The Nature of Genes

• Early ideas to explain how genes work came

from studying human diseases
• Archibald Garrod – 1902
– Recognized that alkaptonuria is inherited via a
recessive allele
– Proposed that patients with the disease lacked a
particular enzyme
• These ideas connected genes to enzymes

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 Beadle and Tatum – 1941
• Deliberately set out to create mutations in
chromosomes and verify that they
behaved in a Mendelian fashion in crosses
• Studied Neurospora crassa
– Used X-rays to damage DNA
– Looked for nutritional mutations
• Had to have minimal media supplemented to grow

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• Beadle and Tatum looked for fungal cells lacking
specific enzymes
– The enzymes were required for the biochemical
pathway producing the amino acid arginine
– They identified mutants deficient in each enzyme of
the pathway
• One-gene/one-enzyme hypothesis has been
modified to one-gene/one-polypeptide
hypothesis

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 Central Dogma
• First described by Francis Crick
• Information only flows from
DNA → RNA → protein
• Transcription = DNA → RNA
• Translation = RNA → protein
• Retroviruses violate this order using reverse
transcriptase to convert their RNA genome into
DNA

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• Transcription
– DNA-directed synthesis of RNA
– Only template strand of DNA used
– U (uracil) in DNA replaced by T (thymine) in RNA
– mRNA used to direct synthesis of polypeptides
• Translation
– Synthesis of polypeptides
– Takes place at ribosome
– Requires several kinds of RNA

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 RNA
• All synthesized from DNA template by
transcription
• Messenger RNA (mRNA)
• Ribosomal RNA (rRNA)
• Transfer RNA (tRNA)
• Small nuclear RNA (snRNA)
• Signal recognition particle RNA
• Micro-RNA (miRNA)
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 Genetic Code
• Francis Crick and Sydney Brenner
determined how the order of nucleotides in
DNA encoded amino acid order
• Codon – block of 3 DNA nucleotides
corresponding to an amino acid
• Introduced single nulcleotide insertions or
deletions and looked for mutations
– Frameshift mutations
• Indicates importance of reading frame
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• Marshall Nirenberg identified the codons that
specify each amino acid
• Stop codons
– 3 codons (UUA, UGA, UAG) used to terminate
translation
• Start codon
– Codon (AUG) used to signify the start of translation
• Code is degenerate, meaning that some amino
acids are specified by more than one codon

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 Mutation
• Somatic: Ex. Golden Delicious Apple and
Navel Oranges (seedless) – propagated
vegetatively

• Germinal: Mutations (dominant) in germ

line cells expressed in progeny
- Short legged sheep
• Spontaneous or induced mutations
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 Conditional Lethal Mutations
• Lethal in one environment (restrictive) but
viable in a second environment (permissive
condition)
• Auxotrophic mutants: unable to synthesize
an essential metabolite
• Temperature-sensitive mutants: grow at one
temperature but not at another (heat or cold
sensitive)
• Suppressor sensitive mutants: viable when a
second genetic factor (suppressor) is present
- It will correct the defect in phenotype 14
 Mutation: Altered Genes
• Point mutations alter a single base
• Base substitution – substitute one base for
another
– Silent mutation – same amino acid inserted
– Missense mutation – changes amino acid
inserted
• Transitions
• Transversions
– Nonsense mutations – changed to stop codon
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 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Normal HBB Normal Abnormal

Sequence Deoxygenated Deoxygenated
Pola Tetramer Tetramer
r
Le Thr Pr Gl Gl Lys Se Amino
u o u u r acids α1 α2 α1 α2
β β β β
C T G A C T C C T G A G A A G A A G T C T Nucleotide
1 2 1 2
s
Hemoglobin "Sticky" non-
tetramer polar sites
Abormal HBB
Sequence
Nonpolar (hydrophobic)

Le Thr Pr va Gl Lys Se Amino

u o l u r acids
Tetramers form long chains
C T G A C T C C T G T G A A G A A G T C T Nucleotide when deoxygenated. This
s distorts the normal red blood
cell shape into a sickle
shape.

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• Frameshift mutations
– Addition or deletion of a single base
– Much more profound consequences
– Alter reading frame downstream
– Triplet repeat expansion mutation
• Huntington disease
• Repeat unit is expanded in the disease allele
relative to the normal

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 DNA Replication Errors
• Point Mutations
- Transitions & Transversions
• Insertions & Deletions
• Microsatellites – Increase or decrease in repeat
number due to replication slippage
- Huntington’s disease – CAG (6-35 expand to
>37)
Progressive degeneration of nerve cells in brain

- Fragile X syndrome – CGG (6-53 expand to

>230)
Brouwer et al. 2009 Bioessays
Normal replication

Daughter strand
Slippage

SSR no. increase

Slippage

SSR no. decrease

http://www.web-books.com/MoBio/Free/images/Ch7F3.gif
Brouwer et al. 2009 Bioessays