Genetics Lec 1 Ex1

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Mutations can affect either

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somatic or germline cells

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Types of Mutation in Human Disease

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Genome Mutation, Chromosome Mutation, Gene Mutations

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Genome Mutation caused by

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chromosome missegregation. Can result in aneuploidy (An extra or missing chromosome)

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Chromosome Mutation caused by

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Caused by chromosome rearrangements.
Approximate frequency = 6x10-4/cell division
• Can result in translocations

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Gene Mutations caused by

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base mutations.
Approximate frequency = 10-10/base pair/ cell division, 10-5 -10-6/locus/ generation
• Can result in point mutations, deletions, and insertions

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Missense mutations
Nonsense mutations
RNA splicing mutations

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AA substitution
premature stop codon
intron/exon splice sites

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Frameshift mutation characteristics

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(# bases NOT multiple of 3)

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Codon deletion/insertion characteristics

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(# base a multiple of 3)

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Gene deletions/duplications characteristics

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(unequal cross-over)

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Insert repeat elements characteristics

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(interrupts coding sequence)

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Types of Point Mutations

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Transitions
purine ↔ purine
pyrimidine ↔ pyrimidine
example: GC ↔ AT
• Transversions
purine ↔ pyrimidine
example: GC ↔ CG

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Three Rules Govern the Genetic Code

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Codons are read in the 5´ to 3´ direction.
• Codons are non-overlapping and the message contains no gaps.
• The message is translated in a fixed reading frame, which is set by the initiation
codon.

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See example mutations

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page 3

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Structure of a gene

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Enhancer
Tissue specific elements
promoters
CAAT box
TATA box
Cap Site transcription start site
ATG initiation codon
TAA, TAG or TGA stop codon

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Ultraviolet (UV) radiation is absorbed by DNA and causes

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covalent links between
adjacent pyrimidines..These “pyrimidine dimers” can be: T^T T^C C^C

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Pyrimidine dimers are non-informational lesions during DNA replication, i.e.,

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they do
not base pair properly.
• Although T^T dimers account for >90% of dimers detected, they do not cause any of
the mutations detected.

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The “A” Rule

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The “A” Rule hypothesizes that during DNA replication, dATP or A residues are
incorporated opposite non-informational lesions.
• This would avoid mutations arising from the most numerous lesions, T^T dimers.
• However, by incorporating dATP or A residues opposite T^C or C^C dimers, one
would generate GC to AT transitions at the C residues of these dimers.
• GC to AT transitions at the C residues of T^C or C^C dimers are the mutations
actually detected after UV mutagenesis.

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Why CpG dinucleotides are mutational hotspots

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It is generally accepted that CpG dinucleotides mutate at a high rate because:
1) cytosine is vulnerable to deamination,
2) cytosines in CpG dinucleotides are often methylated, and
3) deamination of 5-methylcytosine (5mC) produces thymidine.

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Deamination of unmethylated cytosine produces uracil (U), which can be removed

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by
uracil-DNA glycosylase, leading to error-free repair and, therefore, no mutations.

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5mC deamination generates thymine (T), which cannot be processed by this
enzyme. The consequence in humans is that the mutation rate from 5mC to T

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is 10- to 50-
fold higher than other transitions.

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CpG dinucleotides are widely recognized as hotspots for mutations in the germ line,
where they contribute to 30% of all

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point mutations. In addition, CpG dinucleotides in the
coding regions of tumor-suppressor genes are strong hotspots for acquired somatic
mutations leading to cancer.

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The CpG sites in the p53 coding region are methylated in all
human tissues studied and contribute to as many as 50% of all

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inactivating mutations in
colon cancer and to as many as 25% of all inactivating mutations in cancers in general

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outcomes of deamination

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page 7

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5-Methylcytosine hydrolytically
deaminates at a constant rate to form T:G
mismatches (boxed). These mismatches
are presumably repaired by

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the TDG
enzyme. The TDG enzyme recognizes
T:G mismatches in duplex DNA and
cleaves the strand containing the T. The
opposite strand is not cleaved and
subsequent repair is error-free and,
therefore, not mutagenic.

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Mismatches are fixed as C→T
transition mutations if

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the next round
of DNA replication occurs before
repair is complete

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Structure of Hemoglobin

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Two each of two different types of polypeptide chain.
• In normal adult Hb A these are designated α and β.
• The four chains form a globular tetramer abbreviated as α2β2.
• The chains resemble one another markedly both in amino acid sequence and 3-
dimensional configuration

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The genes for the α and α-like chains cluster in tandem arrangement on

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chromosome 16.

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Those for the β and β-like chains are on chromosome

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11

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There are two identical α-globin genes, α1 and α2, which are expressed

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equally

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In the β gene complex, β and γ globins differ in only

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10 of 146 amino acids

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Genetic Disorders of Hemoglobin

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Structural variants
• Thalassemias
• Hereditary persistence of fetal hemoglobin

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Thalassemia

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An imbalance of globin-chain synthesis.
• Most common human single gene disorders.
• Heterogeneous group of diseases of hemoglobin synthesis in which mutation
reduces the level of either the α or β chain

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α-Thalassemia

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The most common forms of α-thalassemia are the result of deletions.
• The arrangement of tandem regions of homology in and around the α genes
facilitates misalignment, homologous pairing, and recombination between the α1
gene domain on one chromosome and the corresponding α2 gene region on the
other.

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Normal α-Thalassemia Genotype

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4
alpha,alpha/alpha,alpha

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Silent Carrier α-Thalassemia Genotype

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3
aa/a-

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alpha-thalassemia trait
(mild anemia, microcytosis)

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2
a-/a-
or aa/- -

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Hb H (B 4) disease
(moderately severe hemolytic
anemia)

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1
a-/- -

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Hydrops fetalis or homozygous
alpha-thalassemia (Hb Bart: y4)

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0
- -/- -