia.
....
“Cases of dominantly inherited α- and β-thalassemias have been reported, the first of which was in an Irish
family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β -globin gene.
....
“Having a single gene for thalassemia may protect against malaria and thus be an advantage. People diagnosed
with heterozygous β-thalassemia have some protection against coronary heart disease.”
Wikipedia
http://www.haematologica.org/content/96/6/905
Chromosomal mutations:
Usually occur when chiasmata form in prophase I.
deletion, duplication, inversion, translocation
(recap from meiosis section)
Chromosomal mutations: nondisjunction
-Occurs when chromosomes fail to properly separate in
anaphase I or anaphase II of meiosis
- Results in aneuploidy (wrong number of chromosomes),
Most aneuploidy in humans is non-viable.
Autosomal trisomy:
Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome)
Trisomy 12 (Chronic Lymphocytic
Leukemia)
Trisomy 8 (Warkany syndrome 2)
Trisomy 9
X/Y-linked aneuploidy is more likely to
be viable.
Mutations are a source of genetic variability within a population.
They can occur any time DNA is replicated and cells divide
(some occur between replications).
But the ones that have the biggest ramifications
are ones that occur in gamete formation (meiosis)
because that alteration will occur in every
cell of any resulting offspring.
What is a gene mutation?
Describe an example of a specific type.
What is a chromosomal mutation?
Describe an example of a specific type.
What is the role of complementary base pairing
in replication, in transcription, and in translation?
And how might this go wrong?
Should we be worried about all mutations?
(Hm…. That sounds like a “No”…)
Defend your answer.
gene
structural gene
allele
gene locus
chromosome
genome
gene mutation
point mutation
base pair substitution
missense mutation
nonsense mutation
insertion/deletion
frameshift mutation
chromosomal mutation
chromosomal deletion
chromosomal duplication
chromosomal inversion
chromosomal translocation
nondisjunction
aneuploidy
autosomal trisomy